Phase I/II Study of Dendritic Cell Therapy Delivered Intratumorally After Cryoablation and Anti-PD-1 Antibody (Pembrolizumab) for Patients With Non-Hodgkin Lymphoma
Phase: PHASE1
Conditions: Aggressive Non-Hodgkin Lymphoma, Indolent Non-Hodgkin Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Recurrent T-Cell Non-Hodgkin Lymphoma, Small Lymphocytic Lymphoma
Sponsor: Mayo Clinic

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 Phase I/II Study of Dendritic Cell Therapy Delivered Intratumorally after Cryoablation and Anti-
PD-1 Antibody (Pembrolizumab) for Patients with Non-Hodgkin Lymphoma 
 
Study Chair:  
 
 
 
 
 
 
  
 
Study Co-Investigators: 
 
 
 
 
 
 
 
 
 
  
   
 
Statisticians: 
 
 
†Study contributor(s) not responsible for patient care 
 
Drug Availability 
Supplied Investigational Agents:  
Mayo Clinic: Autologous dendritic cells (IND# 14322) 
Merck: Pembrolizumab (Anti-PD-1 antibody, MK-3475) 
Supplied Commercial Agent: Prevnar13 
 
 
Document History 
(Effective Date) 
Activation   
March 27, 2017 
Addendum 1 
September 18, 2017 
Addendum 2 
December 12, 2017 
Addendum 3 
April 17, 2018 
Addendum 4 
October 3, 2018 
Addendum 5 
Addendum 6 
May 22, 2019 
August 6, 2019 
Addendum 7 
Addendum 8 
 
 
November 2, 2020 
Pending  
 
 
 
 
 
 

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Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility, test schedule, treatment 
delays/interruptions/adjustments, dose modifications, adverse 
events,forms completion and submission 
 
 
  
CRA - Clinical 
 
 
Forms completion and submission 
 
 
Protocol document, consent form, regulatory issues 
 
 
  
Serious Adverse Events   
  
    
IMPACT Lab 
 
 
 
  
Cryoablation 
 
 
  
 

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Table of Contents 
Phase I/II Study of Dendritic Cell Therapy Delivered Intratumorally after Cryoablation and Anti-PD-1 
Antibody (Pembrolizumab) for Patients with Non-Hodgkin Lymphoma ..................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema Phase I ............................................................................................................................................. 4 
Schema Phase II ............................................................................................................................................ 5 
1.0 
Background ................................................................................................................................... 6 
2.0 
Goals ........................................................................................................................................... 17 
3.0 
Patient Eligibility ........................................................................................................................ 18 
4.0 
Test Schedule .............................................................................................................................. 21 
5.0 
Grouping Factor: ......................................................................................................................... 32 
6.0 
Registration Procedures .............................................................................................................. 32 
7.0 
Protocol Treatment ...................................................................................................................... 34 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 39 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 44 
10.0 
Adverse Event (AE) Reporting and Monitoring ......................................................................... 50 
11.0 
Treatment Evaluation .................................................................................................................. 63 
12.0 
Descriptive Factors ..................................................................................................................... 70 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 70 
14.0 
Body Fluid Biospecimens ........................................................................................................... 73 
15.0 
Drug Information ........................................................................................................................ 76 
16.0 
Statistical Considerations and Methodology ............................................................................... 83 
17.0 
Pathology Considerations/Tissue Biospecimens: None. ............................................................. 91 
18.0 
Records and Data Collection Procedures .................................................................................... 92 
19.0 
Budget Considerations ................................................................................................................ 93 
20.0 
References ................................................................................................................................... 94 
Appendix I 
ECOG Performance Status ................................................................................................ 100 
Appendix II 
NYHA Classification ........................................................................................................ 101 
Appendix III 
FACT-Lym ................................................................................................................... 102 
Appendix IV 
Patient Information Sheet .............................................................................................. 105 
Appendix V 
DEAUVILLE 5-POINT SCALE ...................................................................................... 106 
Appendix VI 
Ann Arbor Staging System ........................................................................................... 107 
Appendix VII 
FLIPI, IPI, and MIPI Tables and MIPI calculator ........................................................ 108 
 

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Schema Phase I   
(Closed to Accrual July 9, 2018) 
Prior to discussing this protocol with a patient, call the Registration Office (507-284-2753) to ensure 
there is a place on the study for the patient. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. When retreating, new baseline disease measurement will be established. The new baseline disease 
measurement will be the disease measurement at the end of the cycle prior to retreatment (see 
Section 7.4). 
2.  Retreatment can be considered at any time when deemed clinically safe. 
 
See Patient Map for more detail (located with the CRFs) 
Cycle Length = 21 days 
Registration 
Cycle 1: Leukapheresis/ Pembrolizumab 
Cycles 2-5: Dendritic cell plus 
pembrolizumab 
Cycles 6-18:  Pembrolizumab 
Observation 
Event 
Monitoring 
Patients experiencing a DLT during cycles 1 or 
2⟶ OBS  
PD during cycles 1-5 of initial treatment ⟶ 
EM 
PD during pembrolizumab only or treatment 
OBS ⟶ retreatment1,2 
Unacceptable Adverse Events ⟶ OBS 
Patient Refusal for further treatment⟶ OBS 
Patient Refusal ⟶ EM 
 
Note:  Treatment OBS is a term to facilitate data 
entry 

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Schema Phase II 
(Opened to accrual on July 9, 2018) 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. When retreating, new baseline disease measurement will be established. The new baseline 
disease measurement will be the disease measurement at the end of the cycle prior to 
retreatment (see Section 7.4). 
 
2.  Retreatment can be considered at any time when deemed clinically safe. 
 
See Patient Map for more detail (located with the CRFs) 
Cycle length = 21 days 
 
 
 
Generic name: Dendritic cell  
Brand name: Dendritic cell  
Mayo abbreviation: DC 
DCVACN 
Availability: Provided through 
Mayo Clinic 
Generic name: Pneumococcal 
 13-valent Conjugate Vaccine 
(Diphtheria CRM197 Protein) 
Brand name: Prevnar13 
Mayo abbreviation:   
PREVNAR13 
Availability: Provided through 
Mayo Clinic 
Generic name: Pembrolizumab, 
MK-3475 (anti-PD-1 antibody) 
Brand name: Keytruda® 
Mayo abbreviation: MK-3475  
Availability: Mayo Clinic Cancer 
Center Pharmacy 
Registration 
Cycle 1: Leukapheresis/ Pembrolizumab  
Cycles 2-18: Dose administration schedule 
per Phase I 
Observation 
Event 
Monitoring 
PD during cycles 1-5 of initial treatment 
⟶ EM 
PD during pembrolizumab only or 
treatment OBS ⟶ retreatment1,2 
Unacceptable Adverse Events ⟶ OBS 
Patient Refusal for further treatment⟶ 
OBS 
Patient Refusal ⟶ EM 
 Note: Treatment OBS is a term to facilitate 
data entry 

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1.0 
Background 
1.1 
Overview of non-Hodgkin lymphoma 
Non-Hodgkin lymphoma (NHL) is the seventh most common type of cancer in both men 
and women 
 In 2014, there were an estimated 71,000 new cases of 
lymphoma in the US and 19,000 deaths. Lymphoma remains one of the top ten causes of 
cancer deaths in the United States in both sexes. 
The introduction of the anti-CD20 monoclonal antibody rituximab in 1999 has improved 
the survival of the most common NHL in the US – diffuse large B-cell lymphoma 
(DLBCL) (Habermann, Weller et al. 2006). Unfortunately, 40% of patients relapse or do 
not respond to first-line treatment with RCHOP and require further treatment. Some are 
salvaged with high-dose chemotherapy and stem cell support but many die of disease. 
There is an unmet need for novel therapies for patients with any type of NHL that relapse 
after induction therapy (Ansell and Armitage 2005). 
Low grade NHL accounts for approximately one third of all cases of NHL. Follicular 
lymphoma (FL) is the second most common NHL. First line treatment option at the time 
of initial diagnosis can range among watchful waiting, localized radiation, immune-
therapy and systemic chemoimmunotherapy depending on disease burden and patient 
symptoms. While this disease can be very responsive to chemoimmunotherapy initially, 
for example with 90% overall response to bendamustine and rituximab or RCHOP 
(Rummel, Niederle et al. 2013), it can become progressively refractory to treatments with 
subsequent relapses. There is no consensus regarding the choice of salvage, second and 
subsequent chemotherapies in treatment of these lymphomas. Ultimately it remains an 
incurable disease. As such, quality of life is an equally important consideration in 
selecting effective treatment while minimizing toxicity, making immunotherapy a 
potentially attractive candidate to delay chemotherapy. 
1.2 
Rationale for targeting immune suppression in NHL  
Systemic host immune suppression is often seen in cancer patients and is thought to 
contribute to patient morbidity via a tumor-mediated immune evasion mechanism. 
Although many investigators have examined tumor cell genetics we have also focused on 
the role of the host immune system. Indeed, polymorphisms in host germ line immune 
genes have been correlated with survival in NHL patients (Habermann, Wang et al. 
2008). The Mayo group has also demonstrated that patients who are immune-
compromised, as measured by low absolute lymphocyte count (ALC) or high absolute 
monocyte count (AMC) have a poorer treatment response compared to those with normal 
ALC or AMC (Siddiqui, Ristow et al. 2006, Behl, Ristow et al. 2007, Porrata, Ristow et 
al. 2007, Wilcox, Ristow et al. 2011, Wilcox, Ristow et al. 2012). Immunologic 
reconstitution such as the rate of lymphocyte reconstitution (Kim, Sohn et al. 2004, 
Porrata and Markovic 2004) and presence of lymphocytes, natural killer cells and 
dendritic cells (DC) in transplanted grafts (Porrata, Gastineau et al. 2003, Gazitt, Akay et 
al. 2006, Porrata, Inwards et al. 2015) have also been associated with improved outcome 
in NHL patients who have received autologous stem cell transplants. These studies 
underline the importance of the patient’s immune competence in determining outcome 
and provide rationale for immune-augmentation in therapy. 
 
 

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1.3 
Rationale for PD-1 blockade therapy 
1.31 
Overview of PD-1 pathway 
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 
excessive immune responses, including autoimmune reactions. PD-1 (encoded by 
the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 that 
has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (Zhang, Schwartz et al. 2004, 
Francisco, Sage et al. 2010). PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the 
CD3 T-cell signaling cascade (Galon, Costes et al. 2006, Talmadge, Donkor et al. 
2007). The mechanism by which PD-1 down modulates T-cell responses is 
similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins. PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B- cells, T 
regs and Natural Killer cells (Kloor 2009), as well as subsets of macrophages and 
dendritic cells (Hillen, Baeten et al. 2008). 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 (Hiraoka 2010). 
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 (Hiraoka 2010). Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell 
inhibitor. 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. 
1.32  
PD-1 is a marker of exhaustion in NHL T cells 
We have shown that PD-1 expression is detected in FL T cells and its diffuse 
pattern of staining is associated with worse survival (Smeltzer, Jones et al. 2014). 
PD-1 expression in FL T cells is increased when FL transformed into DLBCL. In 
FL T cells, dim PD-1 surface expression represents an exhausted T cell 
phenotype and is associated with worse progression free survival (Yang, Grote et 
al. 2015). PD-1 expression is also detected in T cells from almost all types of 
NHL (Xerri, Chetaille et al. 2008, Muenst, Hoeller et al. 2010) and is likely a 

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marker of exhaustion in other types of NHL. 
1.33 
Expression of PD-1 ligands in lymph node and bone marrow in NHL 
In addition to the evidence of PD-1 expression in NHL, expressions of PD-1 
ligands are detected in lymphoma tumors. PD-L1 expression is increased in 
tumor B cells in FL lymph nodes compared to its counterpart in reactive nodes 
(Andorsky, Yamada et al. 2011, Myklebust, Irish et al. 2013). Additionally, 
soluble PD-L1 levels in the peripheral blood in diffuse large B cell lymphoma is 
associated with decreased overall survival (Rossille, Gressier et al. 2014). 
1.34 
PD-L1 signaling and dendritic cell priming of T cell 
The exact mechanism of action and cells targeted by PD-1 blockade is unknown. 
Intriguingly while PD-L1 expression is seen in both Hodgkin lymphoma (HL) 
and NHL, the overall response rate is vastly different between the two diseases, 
87% and 28% respectively (Ansell, Lesokhin et al. 2015); (Lesokhin, Ansell et 
al. ASH Annual Meeting, Blood Abstract #291). In addition to the role of PD-
1/PD-L1 signaling in T cell exhaustion, we have also found that activated DC can 
have increased PD-L1 expression, which interferes with CD8 T cell priming and 
limits differentiation of effector T cell response (Pulko, Liu et al. 2009, Gibbons, 
Liu et al. 2014). Blockade of PD-1/PD-L1 signaling enhanced CD8 T cell 
response and cleared tumors in an animal model (Pulko, Liu et al. 2009, Gibbons, 
Liu et al. 2014). We have found that monocytes and dendritic cells response are 
significantly inhibited in NHL (Wilcox, Wada et al. 2009, Lin, Gustafson et al. 
2011). We hypothesize that PD-1 blockade could increase the anti-tumor efficacy 
of dendritic cell vaccines by enhancing T cell priming.  
1.35 
Preliminary clinical activity of PD-1 blockade in NHL 
PD-1 blockade as a single agent in relapsed/refractory NHL is approximately 
28% (Lesokhin, Ansell et al. ASH Annual Meeting, Blood Abstract #291). In 
relapsed DLBCL, PD-1 blockade after autologous stem cell transplant achieved 
~50% overall response rate in patients who had residual disease after transplant 
(Armand, Nagler et al. 2013). In relapsed FL, 66% ORR and 50% CR were 
observed with the combination therapy of rituximab and anti-PD-1 antibody 
(Westin, Chu et al. 2014). In this study, we will examine the tolerability and 
efficacy of PD-1 blockade with dendritic cell vaccine in NHL. 
1.36 
Clinical Trial Data 
Pembrolizumab (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. 
As of 18-Oct-2013, 1,000 patients have been treated with Pembrolizumab at 
several dose schedules, including 10 mg/kg every 2 weeks. MK-3475 has been 
generally well tolerated, as expected based on preclinical findings and other anti-
PD-1 monoclonal antibodies. As of 18-Oct-2013 no serious infusions reactions 
have been reported in the first human clinical trial (PN001). Less than 1% of 
patients thus far assayed had confirmed positive anti-drug antibody (ADA) 
samples and among these, no or no clear impact on exposure has been observed. 
There is no contraindication to further clinical investigation with Pembrolizumab. 
Pharmacokinetics were as expected, based on Pembrolizumab being an IgG mAb 

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and based on preclinical data, which support dosing once every 2 or 3 weeks. 
Pembrolizumab monotherapy induces an ORR of 25%/27% in patients with 
ipilimumab exposed melanoma by central independent RECIST and oncology 
review/investigator assessed irRC, respectively. Pembrolizumab monotherapy 
induces an ORR of 39%/43% in patients with ipilimumab-naive melanoma by 
central independent RECIST and oncology review/investigator assessed irRC, 
respectively. These responses are remarkably durable. 
The preliminary 1-year survival rate for patients, many of whom have had 
multiple therapies, including ipilimumab, who receive Pembrolizumab is 81%. 
Pembrolizumab monotherapy induces an ORR of 21%/24% in patients with 
previously- treated NSCLC by central independent RECIST/investigator assessed 
irRC, respectively, with these responses also remarkably durable. Preliminary 
data suggest higher levels of PD-L1 expression in tumors of NSCLC are 
associated with increased activity (ORR 67% by investigator assessed irRC/57% 
by central independent RECIST); additional data are required to define the 
optimal PD-L1 cut point. The most commonly reported treatment emergent AEs 
experienced are fatigue (43.8%), nausea (26.7%), cough (25.3%), pruritus 
(24.6%), diarrhoea (22.3%) and rash (21.5%). Immune-related adverse events 
were reported in 21.4% of melanoma patients; most of these events (15.8%) were 
considered drug-related by the investigator. The most commonly reported, 
immune-related adverse events across the dose-schedules are rash (3.2%), 
pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), 
diarrhea (2.2%), and pneumonitis (1.9%). Review of the overall benefit:risk ratio 
of Pembrolizumab favors enrollment of eligible patients into clinical trials of 
MK-3475. The preliminary data suggest that a dose of Pembrolizumab at 2 
mg/kg Q3W is appropriate for patients with melanoma. 
1.37 
Rationale for Dose Selection/Regimen/Modification 
The dose regimen of 200 mg Q3W of Pembrolizumab is planned for all urothelial 
cancer trials. Available PK results in subjects with melanoma, NSCLC, and other 
solid tumor types support a lack of meaningful difference in PK exposures 
obtained at a given dose among tumor types. An open-label Phase 1 trial (PN001) 
in melanoma subjects is being conducted to evaluate the safety and clinical 
activity of single agent Pembrolizumab. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels 
were well tolerated and no dose-limiting toxicities were observed. This first in 
human study of Pembrolizumab showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W). No maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects 
receiving Pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been 
completed. The clinical efficacy and safety data demonstrate a lack of clinically 
important differences in efficacy response or safety profile at these doses. For 
example, in Cohort B2, advanced melanoma subjects who had received prior 
ipilimumab therapy were randomized to receive Pembrolizumab at 2 mg/kg 
versus 10 mg/kg Q3W. The overall response rate (ORR) was 26% (21/81) in the 
2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)). 
The proportion of subjects with drug-related adverse events (AEs), grade 3-5 
drug- related AEs, serious drug-related AEs, death or discontinuation due to an 

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AE was comparable between groups or lower in the 10 mg/kg group. 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other 
solid tumor types support a lack of meaningful difference in pharmacokinetic 
exposures obtained at a given dose among tumor types. Population PK analysis 
has been performed and has confirmed the expectation that intrinsic factors do 
not affect exposure to pembrolizumab to a clinically meaningful extent. Taken 
together, these data support the use of lower doses (with similar exposure to 2 
mg/kg Q3W) in all solid tumor indications. 2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated 
in head and neck cancer in PN012, which are expected to provide additional data 
supporting the dose selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based 
on simulation results indicating that 200 mg will provide exposures that are 
reasonably consistent with those obtained with 2 mg/kg dose and importantly 
will maintain individual patient exposures within the exposure range established 
in melanoma as associated with maximal clinical response. A population PK 
model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed using available data from 476 
subjects from PN001. The distribution of exposures from the 200 mg fixed dose 
are predicted to considerably overlap those obtained with the 2 mg/kg dose, with 
some tendency for individual values to range slightly higher with the 200 mg 
fixed dose. The slight increase in PK variability predicted for the fixed dose 
relative to weight-based dosing is not expected to be clinically important given 
that the range of individual exposures is well contained within the range of 
exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar 
efficacy and safety. The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was 
similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different tumor types and indication 
settings. 
1.4 
Rationale for autologous dendritic cell vaccine therapy 
1.41  
Evidence for dendritic cell vaccine in cancer 
Dendritic cells are the professional antigen-presenting cells that induce and 
regulate both adaptive and innate immune responses (Steinman 1991, 
Boczkowski, Nair et al. 1996, Steinman 2003). DC have been used in the past by 
exposing these cells to some form of tumor antigen in vitro, and then returning 
antigen loaded DC to the patient to stimulate anti-tumor immunity. Clinical trials 
of DC immunotherapy have suggested this approach can result in significant 
stimulation of the immune response against many different forms of cancer. 
The presence of DC within the graft and an associated graft-versus-lymphoma 
response in transplant patients has suggested a role for dendritic cell-based 
vaccines in treating NHL (Hsu, Benike et al. 1996, Dean, Masci et al. 2005, 
Inoges, Rodriguez-Calvillo et al. 2006, Di Nicola, Zappasodi et al. 2009). DC 
immunotherapy consists of exposing dendritic cells to tumor antigen and using 
the antigen-loaded DC as a vaccine to stimulate anti-tumor response.  
1.42 
DC generation for vaccine therapy 
Results of this immunotherapy method against many different forms of cancer 

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have been encouraging in animal models but have had mixed results in clinical 
trials (Rosenberg, Yang et al. 2004). These trials have been difficult to interpret 
as the methods of DC preparation and the resulting quality of DC used in the 
trials have varied significantly. Available evidence suggests that the quality of 
the DC preparation used in a vaccination protocol has a substantial impact on the 
immune response elicited (Finkelman, Lees et al. 1996, Steinman 2003, 
Steinman, Hawiger et al. 2003, Yamazaki, Iyoda et al. 2003). Specifically, the 
functional status of DCs depends on their state of activation at the time they are 
delivered. Completely activated DC (mature DC or mDC) are able to migrate to 
lymph nodes and initiate stimulation of the immune system in vivo, while 
immature DC can inhibit effector T cell function and induce tolerance 
(Dhodapkar, Steinman et al. 2001). Unfortunately, many clinical trials were 
initiated before this distinction came to light and patients received immature DC; 
inhibiting the immune response instead of stimulating it. Thus, the lack of potent 
immune stimulation and unsatisfactory clinical response demonstrated in earlier 
trials of DC immunotherapy may at least in part be attributable to the functional 
state of the DC employed. 
Many published trials in NHL have utilized immature, potentially tolerizing DC 
(see Table 1). This is likely because lymphoma patients have a largely 
unrecognized yet profound deficiency in the ability to generate mature DC using 
conventional DC generation protocols (Lin, Gustafson et al. 2011, Laborde, Lin 
et al. 2014). We have developed a method that consistently generated highly 
pure, mature DC from NHL patients ex vivo. This culture method is serum-free 
and easily adaptable to scale-up GMP practice. This significant improvement in 
DC vaccines assures the potency and purity of the DC preparation. Thus, we by-
pass the immune suppressive qualities we have identified in lymphoma patients 
by isolating the monocytes, culturing them to generate potent immune 
stimulatory DC, and injecting these cells back into the patient. This DC 
manufacturing method was used in LS1081 clinical trial to treat patients with 
newly diagnosed or relapsed/refractory indolent B-cell NHL (Table 1). We were 
able to make adequate vaccines to complete treatments for all 15 patients in the 
study. 
1.43 
In situ DC tumor antigen loading for vaccine therapy 
Differences in loading of DC with antigen in vitro may induce immune tolerance 
rather than stimulation (Steinman 2003, Yamazaki, Iyoda et al. 2003, Marigo, 
Dolcetti et al. 2008). The optimal method for preparation of antigen and antigen 
loading to DC remains to be identified. Animal studies and small clinical trials 
have used whole lymphoma cells, exosomes from heat-shocked lymphoma cells, 
idiotype proteins, and proteoliposomes from tumor cells as antigens (Hsu, Benike 
et al. 1996, Timmerman, Czerwinski et al. 2002, Chen, Wang et al. 2006, Inoges, 
Rodriguez-Calvillo et al. 2006, Neelapu, Gause et al. 2007, Di Nicola, Zappasodi 
et al. 2009). While idiotype containing unique determinants of variable regions of 
the clonal tumor immunoglobulin molecule offer specific, definitive targets for 
immune monitoring of treatment, immune stimulation against tumor may also be 
limited. The production of idiotype protein with recombinant DNA is also labor 
and time intensive and likely not practical for widespread clinical use. Whole 
tumor cells or liposome preparations from the tumor cells are easier to generate 
and contain a wider range of epitopes, but are limited by the quantity of the 
primary tumor. 

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Route of DC delivery also critically impacts efficacy of DC to stimulate an anti-
tumor response. Inconsistent generation of systemic anti-tumor immune 
responses with intravenous and subcutaneous administration has prompted 
evaluation of novel delivery approach (Mody, Dubey et al. 2015). Intratumor DC 
delivery was shown to generate anti-tumor immunity and tumor regression in 
animal models (Kim, Sohn et al. 2004, Song and Levy 2005, Lee, Cho et al. 
2006). Clinical trials to date have shown this approach to be safe with promising 
response (Table 1; LS1081 preliminary results)(Kolstad, Kumari et al. 2015). 
Antigen can be generated in vivo using conventional therapies including 
chemical, radiation or even cryoablation (Sabel, Arora et al. 2006, Fagnoni, 
Zerbini et al. 2008, Sabel 2009, Kolstad, Kumari et al. 2015). Recently Kolstad et 
al reported promising results in FL patients treated with radiation, and intra-
tumor injection of rituximab and DC ((Kolstad, Kumari et al. 2015); Table 1). 
Cryoablation is an acceptable clinical option for the targeted destruction of 
lymphoma masses. It provides an opportunity for generation of tumor antigen in 
vivo, but currently relies on local ability to generate an active immune response. 
In arm A of our phase I clinical trial LS1081, we used cryoablation as a novel 
approach to in situ lymphoma tumor antigen loading. Patients underwent 
cryoablation of a lymphoma tumor and subsequently received up to eight doses 
of intra-tumor injections of autologous DC over the course of 6 months. Direct 
injection in vivo offers two advantages: delivery of mature DCs into a milieu of 
dying tumor cells, resulting in maximum exposure of tumor cell antigens; and 
avoidance of the suppressive effects of blood monocytes. Systemic response in 
non-cryoablated tumors was assessed. This combined approach was found to be 
feasible and safe. We will now examine combining this approach with 
pembrolizumab to enhance clinical efficacy. 
1.44 
Safety considerations from DC therapy 
DC vaccine therapy clinical trials in B-cell NHL have thus far demonstrated no 
significant adverse events or autoimmunity (Table 1). DC immunotherapy has 
been used for many different tumors types where adverse events (such as induced 
autoimmunity) were monitored. Importantly, very few significant adverse effects 
of DC vaccination have been reported and DC immunotherapy clinical trials 
performed to date have shown no evidence of resultant generation of auto-
immunity. To date, 86 patients have been treated with DC therapy without any 
serious drug related toxicity reported. In our trial LS1081, 15 patients were 
treated without any autoimmunity or grade 3 or higher adverse events attributable 
to treatments. The most common adverse event was injection site pain, more 
often with cryoablation, that usually resolved within 2 days of treatments 
(Table 2). 
 
 

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Table 1. Summary of clinical trials using dendritic cell vaccines for NHL 
Histopath 
Diagnosis 
Phase (N) 
Ag source 
DC source 
Delivery 
Safety 
Clinical 
outcome 
Follicular (Hsu, 
Benike et al. 1996) 
I (4) 
Idiotype 
Blood * 
IV 
No Grade 3-4 
AEs; no AI 
1 CR, 1 PR, 
1 molecular 
CR 
Follicular 
(Timmerman, 
Czerwinski et al. 
2002) 
I (10) 
II (25) 
Idiotype 
Blood * 
IV 
No Grade 3-4  
AEs; no AI 
I: 3 CR,  
1 PR, 6 PD 
II: 16 CR, 
7 PR, 2 PD 
Follicular, lympho- 
plasmacytoid (Di 
Nicola, Zappasodi 
et al. 2009) 
I (18) 
Heat-shocked 
autologous 
tumor cells 
Matured from 
monocytes 
SC 
No Grade 3-4  
AEs; no AI 
3 CR, 3 PR, 
8 SD,4 PD 
Follicular 
(Kolstad, 2015) 
I (14) 
in situ loading 
via intra-
tumor 
injection 
Immature DC 
from 
monocytes 
Intra-tumor 
No Grade 3-4 
AEs; No AI 
2 CR, 3 PR 
Indolent B-cell 
NHL 
(LS1081 
preliminary results) 
I (Arm A: 
10; Arm 
B: 5) 
Arm A: in situ 
via intra-
tumor 
injections 
Arm B: tumor 
lysate 
Matured from 
monocytes 
Arm A: 
intra-tumor 
Arm B: 
intradermal 
No Grade 3-4 
AEs; no AI 
Arm A: 
5 PR 
Arm B: 
1 CR, 2 PR 
Blood-derived DC used gradient centrifugation and adhesion method. DCs were characterized by 
negative phenotype markers without description of maturation markers normally used in release criteria. 
(AI = autoimmunity. CR = complete remission. IV = intravenous. PD = progressive disease. PR = partial 
remission. SC = subcutaneous. SD = stable disease.) 
Table 2. Summary of adverse events attributable to treatments in LS1081 study 
Adverse Event 
Grade 
1 
2 
3 
4 
N 
% 
N 
% 
N 
% 
N 
% 
Type 
Arm 
 
 
 
 
 
 
 
 
Urticaria 
A 
2 
25.0 
1 
12.5 
 
 
 
 
Bronchospasm 
A 
 
 
1 
12.5 
 
 
 
 
Injection site reaction 
A 
 
 
1 
12.5 
 
 
 
 
Lymph node pain 
A 
 
 
1 
12.5 
 
 
 
 
Rash maculo-papular 
A 
 
 
1 
12.5 
 
 
 
 
Vasovagal reaction 
A 
 
 
 
 
1 
12.5 
 
 
 
Grade 3 vasovagal reaction was due to line placement for leukopheresis prior to active vaccine 

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treatment. Reaction resolved with IV fluids and reverse Trendelenburg maneuver. 
1.5 
Rationale for pneumococcal conjugate vaccine (PCV) therapy 
We have found that, compared to healthy donors, NHL patients have significantly 
decreased number of lymphocytes, particularly CD4+ cells (Lin, Gustafson et al. 2011). 
This combined with the in vitro suppressed immune function argue for T cell stimulation 
to augment immune response with DC vaccine. PCV (Prevnar®) is approved by the US 
Food and Drug Administration for vaccination against pneumococcal infections in 
children and works by activating helper T cells to interact with B cells for antibody 
production (Pletz, Maus et al. 2008). Pneumococcal vaccination has been shown to be 
safe and recommended for cancer patients that will or have undergone chemotherapy 
(Melcher 2005). Thus, the use of pneumococcal vaccines presents little if any additional 
risk to the patient. The use of these vaccines does allow determination of the state of the 
immune system and its response to the DC based vaccines. Prevnar has been used in two 
clinical trials for multiple myeloma patients in this manner. These trials included one 
with adoptive T cell transfer after stem cell transplant (Rapoport, Stadtmauer et al. 2005) 
and another with lenalidomide (Noonan et al. ASH Annual Meeting 2008, Blood abstract 
2772). Both trials reported minimal toxicity. In addition there may be a bystander effect 
on immunity with enhanced lymphocyte trafficking and the response to one antigen 
leading to enhanced response to anti-tumor antigens (Mitchell, Batich et al. 2015). 
Preliminary study in our lab showed that Prevnar enhanced mature DC stimulated CD4 T 
cell proliferation by approximately 1.75 fold compared to mature DC stimulation alone 
(Figure 1). Importantly, a review of the results of DC therapy in melanoma suggest that 
addition of adjuvant capable of T cell help, significantly improved overall clinical 
response (Engell-Noerregaard, Hansen et al. 2009, Mitchell, Batich et al. 2015). We are 
including this vaccine to enable us to monitor the immune response prior to and after our 
intervention. The vaccine will also allow us to quantify any potential in vivo bystander 
effect due to the combination of DC and pneumococcal vaccine. In the LS1081 study, no 
adverse events were seen with Prevnar administrations. 
 
 
Figure 1. CD4+ T cell proliferation is stimulated with mature dendritic cells pulsed 
with Prevnar. Monocyte-depleted PBMNC from healthy donors were labeled with 
CFSE and cultured for 7 days without stimulation or with Prevnar, autologous mature 
dendritic cells (mDC), or autologous mDC pulsed with Prevnar. At the end of culture, 
cells were stained with 7-AAD, anti-CD3 and anti-CD4 and analyzed by flow cytometry. 
Percent of live, CD4 T cells that proliferated are shown here for 3 donors. CD4 T cell 
proliferation was the greatest in co-culture with Prevnar-pulsed mDC. 
 
1.51 
Safety considerations for the use of 13-valent pneumococcal conjugate vaccine 
(PCV) therapy 
PCV (Prevnar®) is approved by the US Food and Drug Administration for 
vaccination against pneumococcal infections in children and works by activating 
helper T cells to interact with B cells for antibody production (Pletz, Maus et al. 

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2008). Pneumococcal vaccination is considered safe for cancer patients 
undergoing chemotherapy with mild side effects including soreness, low-grade 
fever and induration at the site of vaccination lasting 1-3 days (Melcher 2005). It 
has been used in two clinical trials for multiple myeloma patients, one with 
adoptive T cell transfer after stem cell transplant (Rapoport, Stadtmauer et al. 
2005) and another with lenalidomide (Noonan et al. ASH Annual Meeting 2008, 
Blood Abstract #2772). Both trials reported minimal toxicity and some evidence 
of improved immune response. As in Rapoport et al, we will use this 
pneumococcal vaccine to evaluate and monitor the developing immune response. 
The proposed Prevnar13 (Prevnar) dosing schedule in this study is similar to the 
Prevnar schedule in LS1081 study. No significant toxicities were observed in 15 
patients who received Prevnar along with their DC vaccines. We will use the 
dose administration and timing as approved for use (Prevnar product insert; 
 
 
1.6 
Cryoablation therapy 
1.61   Cryoablation background 
Percutaneous cryoablation systems are currently available from two 
manufacturers including Endocare, Incorporated (Irvine, CA) and Galil Medical 
(St. Paul, MN), each are FDA 510K cleared for treatment of soft-tissue tumors. 
Since 2003, investigators in this study have used cryoablation for the treatment of 
renal, lung, soft tissue, and bone tumors, including treatment of patients enrolled 
in the LS1081 study. Probes may be placed either percutaneously or 
intraoperatively using US or CT image guidance. 
The mechanism of cryoablation is based on delivery of argon gas through a 
segmentally insulated probe with outer diameter ranging from 1.7 – 2.4 mm, with 
expansion of the gas within the probe lumen, resulting in rapid cooling (via Joule 
Thompson effect). With expansion of the argon gas within the probe, rapid and 
extreme temperature drops are produced along the distal, uninsulated probe shaft 
reaching –100 ºC within a few seconds. Adjacent tissues are quickly frozen, 
resulting in the formation of an iceball. Thawing of the iceball is achieved with 
active instillation of helium gas into the cryoprobes instead of argon gas.  
Cell death is due to two primary causes. First, rapid freezing immediately 
adjacent to the probe results in intracellular ice formation, organelle disruption, 
and subsequent cell destruction. At a further distance from the probe, relative 
gradual cooling causes osmotic differences across the cell membrane with 
secondary cellular dehydration and death. Subsequently, further cell death occurs 
due to thrombosis of affected blood vessels and resultant ischemic necrosis. 
The size of the iceball varies depending on the length of uninsulated tip, with 
commonly used cryoprobes generating an iceball of about 3 cm in diameter and 5 
cm in longitudinal length along the probe shaft. The growth and size of the 
iceball can be controlled by the delivery system through the relative amount of 
argon passed through the cryoprobe. Given relative cellular tolerance to freezing 
temperatures, cell death occurs within about 3-5 mm internal to the iceball 
margin (Campbell, Krishnamurthi et al. 1998; Chosy, Nakada et al. 1998). A 
target lesion is typically treated with curative intent using two freezing cycles of 
approximately 10 minutes each, separated by a 5-minute thaw period (Figure 2). 

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Figure 2. Example of lymphoma tumor cryoablation. Low grade follicular lymphoma 
lesion involving the left kidney (left panel yellow circle) can be seen before and during 
the course of cryoablation (middle panel). The probe used for cryoablation is indicated by 
the white arrow and the growing ice ball identified by the red arrows. The size and 
predictability of the growth of the ice ball is independent of the tumor source. Right panel 
shows resolution of the lesion after treatment. 
1.62 
Safety considerations for cryoablation 
Outside of the liver, complications due to cryoablation are primarily related to 
inadvertent tissue injury at the ablation site. A large experience exists regarding 
percutaneous cryoablation of renal tumors, showing a major complication rate of 
5-8% (Silverman, Tuncali et al. 2005, Littrup, Ahmed et al. 2007, Atwell, Farrell 
et al. 2008, Atwell, Carter et al. 2012). Similar to RFA, the majority of 
complications are related to local tissue trauma, including hemorrhage in about 
3% of patients. Allowing for a more limited published experience, complications 
following bone and soft tissue ablation are even more infrequent, ranging from 0-
2% (Beland, Dupuy et al. 2005, Ullrick, Hebert et al. 2008, Callstrom, Dupuy et 
al. 2013). Unique to cryoablation, compared to RFA, is the ability to visualize the 
cytotoxic ice develop using CT imaging, allow the user to precisely control the 
volume of tissue treated and minimize adjacent tissue injury (Figure 2). 
Of particular note, a systemic phenomenon called “cryoshock” has been observed 
primarily in the cryoablation of liver tumors. Cryoshock is clinically manifested 
by severe coagulopathy, disseminated intravascular coagulation, and multiorgan 
failure, possibly related to a systemic inflammatory response syndrome. This 
syndrome has been seen in about 1% of cases of hepatic cryotherapy and only 
0.04% of prostate cryoablations (Seifert and Morris 1999). We have used clinical 
cryoablation alone to treat a limited number of patients with lymphomatous 
tumor masses with no serious safety issues identified. In the LS1081 study, no 
cryoshock or ≥Grade 3 adverse events were observed with cryoablation 
treatments (Table 1). 
1.7 
This Study and Research Hypothesis 
This study is a phase I/II design where the phase I portion will confirm the starting dose 
and regimen of the phase II portion (which is expected to be dose level 1) and the phase 
II portion will receive the same regimen as determined by the phase I portion.  The 
patient population in the phase II portion is patients with Non-Hodgkin lymphoma.  
Given the evidence of PD-1 and its ligands expression in neoplastic lymphoma cells, the 

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tumor microenvironment, and systemically, we hypothesize that PD-1 blockade 
combined with DC vaccine will enhance DC priming of T cells with anti-tumor antigen 
and activate T cell functions. The combined immunotherapy with pembrolizumab, 
cryoablation followed by intra-tumor injection of DC vaccines will generate anti-tumor 
immunity and clinical regression of lymphoma. 
2.0 
Goals 
2.1 
Phase I  
2.11 
Primary 
Evaluate the optimal dose schedule, safety and tolerability as measured by the 
incidence of significant toxicity of combination therapy with anti-PD-1 
monoclonal antibody, cryoablation, and intra-tumor injection of autologous 
dendritic cell into the cryoablated tumor. 
2.12 
Secondary 
2.121  Evaluate the feasibility of this combination immunotherapy. 
2.122  Evaluate patient quality of life 
 
2.2 
Phase II 
2.21 
Primary 
Test the efficacy (overall response rate) of combination therapy with anti-PD-1 
monoclonal antibody, cryoablation, and intra-tumor injection of autologous 
dendritic cell vaccine. 
2.22 
Secondary 
2.221  Evaluate the PR and CR rate of this combination immunotherapy. 
2.222  Evaluate the progression free survival, treatment free survival, duration 
of response, disease-free rate at 2 years, and overall survival of this 
combination immunotherapy. 
2.223  Evaluate the safety of this combination immunotherapy. 
2.23 
Correlative Studies 
2.231  Assess the effect of combination immunotherapy on patients’ immune 
status and anti-tumor immune response. 
2.232  Assess the potential association between PD-1/PD-L1/PD-L2 expression 
in tumor and blood with clinical efficacy. 
2.233  Assess the potential association between tumor antigen mutations and 
antigen-specific immune response with clinical efficacy. 
2.234 Evaluate patient quality of life.  
 
 

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3.0 
Patient Eligibility 
3.1 
Inclusion Criteria 
3.11 
Age ≥18 years. 
3.12 
Histological confirmation of biopsy-proven non-Hodgkin lymphoma, excluding 
chronic lymphocytic leukemia, primary CNS lymphoma and Burkitt’s 
lymphoma. 
Note: Small lymphocytic lymphoma (SLL) is allowed.  
3.13 
Patients with indolent NHL must have had ≥1 regimen of rituximab-containing 
regimen. 
Note: This includes FL, marginal lymphoma and MALT.  
3.14 
Patients with aggressive NHL must have had ≥2 regimens. 
Note: This includes DLBCL, MCL, PMBCL, and T cell lymphoma. 
Patients with aggressive NHL must have received prior therapy – at a minimum: 
• 
Anti-CD20 monoclonal antibody unless tumor is CD20 negative and 
• 
An anthracycline containing regimen. 
• 
Transformed FL must have had therapy for FL and be refractory to 
chemotherapy for DLBCL. 
Chemotherapy refractory disease in aggressive NHL is defined as 
• 
Stable disease of ≤12 months or progressive disease as best response to most 
recent chemotherapy containing regimen. 
• 
Disease progression or recurrence ≤12 months of prior autologous SCT. 
Patients with aggressive NHL must have failed autologous HSCT, or are 
ineligible or not consenting to autologous HSCT. 
3.15 
Patient must have at least 3 measurable lesions that are ≥1.5 cm in one 
dimension. One of the lesions must be ≥2.0 cm and is amenable to image-guided 
cryoablation and multiple vaccine injections as determined by Interventional 
Radiology and PI (including tumors that can be safely accessed using imaging 
guidance and treated with minimal risk to adjacent structures). 
3.16 
ECOG Performance Status (PS) 0 or 1(Appendix I). 
3.17 
The following laboratory values obtained ≤14 days prior to registration. 
● 
Absolute neutrophil count (ANC) ≥1000/mm3 
● 
Absolute lymphocyte count ≥200/mm3 
● 
Platelet count ≥50,000/mm3 
● 
Hemoglobin ≥8.0 g/dL 
● 
Total bilirubin ≤1.5 x upper limit of normal (ULN), unless due to Gilbert’s 
disease.   
● 
Aspartate transaminase (AST/SGOT) and alanine transaminase  
(ALT/SGPT) ≤2.5 x ULN 
● 
Creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min for 
subject with creatinine˃1.5 x institutional ULN 
3.18 
Negative serum pregnancy test for women of childbearing potential ≤7 days prior 
to registration. 
Note: A second pregnancy test may be required ≤72 hours prior to receiving the 
first dose of study medication. 

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3.19a 
Negative human immunodeficiency virus (HIV), hepatitis B and C, and 
tuberculosis (TB) test. 
3.19b Provide written informed consent. 
3.19c 
Willing to return to the enrolling institution for follow-up (during active 
treatment and active monitoring phase of the study). 
3.19d Ability to complete questionnaire(s) by themselves or with assistance. 
3.19e 
Willing to provide tissue and blood samples for research purposes (see Sections 
6.0, 14.0 and 17.0). 
3.19f 
Willing to use adequate contraception as defined in Section 9.0 while on the 
study and until 120 days after the last dose of study drug. 
3.2 
Exclusion Criteria 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
● 
Pregnant women 
● 
Nursing women 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 3.23 
Serious non-malignant disease such as active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations or other conditions which in the opinion of the 
investigator would compromise protocol objectives. 
3.24 
Currently receiving or have received any other investigational agent considered 
as a treatment for the primary neoplasm ≤28 days or within 4 half-lives 
(whichever is shorter) of the agent prior to registration.  
3.25 
History of other primary malignancy requiring systemic treatment within 6 
months of protocol enrollment.  
Patients must not be receiving chemotherapy or immunotherapy for another 
cancer. Patients must not have another active malignancy requiring active 
treatment with the following acceptable EXCEPTIONS: 
• 
Basal cell carcinoma, squamous cell carcinoma, or melanoma of the skin that 
has undergone or will undergo potentially curative therapy 
• 
In situ cervical cancer that has undergone or will undergo potentially curative 
therapy 
3.26 
Prior allogeneic bone marrow or peripheral blood stem cell transplantation. 
3.27 
Prior autologous bone marrow or peripheral blood stem cell transplantation ≤100 
days prior to registration or if recovery from the transplant is inadequate. 
3.28 
Major surgery other than diagnostic surgery ≤4 weeks prior to registration. 
3.29a 
Prior chemotherapy or radiation therapy ≤2 weeks prior to registration or who 
has not recovered (i.e. to ≤Grade 1 or baseline) from an adverse event due to the 
previously administered therapy. 

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3.29b History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine 
or any component of the formulation, including diphtheria toxoid. 
3.29c 
Active autoimmune disease such as Crohn’s disease, rheumatoid arthritis, 
Sjögrens’ disease, systemic lupus erythematosis, or similar conditions requiring 
systemic treatment within the past 3 months or a documented history of clinically 
severe autoimmune disease/syndrome difficult to control in the past. 
EXCEPTIONS: 
• 
Vitiligo or resolved childhood asthma/atopy 
• 
Intermittent use of bronchodilators or local steroid injections  
• 
Hypothyroidism stable on hormone replacement,  
• 
Diabetes stable with current management 
• 
History of positive Coombs test but no evidence of hemolysis 
• 
Psoriasis not requiring systemic treatment 
• 
Conditions not expected to recur in the absence of an external trigger 
3.29d Coagulopathy, including the use of Coumadin or heparin anticoagulants that 
cannot be discontinued for the cryoablation procedure. NOTE: Heparin for line 
patency without detectable lab abnormalities for coagulation will be allowed. 
3.29e 
Corticosteroid use ≤2 weeks prior to registration. 
NOTE: Patients must be off corticosteroids for at least 2 weeks prior to 
registration. This includes oral, IV, subcutaneous, or inhaled route of 
administration. Patients on chronic corticosteroid for adrenal insufficiency or 
other reasons may enroll if they receive less than 10 mg/day of prednisone (or 
equivalent). 
3.29f 
Active CNS malignancy. 
3.29g Evidence of interstitial lung disease or active, non-infectious pneumonitis. 
3.29h Received a live vaccine ≤30 days prior to registration. 
3.29i 
New York Heart Association Classification III or IV cardiovascular disease 
(Appendix II) or recent myocardial infarction or unstable angina pectoris or 
cardiac arrhythmia ≤30 days prior to registration. 
 
 
 

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4.0 
Test Schedule 
4.1 
Test Schedule: Phase I Dose Level 1 and Phase II (Phase I closed to accrual) 
  
 
 
Active Monitoring 
 
Baseline 
Initial Treatment or Retreatment18 
 
 
Cycle 1 
Cycle 210 & 310 
Cycle 410 & 510 Cycles 6 – 18 
Optional 
Pembro 
Year 
Day 1,  
e er c cle
Tests and procedures 
≤14 days 
prior to 
Registratio
Day 1 
Day 1 Day 2 Day 8 Day 15 Day 1 
Day 2 
Day 1 
 
 
  
±2 days* ±2 days ±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
Physical exam and PS 
X 
  
X 
  
 
 
X 
 
X16 
X16 
Limited exam for AE assessment (as of Add 5) 
• 
Can be done with RN/APP   
 
 
 
 
X 
X 
 
 
 
 
Serum pregnancy test 
X1 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C, Quantiferon TB test 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab administrationR 
 
X7 
X 
 
 
 
X 
 
X 
X 
CryoablationR 
 
 
 
X14 
 
 
 
 
 
 
Leukapheresis and DC manufacturingR 
 
X7 
 
 
 
 
 
 
 
 
Cellular Vaccine (DC) administrationR 
 
 
 
X2 
X2 
X2 
 
X2 
 
 
Prevnar administration 
 
 
 
X2 
 
 
 
X2 
 
 
Chemistry Profile (Creatinine, T. Bili, AST, 
ALT, Alk Phos) 
X 
X 
X 
 
 
 
X 
 
X 
X 
β2microglobulin (follicular only) 
X 
 
 
 
 
 
 
 
 
 
Thyroid function cascade (TSH, reflex to T3, 
T4 if abnormal) 
X 
 
X 
 
 
 
X 
 
X 
X 
LDH 
X 
 
  
  
 
 
X15 
 
X15 
X19 
Coagulation (INR) 
X 
 
 
 
 
 
 
 
 
 
Hematology (ALC, WBC with differential, 
Hgb, PLT) 
X 
X12 
X 
 
 
 
X 
 
X 
X 
Adverse Event Assessment 
X 
  
X 
X 
x 
x 
X 
X 
X 
X 

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Addendum 8 
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Active Monitoring 
 
Baseline 
Initial Treatment or Retreatment18 
 
 
Cycle 1 
Cycle 210 & 310 
Cycle 410 & 510 Cycles 6 – 18 
Optional 
Pembro 
Year 
Day 1,  
every cycle
Tests and procedures 
≤14 days 
prior to 
Registratio
Day 1 
Day 1 Day 2 Day 8 Day 15 Day 1 
Day 2 
Day 1 
 
 
  
±2 days* ±2 days ±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
Radiologic evaluations (CT Chest, abdomen 
and pelvis, neck if clinically indicated, or 
PET/CT) 
X5 
X8 
 
 
 
 
X9 
 
X9 
X19 
Research blood for Immune MonitoringR 
 
X7 
X6 
 
 
 
X6 
 
X6 
X19 
Tumor biopsies3,R 
 
X3,4,13 
 
 
 
 
 
 
X3,4 
 
FACT-Lym 
X 
  
X6 
 
 
 
X6 
 
X6 
X19 
NOTE: All tests, and procedures and QOL indicated to be conducted on Day 1 of any cycle should be done PRIOR to treatment on that 
cycle  
NOTE: For this study, 1 week is equal to 7 days and 1 month is equal to 28 days. Once cycle is equal to 3 weeks or 21 days 
NOTE: If a patient goes off treatment for any reason prior to cycle 18, the patient will follow schedule 4.3 or 4.4 (see Section 13.0) 
NOTE: Decision for optional additional year of Pembro is determined based on clinical response and approval by PI and sponsor.  
 
*Cycle 2 Day 1 window ±4 days  
1. For women of childbearing potential only. Must be done ≤7 days prior to registration. Pregnancy testing will be repeated if patient qualifies 
for re-treatment.  
2. If the previously cryoablated lesion no longer appears viable by imaging, DC will be injected into the previously treated region. Prevnar will 
be injected in the region of the first treated lesion. Patient will get DC until supply exhausted or maximum of 8 doses whichever comes 
first. 
3. An index tumor for biopsy is identified as accessible via needle biopsy that is not the cryoablation site. 
4. An index tumor lesion that is not the cryoablated or treated lesion may be biopsied if it is easily accessible or amenable to image-guided 
biopsy; Day 1 Cycle 1 (may be done any time prior to Day 1 Cycle 1), Day 1 Cycle 6, and Day 1 Cycle 19 (8 weeks post last dose of 
treatment) and at the time of disease progression. For the time point of Day 1 Cycle 1 and at time of disease progression, if excisional 
biopsy is done for diagnostic purposes, then remaining tissue after pathology review can be used for research studies.  
5. Up to 28 days prior to registration. 
6. Blood draw for immune monitoring and FACT-Lym should be collected prior to pembrolizumab administration, DC vaccine injection and 
Prevnar administration. Blood draw for immune monitoring and FACT-Lym during treatment period will be collected on Day 1 of Cycles 1, 

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Addendum 8 
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2, 4, 6, 8, 12 and 18.  
7. Cycle 1 Day 1 order: blood for immune monitoring, leukapheresis, and pembrolizumab administration. 
8. CT or MRI does not need to be repeated if the baseline CT whole body or PET/CT is deemed adequate by study investigator. 
9. Imaging performed during active treatment period on Day 1 of Cycles 4, 8, 12, and 18.  All patients who received at least 2 cycles of 
treatments and do not have evidence of PD should be evaluated for formal clinical response. 
10. If not enough DC, then proceed to Cycle 6. 
11. Patients with residual or progressive disease may be retreated if deemed clinically feasible. See Section 7.12. These patients will follow 
the same test schedule for retreatment, starting with Day 1 Cycle 2. 
12. If the baseline CBC with differential is more than 3 days from the date of leukapheresis, then a CBC with differential needs to be drawn 
at or within 3 days from leukapheresis. 
13. If an index tumor is amenable for excisional biopsy at Cycle 1 Day 1, then excisional biopsy may be performed at the discretion of the 
investigator. In this case, a separate index tumor will be identified for subsequent research biopsies.  
14. Cryoablation is performed on Day 2 of Cycle 2 only. If the previously identified tumor for cryoablation is decreased in size and can no 
longer be cryoablated, another tumor amenable to cryoablation will be identified for treatment. If no additional tumors can be identified for 
cryoablation, DC will be injected into the previously identified shrinking tumor. 
15. LDH performed on Day 1 of Cycles 4, 6, 8, 12, and 18. 
16. After Cycle 10, responsive or stable patients can be followed every other cycle by treating physician/provider until last cycle of treatment. 
However, patients will be followed by nurse at each cycle of treatment for adverse event assessment. They will be seen as needed by 
provider. 
17. If subject thyroid function tests are within normal at the end of treatment and have no clinical signs and symptoms of thyroiditis, thyroid 
function test does not need to be performed during active monitoring. If thyroid function tests are abnormal during treatment, these tests 
need to be followed until they return to normal. 
18. Retreatment starts at cycle 2. 
19. Every 3 months. 
R Research funded. 
 

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Addendum 8 
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4.2 
Test Schedule: Phase 1 Dose Level -1 (Use test schedule 4.1) 
Active Monitoring 
Baseline 
Initial Treatment or Retreatment18 
  
Cycle 1 
Cycle 210 & 310 
Cycle 410 - 710 
Cycles 8 – 18 
Optional 
Pembro Year 
Day 1,  
every cycle 
Tests and procedures 
≤14 days 
prior to 
Registration  
Day 1 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 1 
Window
 
  
±2 days* 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
Physical exam and PS 
X 
X 
X 
X 
 
X 
 
X16 
X16 
Serum pregnancy test 
X1 
 
 
 
 
 
 
 
 
Pembrolizumab administrationR 
 
X7 
X 
 
 
X 
 
X 
X 
CryoablationR 
 
 
 
X14 
 
 
 
 
 
Leukapheresis and DC 
manufacturingR 
 
X7 
 
 
 
 
 
 
 
Cellular Vaccine (DC) 
administrationR 
 
 
 
X2 
X2 
 
X2 
 
 
Prevnar administration 
 
 
 
X2 
 
 
X2 
 
 
Chemistry Profile (Creatinine, T. 
Bili, AST, ALT, Alk Phos) 
X 
X 
X 
 
 
X 
 
X 
X 
β2 microglobulin (follicular only) 
X 
 
 
 
 
 
 
 
 
Thyroid function cascade (TSH, 
reflex to T3, T4 if abnormal) 
X 
 
X 
 
 
X 
 
X 
X 
LDH 
X 
 
  
 
 
X15 
 
X15 
X19 
Coagulation (INR) 
X 
 
 
 
 
 
 
 
 
Hematology (ALC, WBC with 
differential, Hgb, PLT) 
X 
X12 
X 
 
 
X 
 
X 
X 
Adverse Event Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
Radiologic evaluations (CT whole 
body, or PET/CT) 
X5 
X8 
 
 
 
X9 
 
X9 
X19 
Research blood for Immune 
MonitoringR 
 
X7 
X6 
 
 
X6 
 
X6 
X19 

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Active Monitoring 
Baseline 
Initial Treatment or Retreatment18 
  
Cycle 1 
Cycle 210 & 310 
Cycle 410 - 710 
Cycles 8 – 18 
Optional 
Pembro Year 
Day 1,  
every cycle 
Tests and procedures 
≤14 days 
prior to 
Registration  
Day 1 
Day 1  
Day 8 
Day 15 
Day 1 
Day 8 
Day 1 
Window
 
  
±2 days* 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
±2 days 
Tumor biopsies3, R 
 
X3, 4, 13 
 
 
 
 
 
X3, 4 
 
FACT-Lym 
 
X 
X6 
 
 
X6 
 
X6 
X19 
NOTE: All tests, and procedures and QOL indicated to be conducted on Day 1 of any cycle should be done PRIOR to treatment on that 
cycle  
NOTE: For this study, 1 week is equal to 7 days and 1 month is equal to 28 days. Once cycle is equal to 3 weeks or 21 days 
NOTE: If a patient goes off treatment for any reason prior to Cycle 18, the patient will follow Schedule 4.3 or 4.4 (see Section 13.0) 
NOTE: Decision for optional additional year of pembro is determined based on clinical response and approval by PI and sponsor. 
 
*Cycle 2 Day 1 window ±4 days  
1.  For women of childbearing potential only. Must be done ≤7 days prior to registration.  Pregnancy testing will be repeated if patient qualifies 
for re-treatment.  
2. If the previously cryoablated lesion no longer appears viable by imaging, DC will be injected into the previously treated region. Prevnar will 
be injected in the region of the first treated lesion. Patient will get DC until supply exhausted or maximum of 8 doses whichever comes first. 
3. An index tumor for biopsy is identified as accessible via needle biopsy that is not the cryoablation site. 
4. An index tumor lesion that is not the cryoablated or treated lesion may be biopsied if it is easily accessible or amenable to image-guided 
biopsy; Day 1 Cycle 1 (may be done any time prior to Day 1 Cycle 1), Day 1 Cycle 8, and Day 1 Cycle 19 (8 weeks post last dose of 
treatment) and at the time of disease progression. For the time point of Day 1 Cycle 1 and at time of disease progression, if excisional 
biopsy is done for diagnostic purposes, then remaining tissue after pathology review can be used for research studies.  
5. ≤28 days prior to registration. 
6. Blood draw for immune monitoring and FACT-Lym should be collected prior to pembrolizumab   DC injection and Prevnar administration. 
Blood draw for immune monitoring and FACT-Lym during treatment period will be collected on Day 1 of Cycles 1, 2, 4, 8, 12 and 18.  
7. Cycle 1 Day 1 order: blood for immune monitoring, leukapheresis, and pembrolizumab administration. 
8. CT or MRI does not need to be repeated if the baseline CT whole body or PET/CT is deemed adequate by study investigator. 
9. Imaging performed during active treatment period on Day 1 of cycles 4, 8, 12, and 18. All patients who received at least 2 cycles of 
treatments and do not have evidence of PD should be evaluated for formal clinical response. 

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10. If not enough DC, then proceed to cycle 8. 
11. Patients with residual or progressive disease may be retreated if deemed clinically feasible. See Section 7.12. These patients will follow 
the same test schedule for retreatment, starting with Day 1 Cycle 2. 
12. If the baseline CBC with differential is more than 3 days from the date of leukapheresis, then a CBC with differential needs to be drawn at 
or within 3 days from leukapheresis. 
13. If an index tumor is amenable for excisional biopsy at Cycle 1 Day 1, then excisional biopsy may be performed at the discretion of the 
investigator. In this case, a separate index tumor will be identified for subsequent research biopsies.  
14. Cryoablation is performed on Day 8 of Cycle 2 only. If the previously identified tumor for cryoablation is decreased in size and can no 
longer be cryoablated, another tumor amenable to cryoablation will be identified for treatment. If no additional tumors can be identified for 
cryoablation, DC will be injected into the previously identified shrinking tumor. 
15. LDH performed on Day 1 of Cycles 4, 8, 12, and 18. 
16. After Cycle 10, responsive or stable patients can be followed every other cycle by treating physician/provider until last cycle of treatment. 
However, patients will be followed by nurse at each cycle of treatment for adverse event assessment. They will be seen as needed by 
provider. 
17. If subject thyroid function tests are within normal at the end of treatment and have no clinical signs and symptoms of thyroiditis, thyroid 
function test does not need to be performed during active monitoring. If thyroid function tests are abnormal during treatment, these tests 
need to be followed until they return to normal. 
18. Retreatment starts at cycle 2. 
19. Every 3 months. 
R Research funded. 
 
 
 

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4.3 
Test Schedule for Observation for patients who do not complete initial active treatment for any reason or do not have 
dendritic cells for retreatment.   
 
Active Monitoring 
Tests and procedures 
Observation3 
Day 1 of each observation cycle 
Every 3 months for 1 year (start at 
Week 62 or 8 weeks after last dose 
whichever is earlier) 
Documented PD at any time during this 
protocol treatment or observation, prior to 
entering event monitoring, at End of 
Observation 
Physical exam and PS 
X 
X 
Serum pregnancy test 
 
 
Pembrolizumab (MK-3475) administrationR 
 
 
CryoablationR 
 
 
Leukapheresis and DC manufacturingR 
 
 
Cellular Vaccine (DC)  administrationR 
 
 
Prevnar administration 
 
 
Chemistry Profile (Creatinine, TBili, AST, ALT, Alk Phos) 
X 
X 
Thyroid function cascade 
X4 
 
LDH 
X 
X 
Coagulation (INR) 
 
 
Hematology (ALC, WBC with differential, Hgb, PLT) 
X 
X 
Adverse Event Assessment 
X 
X 
Radiologic evaluations (CT whole body, or PET/CT) 
X 
X 
Research blood for Immune MonitoringR 
X 
X 
Tumor biopsies1, R 
X1, 2 
X1, 2 
FACT-Lym 
X 
X 
1. An index tumor for biopsy is identified as accessible via needle biopsy that is not the cryoablation site. 
2. An index tumor lesion that is not the cryoablated or treated lesion may be biopsied if it is easily accessible or amenable to image-guided 
biopsy; Day 1 Cycle 1 (may be done any time prior to Day 1 Cycle 1), Day 1 Cycle 8, and Day 1 Cycle 19 (8 weeks post last dose of 
treatment) and at the time of disease progression. For the time point of Day 1 Cycle 1 and at time of disease progression, if excisional 

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biopsy is done for diagnostic purposes, then remaining tissue after pathology review can be used for research studies.  
3. Patients with residual or progressive disease may be retreated if deemed clinically feasible.  See Section 7.12.  These patients will follow 
the same test schedule for retreatment, starting with Day 1, Cycle 2. 
4. If subject thyroid function tests are within normal at the end of treatment and have no clinical signs and symptoms of thyroiditis, thyroid 
function test does not need to be performed during active monitoring. If thyroid function tests are abnormal during treatment, these tests 
need to be followed until they return to normal. 
R Research funded. 
 
 

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4.4 
Test Schedule for Event Monitoring for patients who refuse additional treatment or observation for any reason  
CRF 
Event Monitoring Phase1 
q. 3 months during Yr 1 
post-treatment;  
q. 4 months during Yr 2 
post- treatment;  
q 6 months during 
subsequent yrs up to 4 yrs 
post registration until PD 
At PD2 
After PD 
q. 6 months until 
4 yrs post 
registration 
Death 
New Primary 
Event Monitoring  
X2 
X2 
X 
X 
At each occurrence 
 
1. 
If a patient is still alive 4 years after registration, no further follow-up is required. 
2. 
Submit copy of documentation of response or progression in the Supporting Documentation form in Medidata Rave. 
 
 
 
 

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4.5 
Test Schedule for Treatment Observation for patients who have dendritic cells for retreatment 
Treatment Observation 
Tests and procedures 
Day 1 of each cycle  
Every 3 months for 1 year 
post treatment(start at Week 
62 or 8 weeks after last dose 
whichever is earlier) 
Day 1 of each cycle 
(Every 4 months during second 
year post treatment, every 6 
months thereafter until 4 yr post 
registration)  
Documented PD at any 
time during treatment or 
observation, prior to 
entering event 
monitoring, at End of 
Observation 
Physical exam and PS 
X 
 
X 
Serum pregnancy test 
 
 
 
Pembrolizumab (MK-3475) administrationR 
 
 
 
CryoablationR 
 
 
 
Leukapheresis and DC manufacturingR 
 
 
 
Cellular Vaccine (DC) administrationR 
 
 
 
Prevnar administration 
 
 
 
Chemistry Profile (Creatinine, TBili, AST, ALT, 
Alk Phos) 
X 
 
X 
Thyroid function cascade 
X3 
 
 
LDH 
X 
 
X 
Coagulation (INR) 
 
 
 
Hematology (ALC, WBC with differential, Hgb, 
PLT) 
X 
 
X 
Adverse Event Assessment 
X 
 
X 
Radiologic evaluations (CT whole body, or 
PET/CT) 
X 
 
X 
Research blood for Immune MonitoringR 
X 
 
X 
Tumor biopsies 1, R 
X1, 2 
 
  X1,2 
FACT-Lym 
X 
 
X 

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Treatment Observation 
Tests and procedures 
Day 1 of each cycle  
Every 3 months for 1 year 
post treatment(start at Week 
62 or 8 weeks after last dose 
whichever is earlier) 
Day 1 of each cycle 
(Every 4 months during second 
year post treatment, every 6 
months thereafter until 4 yr post 
registration)  
Documented PD at any 
time during treatment or 
observation, prior to 
entering event 
monitoring, at End of 
Observation 
Event Monitoring Form* 
 
X 
 
* Also complete at PD, every 6 months post PD until 4 yr post registration, death and at each new occurrence of primary up to 4 years post 
registration. If a patient is still alive 4 years after registration, no further follow-up is required. Submit copy of documentation of response or 
progression in the Supporting Documentation form in Medidata Rave. 
1. An index tumor for biopsy is identified as accessible via needle biopsy that is not the cryoablation site. 
2. An index tumor lesion that is not the cryoablated or treated lesion may be biopsied if it is easily accessible or amenable to image-guided 
biopsy; Day 1 Cycle 1 (may be done any time prior to Day 1 Cycle 1), Day 1 Cycle 8, and Day 1 Cycle 19 (8 weeks post last dose of 
treatment) and at the time of disease progression. For the time point of Day 1 Cycle 1 and at time of disease progression, if excisional 
biopsy is done for diagnostic purposes, then remaining tissue after pathology review can be used for research studies.  
3. If subject thyroid function tests are within normal at the end of treatment and have no clinical signs and symptoms of thyroiditis, thyroid 
function test does not need to be performed during active monitoring. If thyroid function tests are abnormal during treatment, these tests 
need to be followed until they return to normal. 
 
R 
Research funded. 
 
 
4.6   
Test Schedule:  Phase II 
Test schedule for Phase II will follow Phase I dose level 1 (See Section 4.1). 
 

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5.0 
Grouping Factor: 
5.1 
Phase: I vs. II 
5.2  
Dose Level (Phase I only) (As assigned by MCCC Registration Office): 
1 vs -1  
6.0 
Registration Procedures 
6.1 
Phase I –Closed to accrual July 9, 2018 
Prior to discussing this protocol with a patient, call the Registration Office 
 for dose level and to ensure there is a place on the study for 
the patient. 
Registration Procedures 
To register a patient, fax 
 a completed eligibility checklist to the 
Mayo Clinic Cancer Center (MCCC) Registration Office between 8 a.m. and 
4:30 p.m. central time Monday through Friday. 
6.2  
Phase II – Opened to accrual July 9, 2018 
Registration Procedures 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page 
and enter the registration/randomization application. The 
registration/randomization application is available 24 hours a day, 7 days a 
week. Back up and/or system support contact information is available on the 
Web site. If unable to access the Web site, call the MCCC Registration Office 
at 
between the hours of 8 a.m. and 4:30 p.m. Central Time 
(Monday through Friday). 
 
The instructions for the registration/randomization application are available on 
the MCCC web page
 and detail the 
process for completing and confirming patient registration. Prior to initiation 
of protocol treatment, this process must be completed in its entirety and a 
MCCC subject ID number must be available as noted in the instructions. It is 
the responsibility of the individual registering the patient to confirm the 
process has been successfully completed prior to release of the study agent. 
Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
● 
Contact the MCCC Registration Office 
 If the patient 
was fully registered, the MCCC Registration Office staff can access the 
information from the centralized database and confirm the registration. 
● 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.3 
Phase I and Phase II 
6.31 
Correlative Research  
A mandatory correlative research component is part of this study; the 
patient will be automatically registered onto this component (see 
Sections 3.19d, 14.1, and 17.1 for required research samples). 

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6.32 
Verification 
Prior to accepting the registration, the registration/randomization 
application will verify the following: 
● IRB approval at the registering institution 
● Patient eligibility 
● Existence of a signed consent form 
● Existence of a signed authorization for use and disclosure of 
protected health information 
6.33 
Documentation 
Documentation of IRB approval must be on file in the 
Registration Office before an investigator may register any 
patients. 
In addition to submitting initial IRB approval documents, ongoing 
IRB approval documentation must be on file (no less than annually) 
at the Registration Office 
If the necessary 
documentation is not submitted in advance of attempting patient 
registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, 
submission of annual IRB approvals to the Registration Office is no 
longer necessary. 
6.34 
At the time of registration, the following will also be recorded: 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research of lymphoma at Mayo. 
• 
Patient has/has not given permission to store and use his/her 
sample(s) for future research to learn, prevent, or treat other 
health problems. 
• 
Patient has/has not given permission to give his/her sample(s) to 
researchers at other institutions. 
6.35 
Treatment on this protocol must commence at the Mayo Clinic 
Rochester under the supervision of a hematologist. 
6.36  
Treatment cannot begin prior to registration and must begin ≤21 days 
after registration. 
6.37  
Pretreatment tests / procedures must be completed within the guidelines 
specified on the test schedule (see Section 4.0). 
6.38 
All required baseline symptoms (see Section 10.6) must be documented 
and graded.  
6.39a 
Study drug is available on site. 
6.39b Patient questionnaire booklet is available on site; copies are not 
acceptable for this submission.   
 
 
 

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Addendum 8 
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7.0 
Protocol Treatment 
7.1 
Phase I Treatment Schedule  (Closed to accrual July 9, 2018 
The tolerated dose of this regimen in the phase I portion of this study will be used 
to treat patients enrolled in the phase II portion of this study.  Patients will be 
enrolled on dose level 1 and if the regimen is intolerable, patients will be enrolled 
on dose level -1. 
 
Phase II Treatment Schedule (Opened to accrual July 9, 2018) 
7.11 
Phase I dose level 1 and Phase II  
7.111  Dose level 1 schedule 
Agent 
Dose Level 
Number 
of doses 
Route 
Cycles1 
 
Pembrolizumab 
200 mg 
18 
IV 
1-18 (Day 1) 
DC 
not less than 30 and no 
more than 60 million  
DC3 
8 
Injection to 
cryoablated 
tumor 
22 (Day 2, 8, 15) 
3 (Day 2, 8, 15) 
4, 5 (Day 2) 
Cryoablation  
 
 
 
2 (Day 2) 
Prevnar13 
0.5 mL 
4 
Injection near 
cryoablated 
tumor 
22 (Day 2),  
3, 4, 5 (Day 2) 
Cycle Definitions: 1 week = 7 days; 1 month = 28 days; 1 cycle = 21 days. 
1 All timepoints are ±2 days 
2 The day of cryoablation 
3 Depending on availability after manufacturing 
 
7.112 Phase I dose level 1 schedule Treatment by Cycle 
Cycle 
Duration 
Timepoint 
Day 
Cycle 1 
3 weeks 
Week 1 to Week 3 Day 1: Leukapheresis followed by 
pembrolizumab 
(DC manufacturing in lab) 
Cycle 2 
3 weeks 
Week 4 to Week 6 Day 1: Pembrolizumab 
Day 2: Cryoablation2 of tumor followed by intra-
tumor injection of DC and injection of Prevnar13 
in nearby region 
Day 8: DC as per section 7.1151 
Day 15: DC as per section 7.1151 
Cycle 3 
3 weeks 
Week 7 to Week 9 Day 1: Pembrolizumab 
Day 2: Prevnar13, DC per Section 7.1151 
Day 8: DC per Section 7.1151 
Day 15: DC per Section 7.1151 

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Addendum 8 
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Cycle 
Duration 
Timepoint 
Day 
Cycles 4 - 5 
3 weeks 
 
Day 1: Pembrolizumab 
Day 2: Prevnar13, DC as per Section 7.31 
Cycles 6 - 18 
3 weeks 
 
Day 1: Pembrolizumab 
Tumor biopsy on Day 1 of Cycle 6 only 
1. If supply exhausted, start Cycle 6 of pembrolizumab. 
2. If the previously identified tumor for cryoablation is decreased in size and can no 
longer be cryoablated, another tumor amenable to cryoablation will be identified 
for treatment. If no additional tumors can be identified for cryoablation, DC will be 
injected into the previously identified shrinking tumor. 
7.113 Pembrolizumab, monoclonal anti-PD1 antibody 
Patients will receive pembrolizumab at 200 mg IV every 3 weeks 
for 18 cycles. If patient experienced adverse events requiring 
dosing delay (see Section 8), the new dosing interval (increased 
interval) can be defined as the new cycle length. Patients who 
achieved CR before Cycle 5 will complete treatments through 
cycle 6 and can then stop treatment at the discretion of the 
treating provider and investigators. Patients who achieved CR at 
or after cycle 5 could continue treatments for 2 more cycles and 
stop treatment at the discretion of the treating provider.  The 
designed maximum length of treatment is 12 months (365 days). 
If the patient is continuing to benefit from treatment after 12 
months, the patient may continue to receive treatment up to 24 
months at investigator/sponsor discretion.  
7.114 Pneumococcal vaccination 
Patients will have four pneumococcal vaccinations 
(Prevnar13®) in dose 1 (phase I dose level 1schedule) and six 
pneumococcal vaccinations (Prevnar13®) in dose -1 (phase I 
dose level -1 schedule). These injections will be concurrent 
with the first DC vaccine administration at each cycle (Cycles 
2 - 5 for phase I dose level 1 and Cycles 2 - 7 for phase I dose 
level -1). The will be administered near the region of DC 
injection. 
7.115 Cellular vaccines (DC)  
For DC manufacturing, patients will undergo leukapheresis 
from which monocytes will be collected by immunomagnetic 
isolation and cultured in vitro under GMP condition to generate 
mature DC. 
Autologous mature dendritic cells (DC) will be prepared for 
administration into cryoablated tumor. DC, the generated 
mature DC, will be frozen and stored until ready for use. A 
minimum of 30x106 and a maximum of 60x106 mature DC 
will be used for each injection. Minimum DC necessary for 16 
injections will be manufactured. Additional DC and lysate will 
be stored for immune monitoring assays and potential 
additional vaccination. 

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Addendum 8 
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7.116 DC Administration 
Each patient will undergo percutaneous cryoablation of a single 
lymphoma tumor as specified by the PI and interventional 
radiologist.  
Our general cryoablation technique has been previously 
described (Atwell, Farrell et al. 2008). Due to the extended 
length of the procedure, requiring the patient to lie still (expected 
duration 45 minutes), sedation will be managed by the 
Department of Anesthesia. Using ultrasound and/or CT 
guidance, a cryoprobe will be placed in the index lymphoma 
node. The node will be treated using a conventional freeze-thaw-
freeze cycle with the endpoint being the generation of an iceball 
that measures no more than 75% of the diameter of the index 
tumor. Specifically, incomplete treatment of the lymphoma 
treatment lesion will significantly minimize the risk of thermal 
injury to adjacent structures, yet still achieve the desired 
cytotoxic cell injury.  
Following the freezing procedure, the cryoprobe will be actively 
warmed and then withdrawn. After the node has thawed, a 22 G 
needle will be placed under ultrasound or CT-guidance into the 
ablated portion of the node. The DC will be administered 
through this needle in 10 – 15 divided injections over different 
areas of the cryoablated region and then flushed with 1ml of 
sterile saline. Prevnar will be injected into the immediately 
adjacent soft tissues of the cryoablated lesion. The patient will be 
transferred to the radiology recovery area and observed until 
discharge criteria are met prior to dismissal from the hospital 
(minimum 2 hours). 
Doses 2-8. Patients will receive seven additional doses of DC 
injected into the cryoablated lesion using ultrasound, CT or MRI 
guidance. Prevnar will be injected in the region immediately 
adjacent to the previously cryoablated lesion. 
Patients will be monitored for 2 hours following cryoablation 
and DC injections or 30 minutes following only DC injections 
for acute toxicity. Known potential toxicity of DC injection 
includes dermatitis, anaphylaxis, allergic reactions such as 
bronchospasm or generalized urticaria, autoimmune reactions, 
bone pain, myalgia/arthralgia, reaction at the site of injection and 
renal dysfunction. 
 
 

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7.12 
Phase I dose level -1 (De-Escalation Schedule) (closed to accrual July 9, 
2018) 
7.121 Phase I Dose level -1 Schedule  
Agent 
Dose Level 
Number 
of doses 
Route 
Cycles1 
Pembrolizumab 
200 mg 
18 
IV 
1-18, Day 1 
DC 
not less than 30 and no 
more than 60 million  
DC 
8 
Injection into 
Cryoablated tumor 
22(Day 8, 15),  
3 (Day 8, 15),  
4, 5, 6, 7 (Day 8) 
Prevnar13 
0.5 mL 
6 
Injection near 
cryoablated tumor 
22(Day 8),  
3-7 (Day 8),  
1 All time points are ±2 days 
2 The day of cryoablation 
 
7.122 Phase I dose level -1 Schedule Treatment by Cycle 
Cycle 
Duration 
Timepoint 
Day 
Cycle 1 
3 weeks 
Week 1 to Week 3 
Day 1: Leukapheresis followed by pembrolizumab 
(DC manufacturing in lab) 
Tumor biopsy 
Cycle 2 
3 weeks 
Week 4 to Week 6 
Day 1: Pembrolizumab 
Day 8: Cryoablation2 of tumor followed by intra-
tumor injection of DC vaccine and injection of 
Prevnar13 in nearby region 
Day 15: DC per Section 7.1151 
Cycle 3 
3 weeks 
Week 7 to Week 9 
Day 1: Pembrolizumab 
Day 8: Prevnar13, DC per Section 7.1151 
Day 15: DC vaccine per Section 7.1151 
Cycle 4 - 7 
3 weeks 
 
Day 1: Pembrolizumab 
Day 8: Prevnar13, DC per Section 7.1151 
Cycles 8 - 18 
3 weeks 
 
Day 1: Pembrolizumab 
Tumor biopsy on Day 1 of Cycle 8 only 
1. If supply exhausted, start Cycle 8 of pembrolizumab. 
2. If the previously identified tumor for cryoablation is decreased in size and can no 
longer be cryoablated, another tumor amenable to cryoablation will be identified 
for treatment. If no additional tumors can be identified for cryoablation, DC will be 
injected into the previously identified shrinking tumor. 
7.13 
Treatment by a local medical doctor is not allowed. 
7.14  
Dosing plan 
Cohorts of 3 patients will be treated at a dose level at a time (see Section 
16.0).  The study will temporarily close between patient cohorts . Doses 
will not be escalated in any individual patient. 
7.15  
Duration of treatment 

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Duration of treatment is a maximum of 12 months from start of Cycle 1. 
If a patient remains on cycles with a length of 21 days without treatment 
delays, this will be 18 cycles total. If the cycle length is increased due to 
dosing frequency changes or dose delays, the number of cycles will be 
reduced to not exceed 12 months of treatment total. If a patient is 
continuing to benefit from treatment after 12 months, he or she may 
continue to receive pembrolizumab every 3 weeks for up to 24 months 
total from start of cycle 1 at the investigator/sponsor discretion. If a 
patient achieved CR before Cycle 5, the patient will continue through 
Cycle 6 and could stop at the discretion of the treating provider and 
investigator. If a patient achieved CR at or after Cycle 5, the patient 
could continue treatment for 2 more cycles at the discretion of treating 
provider. 
7.16 
Dose Limiting Criteria (DLT) 
For this protocol, DLT will be defined as an adverse event attributed 
(definitely, probably, or possibly) to the study treatment during the first 
two cycles of treatment AND meeting the following criteria. 
CTCAE System Organ Class 
DLT Definition (CTCAE v4) 
Investigations 
Neutrophil count decreased 
Platelet count decreased 
≥Grade 4 ANC or PLT for ≥7 days 
Infections and infestations 
Other, specify 
Any ≥ Grade 3 
Blood and lymphatic system disorders 
Febrile neutropenia 
Defined as fever ≥38.5oC (38 >1 hour) with grade 
≥4 neutropenia 
Skin and subcutaneous tissue disorders 
Erythema multiforme 
Skin ulceration 
Urticaria 
≥ Grade 3 erythema multiforme, ulceration, or 
urticaria that does not resolve to <Grade 2 within 
three weeks 
Respiratory, thoracic and mediastinal 
disorders 
Bronchial obstruction 
Pneumonitis 
Wheezing 
≥Grade 3 bronchial obstruction, pneumonitis, or 
wheezing 
Immune system disorders 
Allergic reaction 
Autoimmune disorder 
≥Grade 3 allergic reaction or autoimmunity 
All Other Non-Hematologic 
≥Grade 3 that does not resolve to < Grade 2 
≤ 72 hours per NCI Common Terminology 
Criteria for Adverse Events 
Note: any adverse event that leads to a permanent discontinuation of the study agent is 
considered a DLT. 
7.17 
Dose levels 
The dose level of pembrolizumab is fixed at 200 mg IV on Day 1 of 
every 21 days. The DLT criteria will be used to determine the 
timing of the subsequent administration of pembrolizumab, not for 
adjustment of the dose level. The dose interval may be increased by 
7 days each time, the maximum dosing interval allowed is 8 weeks.  

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The study involves DC injection at only one dose level, but has 
potentially multiple injections over time. The DLT criteria will be 
used to determine timing of the subsequent administration of DC, 
and not for adjustment of DC dose level. 
Note: This study will not allow dose reduction, only dose 
interval changes. 
7.2 
Patients experiencing a DLT  
Investigators are to contact the Study Chair as soon as any DLT occurs. Patients 
who experience DLT will go to observation.   
7.3 
Continued pembrolizumab treatment 
Patients may continue on pembrolizumab treatment for 1 year after initial 
treatment is terminated (please check with Study Chair).  
7.4 
Retreatment 
Patients who qualify for retreatment (see Section 13.0) will not change dose 
levels and will follow the original treatment schedule starting at cycle 2. When 
retreating, new baseline disease measurement will be established. The new 
baseline disease measurement will be the disease measurement at the end of the 
cycle prior to the retreatment.   Patients may receive all DC according to 
schedule as long as they do not have continued progression of disease, develop 
major adverse events, and have DC available.  
Patients will not undergo any additional leukapheresis for the purpose of 
manufacturing additional DC.  
7.5 
Phase II  
Treatment schedule for phase II will be defined as the treatment regimen from 
the MTD dose schedule in phase I.  
NOTE: Phase II’s dose schedule will follow Phase I Dose Level I (See Section 
7.1) 
8.0 
Dosage Modification Based on Adverse Events 
8.1 
Treatment schedule modifications in patients based on adverse events 
8.11  
Patients will be evaluated by the study team prior to each dose of DC for 
an adverse event check.  Determination will be made if the adverse event 
is treatment related (possible, probable or definite), i.e. a toxicity (see 
Section 10; Adverse event monitoring and reporting). If any adverse 
event has occurred, then the treatment schedule will be modified as in 
8.12, 8.13, or 8.2. For cycles involving only pembrolizumab treatments 
(Cycles 1 and 6-18 for dose level 1 and Cycles 1 and 8-18 for dose level 
-1), refer to Section 8.2. 
8.12  
For Grade 1/2 adverse event during cycles with DC injections (Cycles 2 
– 5 for dose level 1 and Cycles 2 – 7 for dose level -1): We will allow a 
delay in DC treatment up to four weeks for dermatological AEs ≤Grade 
2; for all other Grade 1/2 adverse events not listed in Table 7.16 or 8.2, 
no change in procedure is required or expected.  
8.13 
For Grade 2/3/4 adverse events (Grade 2/3/4 described in Table 8.2 or 

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Addendum 8 
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any grade 3/4), pembrolizumab dose schedule will be modified as 
described in Table 8.2.   DC and Prevnar13 injections for the cycle in 
which pembrolizumab are delayed will also be delayed and resumed 
when pembrolizumab resumption criteria has been met. For a grade 2/3/4 
adverse event per Table 7.16 that is attributed to treatment and does not 
resolve within two weeks, if the patient has not completed all treatments, 
he or she will not receive any further treatment on this trial. The patient 
will go to observation phase.  
8.2 
Treatment schedule modifications for pembrolizumab  
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology. These adverse events may 
occur shortly after the first dose or several months after the last dose of 
treatment. Pembrolizumab must be withheld for drug-related toxicities and severe 
or life-threatening AEs per Table 8.21 below. See Section 9.0 for supportive care 
guidelines, including use of corticosteroids. 
Table 8.21 
Dose Modification Guidelines for Drug-Related Adverse Events 
for Pembrolizumab 
CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Gastrointestinal 
disorders 
Diarrhea or 
Colitis 
2-3 
AE resolves to Grade 
 0-1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
4 
Permanently discontinue 
Permanently discontinue 
Investigations 
AST, or ALT, or 
Blood bilirubin 
 
2 
AE resolves to Grade 
 0-1 
AE does not resolve within 12 
weeks of last dose. 
 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Metabolism and 
nutrition disorders 
Glucose 
intolerance (Type 
1 diabetes 
mellitus [if new 
onset]) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
associated with evidence 
of beta cell failure 
Resume pembrolizumab when 
patients are clinically and 
metabolically stable. 
Endocrine disorders 
Endocrine 
disorders – Other, 
specify: 
Hypophysitis 
2-4 
AE resolves to Grade 0-
1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 

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CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Endocrine disorders 
Hyperthyroidism 
3 
AE resolves to Grade 0-
1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
4 
Permanently discontinue 
Permanently discontinue 
Endocrine disorders 
Hypothyroidism 
2 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
General disorders and 
administration site 
conditions 
Infusion related 
reaction 
2b 
AE resolves to Grade 
 0-1 
Permanently discontinue if AE 
develops despite adequate 
premedication  
 
 
3-4 
Permanently discontinue 
Permanently discontinue 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
2 
AE resolves to Grade 
 0-1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal and urinary 
disorders 
Acute kidney 
injury or Chronic 
kidney disease  
(e g Renal failure 
or Nephritis) 
2 
AE resolves to Grade 
 0-1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
3-4 
Permanently discontinue 
Permanently discontinue 
 
All Other Drug-
Related Adverse 
Eventsc 
3  
AE resolves to Grade  
0-1 
AE does not resolve within 12 
weeks of last dose or inability 
to reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 12 
weeks 
 
 
4 
Permanently discontinue 
Permanently discontinue 

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CTCAE 
System/Organ/Class 
(SOC) 
Adverse Event 
Hold 
Treatment 
for Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases 
by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be 
discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the 
original infusion rate   (e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms 
resolve and the subject should be premedicated for the next scheduled dose. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment 
with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
Note:  The term “interruption” has the same meaning as “delay”.   
8.21 
Other instructions for pembrolizumab 
If pembrolizumab-related toxicity does not resolve to Grade 0-1 within 
12 weeks after last administration of study drug, study therapy 
discontinuation is recommended. With Investigator agreement, patients 
with a laboratory adverse event still at Grade 2 may continue in the study 
only if asymptomatic and controlled. 
In patients who continue on study therapy after experiencing an Adverse 
Event warranting potential dose modification, if considered drug-related 
by the investigator, once the patient has recovered to Grade 0-1 the 
dosing interval in subsequent cycles will be increased by 1 week (e.g., to 
3 weeks in patients who were on an every 2-week schedule). Following 
each such dose delay due to toxicity, the dosing interval should increase 
by an additional week. For example, patients who began the study on a 
3-week dosing schedule, and have stopped drug twice for due to a drug-
related toxicity that meets the above criteria, should now be dosing every 
5 weeks. 
For patients who experience a recurrence of the same severe AEs listed 
above with rechallenge of pembrolizumab, a consultation with the 
Investigator will occur to determine whether the patient should continue 
in the study. A patient who experiences the same SAE of the same NCI 
CTCAE grade or higher with rechallenge of pembrolizumab must 
discontinue pembrolizumab immediately. 
Reduced dose of pembrolizumab dose (ie, below 200 mg) will not be 
administered. 
Dosing interruptions are permitted in the case of medical / surgical 
events or logistical reasons not related to study therapy (e.g., elective 
surgery, unrelated medical events, patient vacation, and/or holidays). 
Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Study Chair. 
The reason for interruption should be documented in the patient's study 
record. 

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Pembrolizumab (MK-3475) will be withheld for drug-related Grade 4 hematologic toxicities 
per table in 8.3, non-hematological toxicity ≥Grade 3 including uncontrolled laboratory 
abnormalities, and severe or life-threatening AEs per Tables in 8.2 and 8.3. 
 
8.3  
Dose Modification for Hematological Toxicities (Platelet and Hemoglobin only) for 
all agents 
 
Note: hematological toxicity is not based on CTCAE 4.0 except neutrophil, but based on 
lymphoma specific hematological toxicity. 
Dose modification guidelines for drug-related hematological (hemoglobin and platelets) 
adverse events 1, 2  
Toxicity 
Grade  1, 2 
Decrease from 
pretreatment 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject 
(after 
consultation 
with PI) 
NHL specific 
Hematological 
Toxicity  
1 
 
 
2 
11-24% decrease 
in HGB or PLT 
 
25-49% decrease 
in HGB or PLT 
No 
N/A 
N/A 
N/A 
3 
50-74% decrease 
in HGB or PLT 
Yes 
Toxicity 
resolves to 
Grade 0-2 or 
baseline 
May increase 
the dosing 
interval by 1 
week  
Toxicity does 
not resolve 
within 8 
weeks of last 
infusion 
Permanent 
discontinuatio
n should be 
considered 
for any severe 
or life-
threatening 
event. 
Go to 
observation if  
≥2 cycles of 
therapy were 
given, 
otherwise go 
to event 
monitoring 
4 
≥75% decrease in 
HGB or PLT  
Yes 
Toxicity 
resolves to 
Grade 0-2 or 
baseline 
May increase 
the dosing 
interval by 1 
week  
1 
If, at any level of decrease from the baseline value the platelet and/or 
hemoglobin counts are within normal limits or platelet count is still ≥ 
100,000/µL, this will be considered a grade 0. 
2 
If patient has persistent cytopenia, it is recommended to repeat bone marrow 
evaluation to test if there is disease progression. 
 
 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full Supportive Care 
Patients should receive full supportive care while on this study. This 
includes blood product support, antibiotic treatment, and treatment of other 
newly diagnosed or concurrent medical conditions. All blood products and 
concomitant medications such as antidiarrheals, analgesics, and/or 
antiemetics received from within 28 days before the study treatment 
administration until 30 days after the final dose will be recorded in the 
medical records. Leukocyte reduction of all blood products for patients 
on protocol is required. Any blood transfusions administered must be 
irradiated blood products to reduce the risk of transfusion mediated 
graft versus host disease in patients receiving T-cell modulating 
therapy. 
9.11 
Antiemetics 
Antiemetics may be used at the discretion of the treating physician. 
9.12 
NSAIDS 
NSAIDs use limited to standard non-prescription doses. 
9.13 
Blood Products and Growth Factors 
Blood products and growth factors should be utilized as clinically warranted 
and following institutional policies and recommendations. The use of growth 
factors should follow published guidelines of the American Society of Clinical 
Oncology; Update of Recommendations for the Use of Hematopoietic 
Colony-Stimulating Factors: Evidence- Based, Clinical Practice Guidelines. J 
Clin Oncol 24(19): 3187-3205, 2006. 
9.2 
Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology 
Subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures for 
the management of adverse events with potential immunologic etiology are 
outlined below. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the 
investigator does not need to follow the treatment guidance (as outlined below). 
Refer to Section 8.0 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
• 
Pneumonitis:  

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o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with 
or without fever) and of bowel perforation (such as peritoneal signs and 
ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  For 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients 
for changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs 

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and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
• 
Management of Infusion Reactions:  
Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion.  
Table 9.51 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab. 
 
Table 9.21 
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, 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
Subject may be 
premedicated 1.5h (±30 
minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
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. 
(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. 
9.3 
Diet/Activity/Other Considerations 
9.31 
Diet 
Subjects should maintain a normal diet unless modifications are required 

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Addendum 8 
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to manage an AE such as diarrhea, nausea or vomiting. 
9.32 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  
Furthermore, it is not known if pembrolizumab has transient adverse 
effects on the composition of sperm. 
For this trial, male subjects will be considered to be of non-reproductive 
potential if they have azoospermia (whether due to having had a 
vasectomy or due to an underlying medical condition). 
Female subjects will be considered of non-reproductive potential if they 
are either:  
(1) postmenopausal (defined as at least 12 months with no menses 
without an alternative medical cause; in women < 45 years of age a 
high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. In 
the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks 
prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid 
becoming pregnant or impregnating a partner, respectively, while 
receiving study drug and for 120 days after the last dose of study drug by 
complying with one of the following: 
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during 
heterosexual activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with 
cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill 
(estrogen/progestin pill or progestin-only pill), contraceptive 
skin patch, vaginal contraceptive ring, or subcutaneous 

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Addendum 8 
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contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the subject’s 
preferred and usual lifestyle and if considered acceptable by local 
regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method 
of contraception for subjects participating at sites in this country/region. 
Subjects should be informed that taking the study medication may 
involve unknown risks to the fetus (unborn baby) if pregnancy were to 
occur during the study. In order to participate in the study subjects of 
childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days 
prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of trial 
therapy. If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
9.33 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with 
pembrolizumab, the subject will immediately be removed from the study.  
The site will contact the subject at least monthly and document the 
subject’s status until the pregnancy has been completed or terminated.  
The outcome of the pregnancy will be reported to the Sponsor and to 
Merck without delay and within 24 hours to the Sponsor and within 2 
working days to Merck if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn). 
The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus 
or newborn to the Sponsor. If a male subject impregnates his female 
partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as 
described above.  
9.34 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since 
many drugs are excreted in human milk, and because of the potential for 
serious adverse reactions in the nursing infant, subjects who are breast-
feeding are not eligible for enrollment. 
 

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10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all serious adverse events 
to the sponsor as described within the protocol, regardless of attribution to study agent or 
treatment procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant 
risk for human subjects, including reports of mutagenicity, teratogenicity, or 
carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, 
or clinical studies, whether or not conducted under an IND and whether or not 
conducted by the sponsor, that suggest a significant risk in humans exposed to 
the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse 
reaction over the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
Non Mayo sites – complete and 
forward to 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form 
  
 
Will automatically be sent to 
 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
Expedited Reporting 

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Addendum 8 
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Events reported to sponsor within 24 hours, 5 days or 10 days of study team 
becoming aware of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means in 
order to facilitate the review of safety data (may be requested by the FDA or the 
sponsor).  
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects 
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0. A copy of the 
CTCAE version 4.0 can be downloaded from the CTEP web site: 
 
a. Identify the grade and severity of the event using the CTCAE version 4.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, 
treatment or procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via 
the routine data reporting mechanisms defined by the protocol (see Sections 
10.6 and 18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in 
Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the 
study specific consent form, package insert (if applicable), and/or the investigator 
brochure, (if an investigator brochure is not required, otherwise described in the 
general investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 15.0 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or 

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Addendum 8 
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available, is not consistent with the risk information described in the general 
investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but 
have not been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent. Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity or specificity, 
expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the 
discretion of the Principal Investigator; it is possible that this information may 
NOT be included in the protocol or the investigator brochure. Refer to protocol 
or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) 
medical or procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are 
expected to occur within this population and do not require Expedited 
Reporting. These events must still be reported via Routine Reporting (see 
Section 10.6).* 
*Report any clinically important increase in the rate of a serious 
suspected adverse reaction (at your study site) over that which is listed in 
the protocol or investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than 
expected as an expedited event. 
CTCAE Category 
Adverse Event 
CTCAE Grade at which the 
event will not be reported in an 
expedited manner1 
Blood and lymphatic 
system disorders 
Anemia 
 ≤Grade 4 
Investigations 
Platelet count decreased 
  ≤Grade 4 
Neutrophil count decreased 
  ≤Grade 4 
Lymphocyte count decreased 
  ≤Grade 4 
White blood cell decreased 
  ≤Grade 4 
1 These exceptions only apply if the adverse event does not result in 
hospitalization. If the adverse event results in hospitalization, then 
the standard expedited adverse events reporting requirements 
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Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade 
of the event. 
 
The following hospitalizations are not considered to be SAEs because there 
is no “adverse event” (i.e., there is no untoward medical occurrence) 
associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease 
and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery 
replacement) that was in place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of 
progression of the cancer.] 
10.4 
Expedited Reporting Requirements for IND/IDE Agents  
10.41 Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days 
of the Last Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
sponsor within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour  
3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 
7 Calendar Days 

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Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the 
initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. 
Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.31 for exceptions to Expedited Reporting 
10.42 General reporting instructions 
The Mayo IND Coordinator will assist the sponsor-investigator in the 
processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Contact Merck Global Safety facsimile number:  
 
Use Mayo Expedited Event Report form 
 for investigational agents 
or commercial/investigational agents on the same arm.  
Note:  Submit MedWatch form 3500A to Merck & Co., Inc. (Attn: 
and   
Biocompatibles Inc., a BTG International group company at 
   
 10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in 
table10.41 MUST be immediately reported to the sponsor within the 
timeframes detailed in the corresponding table. This reporting includes, 
but is not limited to SAEs that re-occur again after resolution. 
10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others 
(UPIRTSOS) in general, include any incident, experience, or outcome 
that meets all of the following criteria: 

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1. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject 
population being studied; 
2. Related or possibly related to participation in the research (in this 
guidance document, possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk 
of harm (including physical, psychological, economic, or social 
harm) than was previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of 
the physical or psychological harm associated with adverse events. In 
other cases, unanticipated problems place subjects or others at increased 
risk of harm, but no harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is 
not considered an adverse experience for this trial, and if the consent 
form does not indicate that subjects should not get pregnant/impregnate 
others, then any pregnancy in a subject/patient or a male patient’s partner 
(spontaneously reported) which occurs during the study or within 120 
days of completing the study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the Reportable Event coversheet and 
appropriate documentation to 
 
The Mayo Regulatory Affairs Office will review and process the 
submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited 
reporting regardless of causality, unless as noted below. Attribution 
to treatment or other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires expedited 
reporting within 24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during 
the first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE 
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• 
Sudden death NOS: A sudden (defined as instant or within one hour 
of the onset of symptoms) or an unobserved cessation of life that 
cannot be attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts 
and polyps) – Other (Progressive Disease)” under the system 
organ class (SOC) of the same name. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
Per NIH OBA Appendix M, should a patient die during the study or 
study follow-up, no matter what the cause, the study doctor will ask the 
patient’s family for permission to perform an autopsy. If permission is 
granted, a copy of the autopsy report will be sent to the sponsor after all 
identifying information has been removed. An autopsy will help the 
researchers learn more about the safety and efficacy of the treatment. 
Patients should advise their families about their wishes regarding 
autopsy. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE will be reported. Three options are available 
to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). 
Second malignancies require ONLY routine reporting unless otherwise 
specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking 
investigational product becomes pregnant, the subject taking should 
notify the Investigator, and the pregnant female should be advised to call 
her healthcare provider immediately. The patient should have appropriate 
follow-up as deemed necessary by her physician. If the baby is born with 
a birth defect or anomaly, a second expedited report is required. 
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infant, the investigator must obtain consent from the pregnant woman 
and the newborn infant’s parent or legal guardian before any data 
collection can occur. A consent form will need to be submitted to the 
IRB for these subjects if a pregnancy occurs. If informed consent is not 
obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. 
In cases where the child/fetus experiences a serious adverse event other 
than fetal death, the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports 
for “Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy 
agent(s) should be documented in the “Description of Event” section. 
Include any available medical documentation. Include this form: 
 
10.551 Pregnancy 
Pregnancy should be reported in an expedited manner as 
Grade 3 “Pregnancy, puerperium and perinatal conditions 
- Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC. Pregnancy should be followed until 
the outcome is known. 
10.552 Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show 
evidence of respiration, heartbeat, or definite movement of a 
voluntary muscle after expulsion from the uterus, without 
possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and 
perinatal conditions SOC. 
10.553 Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 
days of life” that is felt by the investigator to be at least 
possibly due to the investigational agent/intervention, should 
be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal 
loss)” under the General disorders and administration SOC.  
 
 

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10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse 
events to be graded at each evaluation.  
Grading is per CTCAE v4.0 unless alternate grading is indicated in the 
table below: 
CTCAE  
System/Organ/Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Platelet count decreased
X
X
Neutrophil count decreased 
X 
X 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
Gastrointestinal disorders 
# of stools 
X 
 
Diarrhea 
 
X 
Nausea 
X 
X 
Vomiting 
X 
X 
Respiratory, thoracic and 
mediastinal disorders 
Cough 
X 
X 
Dyspnea 
X 
X 
Pneumonitis 
X 
X 
Skin and subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or 
electronic, as applicable) the following AEs experienced by a patient and 
not specified in Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to 
the study treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study 
treatment or procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to 
the study treatment or procedure. 
10.6232 
Any death more than 30 days after the patient’s last 
study treatment or procedure that is felt to be at least 
possibly treatment related must also be submitted as 
a Grade 5 AE, with a CTCAE type and attribution 
assigned. 
10.7 
Late Occurring Adverse Events 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
 

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10.8 
Merck Additional Event Reporting Instructions 
For the time period beginning when the consent form is signed until treatment 
allocation, 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 
(reference Section 10.10.1 for additional details) that occurs to any subject must 
be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety if it causes the subject to be excluded from the trial, or is the result 
of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, 
or follow up to a serious adverse event, including death due to any cause other 
than progression of the cancer under study (reference Section 10.10.1 for 
additional details), whether or not related to the Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside 
of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
10.81 Definition of an Overdose for This Protocol and Reporting of Overdose 
to the Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined 
as any dose of 1,000 mg or greater (≥5 times the indicated dose). No 
specific information is available on the treatment of overdose of 
pembrolizumab. Appropriate supportive treatment should be provided if 
clinically indicated. In the event of overdose, the subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of 
a Merck product, the adverse event(s) is reported as a serious adverse 
event, even if no other seriousness criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose 
is taken without any associated clinical symptoms or abnormal 
laboratory results, the overdose is reported as a non-serious Event of 
Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be 
reported within 24 hours to the Sponsor and within 2 working days hours 
to Merck Global Safety. 
 
 
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Although pregnancy and lactation are not considered adverse events, it is 
the responsibility of investigators or their designees to report any 
pregnancy or lactation in a subject (spontaneously reported to them), 
including the pregnancy of a male subject's female partner that occurs 
during the trial or within 120 days of completing the trial treatment, or 30 
days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier. All subjects and female partners 
of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be 
reported. 
Such events must be reported within 24 hours to the Sponsor and within 
2 working days to Merck Global Safety. 
 
 
10.83 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as 
Events of Clinical Interest (ECI) and must be reported within 24 hours to 
the Sponsor and within 2 working days to Merck Global Safety. 
 
 
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that 
occurs to any subject must be reported within 24 hours to the Sponsor 
and within 2 working days to Merck Global Safety if it causes the subject 
to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 24 hours to the 
Sponsor and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 10.91 - 
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 

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abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology.  
10.84 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to 
Merck as described in Section 10.1.- Immediate Reporting of Adverse 
Events to the Sponsor and to Merck, unless there is evidence suggesting 
a causal relationship between the drug and the event. Any such event will 
be submitted to the Sponsor within 24 hours and to Merck Global Safety 
within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception 
include any event that is disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events 
and safety data to ensure the safety of the subjects in the trial. Any 
suspected endpoint which upon review is not progression of the cancer 
under study will be forwarded to Merck Global Safety as a SAE within 2 
working days of determination that the event is not progression of the 
cancer under study 
Hospitalization related to convenience (e.g. transportation issues etc.) 
will not be considered a SAE. 
10.85 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.  
10.9 
Biocompatibles Inc., a BTG International group company Additional Event 
Reporting Instructions 
10.91 Product malfunction 
A product malfunction is defined as a failure of the device to meet its 
performance specifications, essential function or otherwise perform as 
intended. Performance specifications include all claims made in the 
labelling for the device. The essential function of a device refers not only 
to the device's labelled use, but for any use widely prescribed within the 
practice of medicine. 
10.92 Reporting of Adverse Events, Serious Adverse Events and Device 
Malfunctions 
The Institution and/or the Sponsor-Investigator shall report all and any 
serious adverse events, product malfunctions or quality complaints 
(regardless of causality) that they become aware of in relation to the 
Product and/or the investigation to BTG.  
All reports will be exchanged in English and Sponsor-Investigator will 
also provide BTG with such information and reasonable assistance as 
may be requested by BTG to allow BTG to comply with their 
obligations.   
The Institution and/or the Sponsor-Investigator shall report all SAEs and 
incidents impacting patient safety to 
(Galil 
product related).  

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10.93 SAEs 
The Sponsor-Investigator will report SAEs within one business day to 
enable BTG to comply with their obligations as the device manufacturer, 
under applicable laws and regulations. 
All reports will contain the following, if available: 
• 
Study title and name of the Sponsor-Investigator.  
• 
Patient number 
• 
Adverse event number 
• 
Date of event occurrence/date notified 
• 
Product details 
o Product name/ part number 
o Size / dose  
o Batch / lot number 
• 
Adverse event details along with comprehensive event   
description  
• 
Action(s) taken to treat or resolve the event 
• 
Outcome 
• 
Investigators opinion of causality of event i.e. related to 
o Drug  
o Device 
o Procedure 
• 
Product returned to BTG/Galil if applicable 
10.94 Device Malfunctions 
The Institution and/or the Sponsor-Investigator shall report all device 
malfunctions and/or quality complaints 
 
(Galil) within one business day of becoming aware of the issue.  
 
 

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11.0 
Treatment Evaluation 
NOTE: For assessment of index (target) and non-target lesions on whole body scan 
performed after completion of DC treatment, the baseline whole body scan will 
be used to assess overall treatment response of index (target) and non-target 
lesions. Include up to 6 index (target) lesions as measurable disease when 
assessing overall clinical response. The treatment lesion(s) is the lesion(s) that is 
cryoablated. This treatment lesion will be measured only at baseline and will 
not be included in assessment of overall clinical response, and will not be 
followed or measured. 
NOTE: Subject(s) with progressive disease on anti-PD-1 monoclonal antibody alone 
prior to receiving cryoablation and intra-tumor injection of autologous DC will 
be continued on treatment to assess clinical response with the addition of these 
therapy as long as the provider and the investigator deemed clinically safe and 
reasonable. 
11.1 
Response Considerations  
Schedule of Evaluations:  PET/CT or whole body CT scans are required at baseline for 
all patients. For the purposes of this study, patients should be reevaluated for disease 
progression at the end of each cycle. In addition to a baseline PET/CT scan, confirmatory 
scans should also be obtained at Day 1 of Cycles 4, 8, 12 and 18 (Section 4).  During 
observation, CT scan should be obtained every 3 months during the first year to evaluate 
for disease progression. 
Definitions for clinical response for patients with lymphoma are from the recently revised 
Cheson’s et al criteria published in 2014 (Cheson, Fisher et al. 2014), derived from the 
original criteria published in 2007 (Cheson 2007). Lymph node measurements should be 
taken from the CT portion of the PET/CT, or other dedicated CT scans where applicable.  
Measurement of lymphadenopathy for purposes of assessing for PR will be determined 
by adding the sum of the products of the maximal perpendicular diameters of measured 
lesions (SPD).  The PPD of a single node is sufficient to evaluate for PD (see Table 11.2).  
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease. For these recommendations, the spleen is considered nodal disease. Disease that 
is only assessable (eg, pleural effusions, bone lesions) will be recorded as present or 
absent only, unless, while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically and pathologically negative. 
Response is based on PET/CT based on the revised 2014 Lugano Classification (Cheson, 
Fisher et al. 2014).  
 
11.2 
Lugano Classification Response criteria (Cheson, Fisher et al. 2014) 
 
PET-CT Based Response 
CT-Based Response 
Complete 
Response 
Complete metabolic response (CMR) 
 
Complete radiologic response 
(CR) 
(all of the following) 
Lymph nodes and 
extralymphatic 
sites   
Score 1, 2, or 3*  with or without a residual mass on 
5PS† 
It is recognized that in Waldeyer’s ring or extranodal 
sites with high physiologic uptake or with activation 
Target nodes/nodal masses 
must regress to ≤1.5 cm in LDi 
No extralymphatic sites of 
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PET-CT Based Response 
CT-Based Response 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake 
Nonmeasured 
lesion 
Not applicable 
Absent 
Organ 
enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
indeterminate, IHC negative 
Partial Response Partial metabolic response (PMR) 
Partial remission (PR) 
(all of the following) 
Lymph nodes and 
extralymphatic 
sites   
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual 
disease 
≥50% decrease in SPD of up to 
6 target measurable nodes and 
extranodal sites 
When a lesion is too small to 
measure on CT, assign 0.5 cm   
X 0.5 cm as the default value 
When no longer visible, 0.0 X 
0.0 cm 
For a node >0.5 cm X 0.5 cm, 
but smaller than normal, use 
actual measurement for 
calculation 
Nonmeasured 
lesions 
Not applicable 
Absent/normal, regressed, but 
no increase 
Organ 
enlargement 
Not applicable 
Spleen must have regressed by 
>50% in length beyond normal 
New lesions 
None 
None 
Bone marrow  
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline (diffuse 
uptake compatible with reactive changes from 
chemotherapy allowed). If there are persistent focal 
changes in the marrow in the context of a nodal 
response, consideration should be given to further 
evaluation with MRI or biopsy or an interval scan 
Not Applicable  
No Response or 
Stable Disease 
No metabolic response (NMR) 
Stable disease (SD) 
Target 
nodes/nodal 
masses, 
extranodal lesions 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of treatment 
<50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met 
Nonmeasured 
Not applicable 
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PET-CT Based Response 
CT-Based Response 
lesions 
progression  
Organ 
enlargement 
Not applicable 
No increase consistent with 
progression  
New lesions 
None 
None 
Bone marrow  
No change from baseline 
Not Applicable 
Progressive 
disease 
Progressive metabolic disease (PMD) 
Progressive disease (PD) 
requires at least 1 of the 
following 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
PPD progression: 
 
An individual node/lesion must 
be abnormal with:  
LDi >1.5 cm and 
Increase by ≥50% from PPD 
nadir and 
An increase in LDi or SDi 
from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, 
the splenic length must 
increase by >50% of the extent 
of its prior increase beyond 
baseline (eg, a 15-cm spleen 
must increase to 
>16 cm). If no prior 
splenomegaly, must increase 
by at least 2 cm from baseline 
New or recurrent splenomegaly 
Extranodal 
lesions 
Nonmeasured 
lesions 
None 
New or clear progression of 
preexisting nonmeasured 
lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (eg, infection, inflammation). 
If uncertain regarding etiology of new lesions, biopsy 
or interval scan may be considered 
Regrowth of previously 
resolved lesions 
A new node >1.5 cm in any 
axis 
A new extranodal site >1.0 cm 
in any axis; if <1.0 cm in any 
axis, its presence must be 
unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, 
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for 

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PET-CT Based Response 
CT-Based Response 
multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant 
lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those 
in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow  quantitatively with  measurement, including pleural 
effusions,  ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed  and followed  by imaging. In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, 
bone marrow), FDG uptake may be greater than in the mediastinum with  complete metabolic response, 
but  should be no higher than surrounding normal physiologic uptake (eg, with  marrow  activation as a 
result  of  chemotherapy or myeloid growth factors). 
†PET Deauville 5PS: 1, no uptake above background; 2, uptake≤mediastinum; 3, uptake > mediastinum 
but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, 
new areas of uptake unlikely to be related to lymphoma. 
Note: Transformation to a more aggressive histology that requires a change in active treatment will be 
considered progressive disease. 
 
11.21 Complete Response (CR).  
The designation of CR requires all of the following: 
11.211 Complete disappearance of all detectable clinical evidence of disease and 
definitely disease-related symptoms if present before therapy. 
11.212 All lymph nodes and nodal masses must have regressed on CT to normal 
size (≤1.5 cm in their greatest transverse diameter for nodes >1.5 cm 
before therapy). Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment 
must have decreased to ≤1.0 cm in their short axis after treatment. 
 
11.213 The spleen and/or liver, if considered enlarged before therapy on the 
basis of a physical examination or CT scan, should not be palpable on 
physical examination and should be considered normal size by imaging 
studies, and nodules related to lymphoma should disappear. However, 
determination of splenic involvement is not always reliable because a 
spleen considered normal in size may still contain lymphoma, whereas 
an enlarged spleen may reflect variations in anatomy, blood volume, the 
use of hematopoietic growth factors, or causes other than lymphoma. 
Similarly, other organs considered to be enlarged before therapy due to 
involvement by lymphoma, such as liver and kidneys, must have 
decreased in size. 
 
 

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11.214 If the bone marrow was involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy 
sample on which this determination is made must be adequate (with a 
goal of >20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample 
that is negative by immunohistochemistry but that demonstrates a small 
population of clonal lymphocytes by flow cytometry will be considered a 
CR until data become available demonstrating a clear difference in 
patient outcome. 
11.22 Criteria for Partial Response (PR) 
The designation of PR requires all of the following: 
11.221 
At least a 50% decrease in sum of the product of the diameters (SPD) 
of up to six of the largest dominant nodes or nodal masses. These 
nodes or masses should be selected according to all of the following: 
• 
they should be clearly measurable in at least 2 perpendicular 
dimensions 
• 
if possible they should be from disparate regions of the body 
• 
they should include mediastinal and retroperitoneal areas of disease 
whenever these sites are involved 
11.222 
No increase should be observed in the size of other nodes, liver, or 
spleen. 
11.223 
Splenic and hepatic nodules must regress by ≥50% in their SPD or, for 
single nodules, in the greatest transverse diameter. 
11.224 
With the exception of splenic and hepatic nodules, involvement of 
other organs is usually assessable and no measurable disease should be 
present. 
11.225 
Bone marrow assessment is irrelevant for determination of a PR if the 
sample was positive before treatment. However, if positive, the cell 
type should be specified (eg, large-cell lymphoma or small neoplastic 
B cells). Patients who achieve a CR by the above criteria, but who have 
persistent morphologic bone marrow involvement will be considered 
partial responders. 
When the bone marrow was involved before therapy and a clinical CR 
was achieved, but with no bone marrow assessment after treatment, 
patients should be considered partial responders. 
11.226 
No new sites of disease should be observed. 
11.227 
CT criteria should be used. 
 
11.23 Criteria for Stable Disease (STAB) 
11.231 
A patient is considered to have SD when he or she fails to attain the 
criteria needed for a CR or PR (see above), but does not fulfill those 
for progressive disease (see below). 
11.232 
There must be no change in the size of the previous lesions on the post- 
treatment CT scan. 

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11.24 Relapsed Disease (after CR)/Progressive Disease (after PR, SD) 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1.0. Lymph 
nodes ≤1.0 x ≤1.0 cm will not be considered as abnormal for relapse or 
progressive disease. 
11.241 
Appearance of any new lesion more than 1.5 cm in any axis during or 
at the end of therapy, even if other lesions are decreasing in size. 
Increased FDG uptake in a previously unaffected site should only be 
considered relapsed or progressive disease after confirmation with 
other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. 
Thus, a therapeutic decision should not be made solely on the basis of 
the PET without histologic confirmation. 
11.242 
At least a 50% increase from nadir in the SPD of any previously 
involved nodes, or in a single involved node, or the size of other 
lesions (eg, splenic or hepatic nodules). To be considered progressive 
disease, a lymph node with a diameter of the short axis of less than 1.0 
cm must increase by 50% and to a size of 1.5 x 1.5 cm or more than 1.5 
cm in the long axis. 
11.243 
At least a 50% increase in the longest diameter of any single previously 
identified node more than 1 cm in its short axis. 
11.244 
Transformation to a more aggressive histology that requires a change 
in active treatment will be considered progressive disease. 
11.3 
Other Response Criteria:  
11.31 Cutaneous Response Criteria:  
Lesions will be measured by physical exam and photographed to evaluate for 
response. Photographs of the skin lesions, marked with a ruler, will be 
saved/uploaded in QREADS for comparison purposes.    
If all target lesions are cutaneous, then the following modified Lugano criteria 
will be utilized. However, if at least one target lesion is not cutaneous, then the 
cutaneous measurements will be grouped with the target nodal/extranodal lesions 
when calculating the SPD and the response criteria per section 11.2 will be 
utilized with reference to the table below for cutaneous definitions whenever 
applicable.  
Modified Lugano Criteria for Cutaneous Lesions 
Response 
Definition 
Complete response 
100% clearance of all skin lesions   
Partial response 
≥50% decrease in SPD of up to 6 target 
measurable cutaneous lesions and not meeting 
Complete response definition  
 
Stable disease 
<50% decrease from baseline in SPD of up to 
6 target measurable cutaneous lesions; no 
criteria for progressive disease are met 

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Modified Lugano Criteria for Cutaneous Lesions 
Response 
Definition 
Progressive disease 
≥50% increase from nadir in SPD of up to 6 
target measurable cutaneous lesions; 
 
New cutaneous lesions 
 
 
11.4  
Patient Reported Outcomes: Quality of Life 
11.41  Patients will complete quality of life assessments at times documented in 
Section 4. The assessments will allow the patients to evaluate themselves 
regarding quality of life, concerns and symptoms.  Patient reported outcome 
results do not impact any treatment related decisions. 
11.42  Patients will complete the Functional Assessment of Cancer Therapy – 
Lymphoma (FACT-Lym). This assessment consists of the FACT-General 
(FACT-G) and the 15-item Lymphoma specific subscale. 
The Functional Assessment of Cancer Therapy – General (FACT-G) was 
developed to measure quality of life in cancer patients receiving therapy.  It was 
initially validated using classical test theory (CTT) methodology in a 
heterogeneous sample of 545 patients with cancer, 8% of whom had either 
leukemia or lymphoma.  The FACT-G is comprised of four subscales: physical 
well-being (PWB; 7-items, score range 0-28), social/family well-being (SWB; 7-
items, score range 0-28), emotional well-being (EWB; 6-items, score range 0-
24), and functional well-being (FWB; 7-items, score range 0-28).  Users of the 
FACT-G are able to generate an overall score and four subscale scores with 
ranges and distributions that are sample-specific.  All questions in the FACT-G 
use a 5-point rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite 
a bit; and 4 = Very much).  Provided more than 50% of the items comprising a 
subscale are answered, a subscale score is computed as the prorated sum of the 
item responses for that subscale.  Prorating, which replaces missing values with 
the mean of the completed items for that subscale, has been shown to be an 
acceptable method of imputing missing data in the FACT instruments when more 
than 50% of the items are answered.  The FACT-G total score is computed as the 
sum of the four subscale scores, provided the overall item response is at least 
80% (i.e., at least 22 of the 27 items were answered) and has a possible range of 
0-108 points.  Negatively worded items are reverse scored prior to summing so 
that higher subscale and total scores indicate better Quality of Life (Cella, Tulsky 
et al. 1993). 
The FACT-Lym adds a lymphoma-specific subscale to the FACT-G.  The 
content in the lymphoma subscale (e.g., “I have night sweats” and “I am bothered 
by itching”) is targeted towards patients on active treatment (Hlubocky, Webster 
et al. 2013). 
 
 

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12.0 
Descriptive Factors  
12.1 
Number of prior treatment regimens (any): 0, 1, 2 >3.  
12.2 
Current disease status: Newly diagnosed vs. residual vs. relapsed vs. refractory. 
12.3 
Previous Auto SCT: Yes vs. no. 
12.4 
Ann Arbor stage: 1 vs.  2 vs.  3 vs. 4 (see Appendix VII). 
12.5 
International Prognostic Index (IPI) (Shipp, 1993): low risk (0 or 1 risk factors) vs. low 
intermediate risk (2 risk factors) vs. high intermediate risk (3 risk factors) vs. high risk (4 
or 5 risk factors) (see Appendix VII). 
12.6 
Follicular Lymphoma International Prognostic Index (FLIPI) (Solal-Celigny, 2004): low 
risk (0 or 1 risk factor) vs. intermediate risk (2 risk factors) vs. high risk (3-5 risk factors) 
(see Appendix VII). 
12.7  
MCL International Prognostic Index (MIPI) (Hoster, 2008): 0-3 vs 4-5 vs 6-11 (see 
Appendix VII). 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
Note:  For additional information regarding follow-up decision, please refer to the patient 
treatment schematic (Patient Map), located with the CRFs and supplementary materials. 
13.1 
Patients who go off protocol at any time to receive non-protocol alternate treatment will 
go to event monitoring (see Section 4.4). 
13.2 
Patients who are CR, PR, or SD not requiring non-protocol alternative treatment will 
continue on initial active treatment per protocol for 18 cycles (12 months). 
Once treatment is completed patients may receive an additional year of optional 
pembrolizumab treatment (provided approval from PI and sponsor).   
• 
If no pembrolizumab treatment will be given, patients will go to Treatment 
Observation (see Sections 4.5 and 13.2) if additional DC is available for 
retreatment or Observation (see Section 4.3) if no additional DC is available for 
retreatment. 
• 
If pembrolizumab treatment will be given, patients will receive treatment for up 
to an additional 18 cycles (12 months) then proceed to  
o 
Treatment Observation (see Sections 4.5 and 13.2), if additional DC is 
available for retreatment.  
o 
Observation (see Section 4.3) if additional DC s not available for 
retreatment. 
13.3 
Treatment Observation 
13.31 If the patient has achieved CR, PR, or SD in initial treatment or optional 
pembrolizumab cycles,  not requiring non-protocol alternative treatment, the 
patient will be observed at the following time points: 8 weeks after the last dose 
of treatment and then every 3 months for 1 year; followed by monitoring every 4 
months for a year, then every 6 months until 4 years post registration. 
During Treatment Observation , the patient may be retreated at any time 

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following PD (see Section 13.8).   
13.4 
Patients who complete Treatment Observation without PD will have completed the study 
4 years post registration. 
13.5 
Patients who develop PD during initial active treatment in the DC + Pembrolizumab 
cycles, will go to the event-monitoring phase(see Section 4.4).  
13.6 
Patients who develop PD during initial active treatment receiving only Pembrolizumab 
(cycles 6+ on dose level 1 or cycles 8+ on dose level -1) will go to observation  (see 
Section 4.4) or retreatment per clinical judgment. 
13.7 
Patients who develop PD during the optional Pembrolizumab treatment will: 
• 
Go to retreatment if DC is available  
• 
Go to observation (see Section 4.3) if DC unavailable or if the patient refuses 
further treatment or if the clinician determines retreatment isn’t feasible. 
13.8 
Patients who develop PD during the observation phase with no DC available for 
retreatment, will go to event monitoring (see Section 4.4).   
13.9a 
Patients who develop PD during the treatment observation phase who have DC available 
will:  
• 
Go to retreatment (see Section 13.9d).  
• 
Complete treatment observation (see Section 4.5) if patient refuses further 
treatment or if clinician determines retreatment isn’t feasible. 
13.9b Patients who go off protocol treatment due to adverse events or DLT during initial 
treatment will go to observation (see Section 4.3).  If PD occurs in observation, patients 
will go to event monitoring (see Section 4.4). 
13.9c 
Patients who go off protocol treatment for reasons other than adverse events during initial 
treatment will go to the event-monitoring phase (see Section 4.4). 
13.9d Retreatment 
Retreatment can be considered at any time when deemed clinically safe. 
 
• 
DC created from the original leukopheresis must be available 
• 
Tumor lesion(s) must be amenable to cryoablation. 
13.9e 
Patient who complete retreatment without PD will go to observation followed by event 
monitoring.  Patients who complete retreatment having PD will go to event monitoring. 
13.9f 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable). 
● 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 
4.4 of the protocol. 
● 
If the patient never received treatment, on-study material must be submitted and 
the patient will go off study.   

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13.9g Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable. All data up until the point of confirmation of a major violation must be 
submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered. Event monitoring 
will be required per Section 4.4 of the protocol. 
13.9h Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 

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14.0 
Body Fluid Biospecimens 
14.1 
Summary Table of Research Blood/Blood Products to Be Collected for This Protocol 
Collect and process all blood/blood products according to instructions and table below. For immunological monitoring Panels1, 2, 
3 and 4 will be collected. 
14.11 Collection During Treatment 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or Body 
Fluid being 
Collected 
Component being 
harvested 
Type of 
Collection 
Tube (color of 
tube top) 
Volume to collect 
per tube (# of tubes 
to be collected) 
Day 1 of 
designate
d cycles1, 2 
Process at 
site? (Yes 
or No) 
Temperature 
Conditions for 
Storage/ 
Shipping3 
Immune 
Monitoring Panel 
1 (14.3) 
Mandatory 
Whole Blood 
Plasma, Cells for 
DNA/RNA,Protein, 
and immunologic 
assays 
EDTA 
(purple) 
6 mL (1) 
10 mL (2) 
X 
No 
Room 
temperature 
Immune 
Monitoring Panel 
2 (14.3) 
Mandatory 
Whole Blood 
Plasma, Cells for 
DNA/RNA, Protein, 
and immunologic 
assays 
Heparin 
(green) 
10 mL (4) 
6 mL (1) 
X 
No 
Room 
temperature 
Immune 
Monitoring Panel 
3 (14.3) 
Mandatory 
Whole Blood DNA/RNA/Protein 
assays 
Streck Cell 
Free DNA 
BCT 
10 mL (1) 
X 
No 
Room 
temperature 
Immune 
Monitoring Panel 
4 (14.2) 
Mandatory 
Whole Blood 
serum 
Serum 
Separator Tube 
(red tiger) 
10 mL (1) 
X 
No 
Room 
temperature 
1. Cycle 1 order: blood for immune monitoring, leukapheresis, and MK-3475 administration. Order after Cycle 1: blood for immune 
monitoring, Pembrolizumab. 
2. Phase I dose level 1: Cycles 1, 2, 4, 6, 8, 12, 18. Phase I dose level -1: Cycles 1, 2, 4, 8, 12, 18. Phase IIwill follow the schedule of 
phase I dose level 1. 
3. All specimens should be sent to Ailing Xue, Human Cell Therapy Lab, Mayo Clinic, 200 First Street SW – Stabile 3, Rochester, 
MN 55905. 
 

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14.12 Blood Collection During Observation 
Correlative 
Study (Section 
for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Component 
being 
harvested 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Documented PD 
requiring active 
treatment at any 
time during 
treatment or 
observation, 
prior to entering 
event 
monitoring, at 
End of 
Observation 
Day 1 of 
Cycles 19-
22 
Every 
3 months 
for 1 year 
(start at 
8 weeks 
after last 
dose) 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping1 
Immune 
Monitoring 
Panel 1 (14.2) 
Mandatory Whole Blood 
Plasma Cells 
for 
DNA/RNA, 
Protein, and 
immunologic 
assays 
EDTA 
(purple) 
6 mL (1) 
10 mL (2) 
X 
X 
No 
Room 
temperature 
Immune 
Monitoring 
Panel 2 (14.2) 
Mandatory Whole Blood 
Plasma Cells 
for 
DNA/RNA, 
Protein, and 
immunologic 
assays 
Heparin 
(green) 
10 mL (4) 
6 mL (1) 
X 
X 
No 
Room 
temperature 
Immune 
Monitoring Panel 
3 (14.3) 
Mandatory Whole Blood DNA/RNA/P
rotein assays 
Streck Cell 
Free DNA 
BCT 
10 mL (1) 
X 
X 
No 
Room 
temperature 
Immune 
Monitoring Panel 
4 (14.2) 
Mandatory Whole Blood 
serum 
Serum 
Separator 
Tube 
10 mL (1) 
X 
X 
No 
Room 
temperature 
1. All specimens should be sent to Ailing Xue, Human Cell Therapy Lab, Mayo Clinic, 200 First Street SW – Stabile 3, 
Rochester, MN 55905 

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14.2 
Background/Methodology  
14.21 In vitro functional studies 
In all cases, we will select CD3+ cells from the remainder of the cells found in 
the leukapheresis. These and T cells collected from subsequent time points can 
be in assessment of T cell functions including proliferation, cytokine production, 
response to Prevnar and DC stimulation and T cell receptor gene sequencing. In 
addition, we will keep samples of mDC from each patient and use these cells to 
stimulate peripheral blood collected as per the test schedule and assay for anti-
tumor response via proliferation, ELIspot, or intracellular cytokine expression. A 
change above two times baseline control or more than 30% from assay prior to 
treatment will be considered significant response.  
14.22 Immune phenotyping 
We will immune phenotype blood for circulating Tregs, central memory and 
effector memory T cells, quantitative T, B, and NK cell panel, dendritic cells and 
immune suppressor cells (CD14+DRneg) and other immune modulating cells per 
our prior experience. PD-1, PD-L1 and PD-L2 expression on leukocyte subset 
will be analyzed. We will also collect and store plasma, serum and may collect 
white blood cells for future protein, RNA or DNA analysis. In particular, based 
on our preclinical studies, for patients with abnormally high percentage of 
CD14+HLA-DRlow/neg monocytes prior to treatment, a change greater than 
10% in the percentage of these cells after treatment would be considered a 
statistically significant change. 
 
 
 

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15.0 
Drug Information 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high 
affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation 
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial.  
15.13 Preparation and storage:  
Vials should be stored in the refrigerator at temperatures between 2-8°C.   
Drug concentrate is further diluted with normal saline (or 5% dextrose) in the 
concentration range of 1 to 10 mg/mL. The infusion solution in the IV bag should 
be immediately administered.  Diluted pembrolizumab solutions may be stored at 
room temperature for a cumulative period of up to 6 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration of 
infusion.  The product can also be stored under refrigeration at 2°C to 8°C for no 
more than 96 hours from the time of dilution. If refrigerated, the diluted solution 
must be allowed to come to room temperature prior to administration. The 
solution must be discarded after 6 hours at room temperature or 96 hours under 
refrigeration.    
15.14 Administration 
Pembrolizumab is administered by intravenous infusion over 30 minutes via a 
0.22 micron in-line filter. The final infusion volume must be between 1 and 10 
mg/mL. Maximum rate of infusion should not exceed 6.7 mL/minute through a 
peripheral or indwelling catheter. Flush the line with 0.9% NaCL following the 
completion of the infusion. 
15.15 Pharmacokinetic information: 
a)  Absorption – Because pembrolizumab is administered intravenously, it 
is immediately and completely bioavailable.  Steady-state concentrations 
of pembrolizumab are reached by 16 weeks of repeated dosing with a 
Q3W regimen and the systemic accumulation is 2.1-fold.  The peak 
concentration, trough concentration, and area under the plasma 
concentration versus time curve at steady state of pembrolizumab 
increased dose proportionally in the dose range of 2 to 10 mg/kg Q3W. 
b)  Distribution – Pembrolizumab has a limited volume of distribution.  
c)  Excretion – CL is approximately 23% lower after achieving maximal 
change at steady state compared with the first dose. The terminal 
elimination half-life (t½) is estimated to be 22 days at steady state. 
d)  Metabolism - Pembrolizumab is catabolized through non-specific 
pathways; metabolism does not contribute to its CL. 
 

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15.16 Potential Drug Interactions 
There are no known significant drug interactions.  
15.17 Known potential toxicities 
Very common known potential toxicities, ≥10%: 
Gastrointestinal disorders: diarrhea, nausea, abdominal pain 
Skin and subcutaneous tissue disorders: rash, pruritis 
General disorders and administration site conditions: fatigue 
Common known potential toxicities, ≥1% to <10%: 
Blood and lymphatic system disorders: anemia 
Immune system disorders: infusion related reaction 
Endocrine disorders: hyperthyroidism, hypothyroidism 
Metabolism and nutrition disorders: decreased appetite 
Nervous system disorders: headache, dizziness, dysgeusia 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, cough 
Gastrointestinal disorders: colitis, vomiting,  constipation, dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions,  
vitiligo, dry skin, erythema 
Musculoskeletal and connective tissue disorders: arthralgia, myositis, 
musculoskeletal pain, arthritis, pain in extremity 
General disorders and administration site conditions: asthenia,  
edema, pyrexia, influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate  
aminotransferase increased, blood alkaline phosphatase increased, blood 
creatinine increased 
 
Uncommon known potential toxicities, ≥0.1% to <1%: 
Infusion related reactions 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Endocrine disorders: hypophysitis, adrenal insufficiency, hyponatremia, 
Thyroiditis, hypopituitarism 
Metabolism and nutrition disorders: type I diabetes mellitus,  
hyponatremia, hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia, confusional state 
Nervous system disorders: epilepsy, lethargy, peripheral neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis, atrial fibrillation 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis, dysphagia 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, alopecia, 
dermatitis, dermatitis acneiform, eczema, hair color changes, papule 
Musculoskeletal and connective tissue disorders: tenosynovitis, myelitis 
Renal and urinary disorders: nephritis, acute kidney injury 
Investigations: blood bilirubin increased, amylase increased, hypercalcemia 
Respiratory: pneumonia aspiration 
 
Rare known potential toxicities, <0.1% (Limited to important or life-threatening): 

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Blood and lymphatic system disorders: immune thrombocytopenic purpura, 
hemolytic anemia 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome, 
exacerbation of myasthenia gravis 
Gastrointestinal disorders: small intestinal perforation 
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema nodosum 
The risk profile for pembrolizumab also includes two important potential risks: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and veno-occlusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors.  
Patients with multiple myeloma who were treated with pembrolizumab in 
combination with either pomalidomide or lenalidomide and dexamethasone, had 
an increased number of serious side effects and deaths as compared to patients 
who received only dexamethasone and either pomalidomide or lenalidomide. The 
benefit-risk profile is unfavorable for the combination of pembrolizumab, 
pomalidomide, and dexamethasone in relapsed refractory multiple myeloma, and 
the combination of pembrolizumab, lenalidomide, and dexamethasone in newly 
diagnosed treatment-naive multiple myeloma. 
 
Post marketing reports identified Vogt-Koyanagi-Harada syndrome and 
hemophagocytic lymphohistiocytosis. 
15.18 Drug procurement 
Pembrolizumab will be provided free of charge to study participants by Merck. 
15.19 Nursing guidelines 
15.191 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.192 
Diarrhea can be seen however is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 9.0 and monitor for effectiveness.  
15.194 
Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 

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15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well”. Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD.  
15.197 
Patients who are started on steroid therapy for any side effects of 
pembrolizimab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper.  
15.198 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199 
Patients should avoid receiving live DC within 30 days of study drug 
administration or per other study guidelines.  
15.200     Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and venoocclusive disease, if they have previously been treated with 
pembrolizumab 
15.201     Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
15.202     Autoimmune hematologic disorders including ITP and hemolytic 
anemia  have been reported. Monitor blood counts closely and report 
any abnormalities to the study team. 
15.203 
Rare neurologic disorders including Guillian-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, parasthesias or numbness, 
tingling to the study team immediately. 
15.2 
Dendritic Cells 
15.21 
Background: The DC used in this study is patient’s autologous dendritic cells 
(DC). Dendritic cells are cells manufactured in lab from monocytes removed 
from patients’ blood by leukapheresis. The dendritic cells need to acquire 
tumor antigens in order to stimulate anti-tumor immunity. Patients will be 
treated with DC placed into a tumor killed using cryoablation where tumor 

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antigen exposure will occur in vivo.  
15.22. 
Formulation: DC is supplied as recently thawed cells prepared from patient 
material. Cells are manufactured and released by the Human Cellular Therapy 
Lab, Mayo Clinic Rochester. Before released for use, cells will undergo testing 
for sterility and potency. 
15.23 
Preparation and storage: DC will be prepared and stored at the Human Cellular 
Therapy Lab, Mayo Clinic Rochester according to approved SOPs included in 
the IND. The drug will be supplied to the appropriate administration area by 
personnel from the Human Cell Therapy Lab. 
15.24 
Administration: Each patient will undergo percutaneous cryoablation of the 
lymphoma tumor lesion to a cryoablated size of less than or equal to 2 cm in 
diameter equal to 50 – 75% of the index lymphoma lesion. Incomplete treatment 
of the index lymphoma tumor lesion will significantly minimize risk of thermal 
injury to adjacent structures, yet result in desired cytotoxic cell injury. Our 
general cryoablation technique has been previously described (Atwell, Farrell et 
al. 2008). Patients will be treated at on the 3W CT scanner. Due to the extended 
length of the procedure, requiring the patient to lie still (expected duration 45 
minutes), sedation will be managed by the Department of Anesthesia. Using 
ultrasound guidance, a cryoprobe will be placed in the index lymphoma node. 
The node will be treated using a conventional freeze-thaw-freeze cycle with each 
freeze stage lasting 10 minutes or until the iceball reaches within 3mm of the 
outer node margin (as determined by CT monitoring at 2 minute intervals). 
Following the freezing procedure, the cryoprobe will be actively warmed and 
then withdrawn. After the node has thawed, a 22 G needle will be placed under 
ultrasound-guidance into the ablated portion of the node. The DC will be 
administered through this needle in 10 – 15 divided injections over different 
areas of the cryoablated region and then flushed with 1 ml of sterile saline. 
15.25 
Pharmacokinetic information: NOTE: this drug is a biologic made up of cells 
from the patient. Classical drug pharmokinetics do not apply. 
15.26 
Potential Drug Interactions: Unknown. 
15.27 
Known potential toxicities: Unknown. 
15.28 
Drug procurement: Drug is manufactured on site in the 
 
 
15.3 
Pneumococcal 13-valent Conjugate Vaccine (Prevnar13) 
15.31  Background: Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 
Protein), is a sterile solution of saccharides of the capsular antigens of 
Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 
19F and 23F individually linked to non-toxic diphtheria CRM197 protein. Each 
serotype is grown in soy peptone broth. 
Potency of the formulated vaccine is determined by quantification of each of the 
saccharide antigens, and by the saccharide to protein ratios in the individual 
glycoconjugates. 
15.32  Formulation: Supplied as ready-to-use prefilled syringes (10 x 0.5-mL prefilled 
syringes per package). Pneumococcal 13-valent Conjugate Vaccine is 
manufactured as a liquid preparation for intramuscular injection. Each 0.5 mL 

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dose of the vaccine is formulated to contain approximately 2.2 μg of each of 
Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 
23F saccharides, 4.4 μg of 6B saccharides, 34 μg CRM197 carrier protein, 100 μg 
polysorbate 80, 295 μg succinate buffer and 125 μg aluminum as aluminum 
phosphate adjuvant. 
15.33  Preparation and storage: Pneumococcal 13-valent Conjugate Vaccine is stored at 
refrigerated temperatures of 2ºC to 8ºC (36ºF to 46ºF) away from freezer 
compartment. DO NOT FREEZE. Discard if frozen. 
15.34 Administration: Shake vigorously immediately prior to use to obtain a uniform 
suspension in the vaccine container. The vaccine should not be used if it cannot 
be resuspended. After shaking, the vaccine is a homogeneous, white suspension. 
Do not mix the vaccine with other products in the same syringe. 
The dose is 0.5 mL to be given intramuscularly. Do not inject intravenously, 
intradermally or subcutaneously. The vaccine should not be injected in the 
gluteal area or areas where there may be a major nerve trunk and/or blood vessel. 
Before injection, the skin at the injection site should be cleansed and prepared 
with a suitable germicide. After insertion of the needle, aspirate and wait to see if 
any blood appears in the syringe, which will help avoid inadvertent injection into 
a blood vessel. If blood appears, withdraw the needle and prepare for a new 
injection at another site. 
15.35 Potential Drug Interactions: Patients receiving therapy with immunosuppressive 
agents (large amounts of corticosteroids, antimetabolites, alkylating agents, 
cytotoxic agents) may not respond optimally to active immunization. 
As with other intramuscular injections, Pneumococcal 13-valent Conjugate 
Vaccine should be given with caution to patients on anticoagulant therapy. 
See complete prescribing information for information regarding co- 
administration of Pneumococcal 13-valent Conjugate Vaccine with other 
vaccines. 
15.36 Known potential toxicities: There is no safety data available in the adult patient 
population. Please see Prevnar13® prescribing information for comprehensive 
toxicity data. 
The following systemic events were noted within 2-3 days of the Pneumococcal 
13-valent Conjugate Vaccine injection in pediatric patients: fever, irritability, 
drowsiness, restless sleep, decreased appetite, vomiting, diarrhea, and urticaria-
like rash. The following local reactions occurred within 3 days of immunization 
pediatric patients: erythema, induration, tenderness and interference with limb 
movement. 
15.37 Drug procurement: Prevnar13 will be purchased with study funds and provided 
free of charge to patients. 
15.38 Nursing Guidelines: 
15.381 Monitor for injection site reaction. Local reaction is usually seen within 3 
days of vaccination, including erythema, induration and tenderness. Treat 
symptomatically and monitor for signs on infection. 
15.382 Patients may experience mild fever. Acetaminophen can be used 
symptomatically. Monitor for effectiveness. 

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15.383 Patients may experience “flu-like” symptoms (fever, irritability, 
decreased appetite, vomiting and diarrhea). Treat symptomatically. 
 
 

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16.0 
Statistical Considerations and Methodology 
16.1 
Overview:  
This is a phase I/II study of dendritic cell therapy and Pembrolizumab for patients with 
non-Hodgkin Lymphoma. The Phase I portion utilizes a 3+3 design with dose de-
escalation only to identify the MTD of this treatment regimen. In this study, MTD means 
the maximum tolerated dose level/schedule. The Phase II portion is designed as an open-
label study of patients having non-Hodgkin lymphoma. 
16.11 Primary Endpoint:  
The primary endpoint of the phase I portion of this trial is to assess DLT to 
determine the maximum tolerated dose level/schedule (MTD). For the phase II 
portion of this trial the pembrolizumab primary endpoint is the clinical response 
of combination therapy with pembrolizumab, cryoablation and intra-tumor 
injection of autologous DC at MTD dose schedule. 
A success will be defined as a confirmed response: PR or CR. Throughout 
Section 16.0, PR or CR will be considered synonymous with “success” in the 
phase II portion, unless specified otherwise.  
16.12  Sample Size 
The phase I portion of this study is expected to require a minimum of 3 and a 
maximum of 12 evaluable patients. The 3 or 6 patients treated at the MTD in the 
phase I portion will also be included in the phase II portion.  
A maximum of 28 additional evaluable patients will be accrued at the MTD dose 
level for a maximum of 34 evaluable patients in the phase II portion of this study. 
We anticipate accruing up to 4 additional patients (1 phase I, 3 phase II) to 
account for ineligibility, cancellation, major treatment violation, or other reasons. 
Therefore, a maximum of 13 patients will be accrued in the phase I portion and a 
maximum of 31 patients will be accrued to the phase II portion for an overall 
maximum of 44 patients for the entire study.  
16.13  Accrual Rate and Study Duration 
The anticipated accrual rate is approximately 1-3 patients per month. Therefore, 
the accrual period for Phase I of this trial is expected to be approximately 
12 months and for phase II to be approximately 22 months. If for any reason 
accrual fails to meet our expectations, we will pursue efforts to open this study at 
Mayo Clinic Scottsdale, AZ site. The maximum total study duration is expected 
to be approximately 4 years, or until the last patient accrued has been observed 
for at least 12 months. 
16.2 
Phase I Portion 
16.21  Study Design 
The phase I study is designed to determine MTD and toxicity profile of dendritic 
cell therapy and pembrolizumab for patients with non-Hodgkin lymphoma using 
a 3+3 design with dose de-escalation only. Three patients will be treated at dose 
level 1 and observed for a minimum of six weeks (i.e. two full cycles and 
completion of Cycle 2 with pembrolizumab, cryoablation, and intra-tumor DC 
injection) before new patients are treated. Doses will not be escalated in any 
individual patient.  

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16.22  MTD Definition 
MTD is defined as the dose level that does not induce DLT in at least one-third 
of patients (1 of 3 or 2 of 6 patients). A total of 6 patients treated at the MTD will 
be sufficient to identify common toxicities at the MTD. For instance, those 
toxicities with an incidence of at least 25% will be observed with a probability of 
at least 82% (1-(1-0.25)6). Refer to Section 7.61 for definition of DLT.  
16.23  MTD Determination 
The phase I portion of this study will follow dose levels and schedules as 
assigned in Section 7. The first cohort of three patients will be treated at dose 
level 1 and observed for 1 cycle of combination of Pembrolizumab, cryoablation, 
and intra-tumor DC injection (completion of Cycle 2) to assess toxicity. 
Decisions on when and how to dose de-escalate are described below. 
16.231  If DLT (see Section 7.6) is not observed in any of the 3 patients, dose 
level 1 will be considered the MTD. 
16.232 If DLT is observed in 1 of 3 patients treated at dose level 1, 3 additional 
patients will be enrolled and treated at the same dose level and 
evaluated after 1 cycle of combination therapy to assess toxicity.  
If no additional DLT is observed, then dose level 1 will be considered 
the MTD. 
If at least one additional DLT is observed in the new cohort of patients 
treated at dose level 1, then the next 3 patients will be treated at dose 
level -1. 
i) If DLT is not observed in any of the 3 patients treated at dose level  
-1, then dose level -1 will be considered the MTD. 
ii)  If DLT is observed in 1 of 3 patients treated at dose level -1, then 
3 additional patients will be treated at this dose level. If no 
additional DLT is observed in the new cohort of patients treated at 
dose level -1, then dose level -1 will be considered the MTD.  
iii) If DLTs are observed in 2 or more of the 6 patients treated at dose 
level -1, then MTD will have been exceeded. 
16.233  If DLT is observed in more than one of the 3 patients treated at dose 
level 1, then the next 3 patients will be treated at dose level -1. Decision 
rules for the 3 patients treated at dose schedule 2 follow 16.232 i) – iii) 
as described above.   
16.234  If a patient fails to complete the first cycle of treatment for reasons other 
than toxicity, the patient will be regarded as inevaluable and will be 
replaced.  
16.24 Analysis Plans 
All the relevant results pertaining to toxicity, MTD, response, timed endpoints 
and laboratory correlates will be examined in an exploratory and hypothesis-
generating fashion. The small sample size and the heterogeneous patient 
population associated with phase I studies restricts the generalizability of the 
results. Any notable statistical result should only be viewed as preliminary 
evidence for the Phase II component rather than a definitive finding in and of 
itself. 

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16.241  Adverse Events / Toxicity Profile (Goal 2.1.11)  
The primary endpoint of the phase I portion is the incidence of dose-
limiting toxicity. A dose-limiting toxicity is defined in section 7.61. 
Toxicities will be assessed using the CTEP Active Version of the 
CTCAE. Non-hematologic toxicities will be evaluated via the ordinal 
CTC standard toxicity grading. Hematologic toxicity measures of 
thrombocytopenia, neutropenia, and leukopenia will be assessed using 
continuous variables as the outcome measures (primarily nadir) as well 
as categorization via CTC standard toxicity grading.  
These data will be assessed in evaluating the tolerability of the regimen 
for future studies. All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be considered 
evaluable for dose-limiting toxicity. Incidence of DLT will be estimated 
by the number of patients with DLT divided by the total number of 
evaluable patients. No more than three patients will receive the first cycle 
of combination immunotherapy (Pembrolizumab and cryoablation and 
DC injections, i.e. Cycle 2 of the overall treatment plan) at any time 
during Phase I of the study. 
For a comprehensive picture of toxicity profile, we will also summarize 
the incidence of other significant toxicities as defined in Section 8 or as a 
Grade 3 or higher adverse event otherwise not described in Section 8, 
that is possibly, probably, or definitely related to treatment. The number 
and severity of all adverse events (overall and by dose level) will be 
tabulated and summarized in this patient population. The Grade 3+ 
adverse events will also be described and summarized in a similar 
fashion. This will provide an indication of the level of tolerance for this 
treatment combination in this patient group.  Frequency distributions, 
graphical techniques and other descriptive measures will form the basis 
of these analyses. Further longitudinal analysis techniques will be 
employed to explore the adverse event profile over time. 
16.242 Feasibility (Goal 2.1.21) 
The feasibility of the regimen will be estimated by the number of patients 
who received at least one dose of intratumoral DC injection divided by 
the total number of patients who received leukapheresis.  Patient accrual 
rate and study completion rates will also be evaluated using summary 
statistics to determine if further studies of this regimen will be feasible. 
16.243 Quality of Life (Goal 2.1.22) 
Quality of life as measured using the FACT-Lym will be utilized.  The 
assessment will be scored according the scoring algorithm. Changes from 
baseline will be calculated at each assessment time points. Mean change 
scores at each time point will be calculated to determine if quality of life 
is reduced over the course of treatment. Longitudinal techniques will be 
employed to describe changes over time.  
16.3 
Phase II Portion 
16.31 Decision Rule 
Pembrolizumab monotherapy induces an ORR of 39% in patients with 

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ipilimumab-naïve melanoma by central independent RECIST review. The 
potential activity of this agent in non-Hodgkin lymphoma (NHL) has not been 
tested. Similar check-point inhibitor Nivolumab (BMS) has reported ORR of 
28% in B-cell NHL (ASH 2014). We estimate that Pembrolizumab may have 
similar single agent activities in NHL. Therefore we hypothesize that an ORR of 
53% with this combination immunotherapy approach will be worthy of further 
testing in this disease population. We will explore if there is a difference in 
histologies enrolled in this study.  Any specific NHL type with a clinical 
response defined as PR or CR in 2 or more patients may be expanded into a 
larger cohort for formal evaluation of ORR at the discretion of the PI and the 
Sponsor.   
For phase II, the largest ORR where the proposed treatment regimen would be 
considered ineffective in this population is 30%, and the smallest ORR that 
would warrant subsequent studies with the proposed regimen in this patient 
population is 53%. The following one-stage design requires 28 evaluable patients 
(22 - 25 from phase II and 3 - 6 from the MTD portion of phase I provided that 
these patients have follicular lymphoma) to test the null hypothesis that the true 
ORR in this patient population is at most 30. 
16.311 
Interim Analysis: No interim analysis was planned for this study due to 
the following reasons: i) patients will be treated and evaluated for 
response up to two years from enrollment. ii) the total expected accrual 
time for this phase is only 18 – 24 months. If we were to conduct an 
interim analysis, all patients in the trial would have been accrued by 
the time patients in the interim analysis set have reached the primary 
endpoint for analysis. 
16.312  
Final Decision Rule: If 12 or fewer of 28 patients achieve overall 
response, then the proposed treatment is considered ineffective; and if 
13 or more patients achieve overall response, then the treatment is 
conserved promising and warrants further study.  
16.313 
Over Accrual: If more than the target number of patients are accrued, 
the additional patients will not be used to evaluate the stopping rule or 
used in any decision making process.  If more than the target number 
of patients are accrued, the additional patients will not be used to 
evaluate the stopping rule or used in any decision making processes; 
however, they will be included in final endpoint estimates and 
confidence intervals. 
16.314  
Power and Significance Level: the power calculation is based solely on 
Phase II. We plan to accrue a total of 28 evaluable patients (including 
follicular lymphoma patients from the MTD cohort in phase I) for 
Phase II of the trial. This sample size provides 81% power at a one-
sided type I error of 0.05 to conclude that the ORR is higher than 30% 
if the true ORR is 53%. Secondary analysis will be performed in which 
Bayesian hierarchical models (Thall et al. 2003) will be used to 
estimate subtype-specific ORRs for the purposes of examining 
differences in response and guiding future plans for subtype-specific 
expansion studies.  
16.315 
Other considerations: Adverse events, quality/duration of response, and 
patterns of treatment failure observed in this study, as well as scientific 

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discoveries or changes in standard care will be taken into account in 
any decision to terminate the study. 
16.32  Analysis Plan 
16.321  Primary Outcome Analyses: 
16.3211  Definition: The primary endpoint of this trial is the proportion of 
complete responses of combination therapy with 
pembrolizumab, cryoablation and intra-tumor injection of 
autologous DC at MTD dose schedule. A success is defined as a 
PR or CR as the objective status during therapy. All patients 
meeting the eligibility criteria who have signed a consent form 
and have begun treatment will be evaluable for response. 
16.3212  Estimation: The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable 
patients. Confidence intervals for the true success proportion will 
be calculated.  
16.322  Secondary Outcome Analyses:  
These analyses will include all patients meeting the eligibility criteria 
who have signed a consent form and have begun treatment. Analyses will 
include all patients enrolled in the Phase II portion of the study and 
analysis of each cohort separately. 
16.323  Complete response (Goal 2.2.21): The response rate will be calculated, 
as above, in each individual cohort as supplementary to the primary 
analysis. 
16. 324  Progression free survival, treatment free survival, and duration of 
response (Goal 2.2.22): 
Survival time is defined as the time from registration to death due to any 
cause. The distribution of survival time will be estimated using the 
method of Kaplan-Meier (Kaplan E 1958). In addition, the overall 
survival rate at 2 years after registration will be reported.  
Treatment free survival time is defined for all evaluable patients who 
have achieved a response as the time from registration to next treatment 
or death due to any cause. The distribution of treatment-free survival will 
be estimated using the method of Kaplan-Meier. In addition, the disease-
free survival rate at 2 years after registration will be reported.  
Duration of response is defined for all evaluable patients who have 
achieved a PR or CR as the date at which the patient’s objective status is 
first noted to be a response to the earliest date progression is 
documented. The distribution of duration of complete response will be 
estimated using the method of Kaplan-Meier. 
16.325 Adverse Events (Goal 2.2.23): All eligible patients that have initiated 
treatment will be considered evaluable for assessing adverse event 
rate(s). The maximum grade for each type of adverse event at each 
evaluation will be recorded for each patient, and frequency tables will be 
reviewed to determine patterns. Additionally, the relationship of the 
adverse event(s) to the study treatment will be taken into consideration. 
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of time on treatment adverse events. 
16.326  Quality of Life (Goal 2.2.24): 
Quality of life as measured using the FACT-Lym will be utilized.  The 
assessment will be scored according to the scoring algorithm.  Changes 
from baseline will be calculated at each assessment time points.  Mean 
change scores at each time point will be calculated to determine if quality 
of life is reduced over the course of treatment.  Longitudinal techniques 
will be employed to describe changes over time. 
16.4 
Analysis of other endpoint 
16.41 Definitions and Analyses of Radiologic Endpoints 
Measurements of index lesion(s) (non-cryoablated lesion) will be evaluated over 
time for each patient as a marker of systemic immune and treatment response to 
Pembrolizumab and localized treatment with cryoablation and DC. The index 
lesion(s) will be selected by the treating physician/investigator and are non-
cryoablated node. The percent change from baseline in index lesion 
measurements will be assessed over time. Differences in values over time will be 
summarized descriptively and graphically. In addition, patients will be classified 
into one of the following categories based on the best response seen in the index 
lesion(s): 
● 
Complete response: disappearance of the node 
● 
Partial response: ≥50% of decrease in measured dimension 
● 
Stable: between 50% decrease to ≤25% increase in dimension 
● 
Progression: >25% increase in measured dimension 
While the evaluation of index lesion(s) may be part of the assessment of overall 
response, it is not the sole criteria for time to progression. The whole body CT or 
PET/CT will be used to assess overall clinical response and time to progression 
using the standard Cheson criteria, as detailed in Section 11. 
16.42  Correlative Endpoints 
Change in immunologic correlates before and after vaccination treatment will be 
evaluated and summarized both quantitatively and graphically. Each of the 
correlative endpoints will be summarized individually, but will also be evaluated 
in terms of their relationships to one another; i.e., we will use Spearman rank 
correlation coefficient to assess the correlations between baseline levels as well 
as between changes before and after treatment in these immunologic markers. In 
addition, these immunologic markers will be correlated with cancer and 
treatment- related outcomes (e.g. response, toxicities). Relationships will also be 
explored graphically using scatter plots. Given the limited sample size, these 
analyses will be considered exploratory. 
 
16.5 
Data & Safety Monitoring: 
16.51 Routine monitoring of accrual and adverse events will be completed by the study 
statistical team on a weekly basis to assess patient safety. 
16.52 Formal monitoring of accrual, adverse event, and any endpoint problems that 
might be developing will be conducted by the Mayo Clinic Cancer Center 
(MCCC) Data Safety Monitoring Board (DSMB).  The DSMB is responsible for 
reviewing accrual and safety data for this trial at least twice a year, based on 

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reports provided by the MCCC Statistical Office. 
 
16.53 Adverse Event Stopping Rules (These rules apply to each arm independently):  
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible”, “probable”, or “definite”) that satisfy 
either of the following: 
• Phase I portion:  
• 
Every 3 patients in the phase I portion of the trial will be monitored 
according to the criteria in Section 7.0 and Section 16.23. 
• 
Death (other than death related to progressive disease) that occurs within 
30 days of the DC cell infusion. 
• Phase II portion: 
• 
If 4 or more patients in the first 12 treated patients experience a grade 4 
or higher non-hematologic adverse event at least possibly related to 
treatment excluding infections. 
•  If after the first 12 patients have been treated, 30% of all patients 
experience a grade 4 or higher non-hematologic adverse event at least 
possibly related to treatment excluding infections 
• 
Death (other than death related to progressive disease) that occurs within 
30 days of the DC cell infusion. 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
16.54 Results Reporting on
 
At study activation, this study will have been registered within the 
 website. The Primary and Secondary Endpoints (i.e., 
“Outcome Measures”) along with other required information for this study will 
be reported on
 For purposes of timing of the Results 
Reporting, the initial estimated completion date for the Primary Endpoint of this 
study is 4 years after the study opens to accrual. The definition of “Primary 
Endpoint Completion Date” (PECD) for this study is at the time the last patient 
registered has been observed for 12 months. 
16.6 
Inclusion of Minorities 
16.61 This study will be available to all eligible patients, regardless of race or ethnic 
origin. 
16.62 Although the planned analysis will, as always, look for differences in treatment 
effect based on racial groupings the sample size is not increased in order to 
provide additional power for subset analyses. 

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16.63 Based on prior studies involving similar disease sites conducted at Mayo Clinic 
in Rochester, MN, we expect about 3% of patients will be classified as minorities 
by race/ethnicity and about 40% of patients will be women. Expected sizes of 
racial subsets are shown in the following table: 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
0 
0 
0 
Not Hispanic or Latino 
18 
26 
0 
44 
Ethnic Category: Total of all subjects 
18 
26 
0 
44 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
0 
1 
0 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
18 
25 
0 
43 
Racial Category: Total of all subjects* 
18 
26 
0 
44 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.) 
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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17.0 
Pathology Considerations/Tissue Biospecimens 
17.1 
Summary Table of Research Tissue Specimens to be collected for this Protocol 
17.11 Tumor Biopsy Schedule: phase I dose schedule 1 and Phase II 
Correlative Study (Section 
for more information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc. 
(# of each to 
submit) 
Prior to 
Day 1 
Cycle 1 
Day 1 
Cycle 6  
and 
Cycle 19 
PD 
Process at 
site? 
(Yes or No) 
Temperature 
Conditions for 
Storage/ 
Shipping1 
Immunohistochemistry, 
immunofluorescence, gene 
sequencing for tumor antigen 
and T cell receptors (17.2) 
Mandatory 
Lymphoma 
tumor in 
normal saline 
Excisional 
biopsy2 or large 
bore needle core 
biopsy 
X 
X 
X 
No 
Ambient 
1. All specimens should be sent to Mary Solseth, IMPACT Lab, Mayo Clinic, 200 First Street SW – Hilton 2, Rochester, MN 55905. 
2. Excisional tumor resection will be performed if possible in place of core needle biopsy for Cycle 1 and PD only. 
 
17.12 Tumor Biopsy Schedule: Phase I dose schedule 2 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of Tissue 
to Collect 
Block, Slides, 
Core, etc. (# of 
each to submit) 
Prior to 
Day 1 
Cycle 1 
Day 1 
Cycle 8  
and 
Cycle 19 
PD 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions for 
Storage 
/Shipping1 
Immunohistochemistry, 
immunofluorescence, 
gene sequencing for 
tumor antigen and T cell 
receptors (17.2) 
Mandatory 
Lymphoma 
tumor in normal 
saline 
Excisional 
biopsy1 or large 
bore needle core 
biopsy 
X 
X 
X 
No 
Ambient 
1. All specimens should be sent to Mary Solseth, IMPACT  Lab, Mayo Clinic, 200 First Street SW – Hilton 2, Rochester, MN 55905. 
 

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17.13  Tumor biopsy schedule: Phase II  
Phase II tumor biopsy will follow Phase I dose schedule 1 (See Section 17.11) 
17.2 
Background and Methodology 
17.21 Analysis of tumor biopsies 
We will examine tumors for tumor-infiltrating lymphocyte and dendritic cell 
phenotype and compare changes prospectively over time. Immuno-
histochemistry, flow, and gene sequencing analysis will be performed. 
Exploratory biomarkers to predict treatment response include but are not limited 
to tumor-infiltrating CD4 and CD8 T cells, NK cells, and PD-1/PDL1/PDL2 
expression on lymphoma and stromal cells. Leftover samples may be used for 
genomic or proteomic analysis. 
17.22 Translational Genomics Research Institute 
De-identified tissue samples will be sent for analysis to 
 lab 
at the Translational Genomics Research Institute (TGen). 
Translational Genomics Research Institute (TGen) 
 
 
 
18.0 
Records and Data Collection Procedures 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Case Report Form packet. 
18.2 
Event monitoring 
See Section 4.4 and data submission table in the case report form packet for the event 
monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation  
This study requires supporting documentation of histologic diagnosis and staging which 
includes the most recent tumor tissue biopsy pathology report, bone marrow biopsy 
report, and imaging reports.  To submit these materials, they can be uploaded into the 
Supporting Documentation form in Medidata Rave.   These reports should be submitted 
within 14 days of registration. 
For response to treatment, supporting documentation includes imaging reports and, if 
applicable, a bone marrow biopsy report.   

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For patients who progress after study therapy, supporting documentation   including 
imaging reports is required.   
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any incomplete case report forms   will be considered “not received” and will not be 
edited or otherwise processed until the case report forms are completed. A list of the 
missing case report forms will be available to the appropriate co-sponsor/participant in 
the Medidata Rave Task Summary 
18.8 
Overdue lists 
A list of overdue materials and forms for study patients will be generated monthly. The 
listings will be sorted by location and will include the patient study registration number. 
The appropriate co-sponsor/participant will be responsible to submit the overdue 
material. 
 
19.0 
Budget Considerations 
19.1 
Costs charged to patient: Routine clinical care 
Pembrolizumab will be provided free of charge by Merck 
 
19.2 
Tests to be research funded: Leukapheresis 
Cryoablation/Anesthesia 
DC and Prevnar13 injections 
Correlative studies outlined in Section 14.0. 
 
19.3 
Other budget concerns:  This study is supported by the following:  
 
 
The Schulze Family Foundation Career Development Grant in Individualized 
Medicine and The University of Iowa/Mayo Clinic Lymphoma SPORE through 
its grant with the National Cancer Institute (CA97274). 
 
Biocompatibles Inc., a BTG International group company (for a limited 
number of patients).  
 
 

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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. 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 ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From 
 
 
 
 

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Appendix II 
NYHA Classification 
 
Class I: 
NO Symptoms with ordinary activity  
Class II: 
Symptoms with ordinary activity  
Class III: 
Symptoms with minimal activity  
Class IV: 
Symptoms at rest 
 

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Appendix III FACT-Lym 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
GP1 
I have a lack of energy ..............................
0 
1 
2 
3 
4 
GP2 
I have nausea ............................................
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I 
have trouble meeting the needs 
of my family ................................
 
0 
  
1 
 
2 
 
3 
 
4 
GP4 
I have pain ................................................
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment ......................................
  0 
1 
2 
3 
4 
GP6 
I feel ill .....................................................
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed ................
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends ............................
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family ....
0 
1 
2 
3 
4 
GS3 
I get support from my friends .....................
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness ............
0 
1 
2 
3 
4 
GS5 
I am satisfied with family 
communication about my illness ................
0 
1 
2 
3 
4 
GS6 
I feel close to my partner (or the person 
who is my main support) ...............
0 
1 
2 
3 
4 

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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
GE1 
I feel sad .............................................................................
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness .........
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness .................
0 
1 
2 
3 
4 
GE4 
I feel nervous ......................................................................
0 
1 
2 
3 
4 
GE5 
I worry about dying ............................................................
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse ...........................
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) .........................
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling ....................
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life .........................................................
0 
1 
2 
3 
4 
GF4 
I have accepted my illness ..................................................
0 
1 
2 
3 
4 
GF5 
I am sleeping well ...............................................................
0 
1 
2 
3 
4 
Q1 
Regardless of your current level of 
sexual activity, please answer the 
following question. If you prefer not to 
answer it, please mark this box  
and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life ..................
0 
1 
2 
3 
4 

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GF6 
I am enjoying the things I usually do for fun .....................
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now .............
0 
1 
2 
3 
4 
 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
P2 
I have certain parts of my body where I experience pain ...
0 
1 
2 
3 
4 
LEU1 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) ..............................
 
0 
 
1 
 
2 
 
3 
 
4 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) ........................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
ES3 
I have night sweats .............................................................
0 
1 
2 
3 
4 
LYM1 
I am bothered by itching .....................................................
0 
1 
2 
3 
4 
LYM2 
I have trouble sleeping at night ..........................................
0 
1 
2 
3 
4 
BMT6 
I get tired easily ..................................................................
0 
1 
2 
3 
4 
C2 
I am losing weight ..............................................................
0 
1 
2 
3 
4 
Ga1 
I have a loss of appetite ......................................................
0 
1 
2 
3 
4 
HI8 
I have trouble concentrating ...............................................
0 
1 
2 
3 
4 
N3 
I worry about getting infections .........................................
0 
1 
2 
3 
4 
LEU6 
I worry that I might get new symptoms of my illness ........
0 
1 
2 
3 
4 
LEU7 
I feel isolated from others because of my illness or 
treatment .............................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
BRM9 
I have emotional ups and downs ........................................
0 
1 
2 
3 
4 
LEU4 
Because of my illness, I have difficulty planning for the 
future ..................................................................................
 
0 
 
1 
 
2 
 
3 
 
4 
 

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Appendix IV Patient Information Sheet 
 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. Please complete this booklet before receiving your next treatment. 
 
2. The booklet contains the Functional Assessment of Cancer Therapy – Lymphoma 
questionnaire. 
 
 
3. Please follow the directions at the top of each page of the questionnaire. 
 
 
4. It is very important that you return the booklet to us, whether you finish the study or not. 
 
 
5. Please return the booklet to your health care provider when finished. 
 
 
 
Thank you for taking the time to help us. 
 
 
 

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Appendix V 
DEAUVILLE 5-POINT SCALE 
 
DEAUVILLE 5-POINT SCALE 
Score 1: No Uptake 
Score 2: Uptake < mediastinum 
Score 3: Uptake > mediastinum but < liver 
Score 4: Moderately increased uptake > liver 
Score 5: Markedly increased uptake > liver and/or new lesions related to lymphoma 
Score X: New areas of uptake unlikely to be related to lymphoma 
 

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Appendix VI Ann Arbor Staging System 
Ann Arbor Staging for Lymphoma: 
NOTE: The staging does not take into account the grade (growth rate) of the tumor tissue, or prognostic 
factors, such as bulky disease, LDH, age, symptomatic.  See FLIPI 
Bone marrow involvement and other so-called extranodal involvement is not unexpected for lymphoma 
can be reversed with treatment. 
  
Stage I - disease in single lymph node or lymph node region.  
Stage II - disease in two or more lymph node regions on same  
side of diaphragm.  
Note: Stage II contiguous means two or more lymph nodes in close proximity (side by side). 
Stage III - disease in lymph node regions on both sides of the  
diaphragm are affected.  
Stage IV - disease is wide spread, including multiple involvement at  
one or more extranodal (beyond the lymph node) sites, such as the  
bone marrow (which is involved commonly), liver, pleura (thin lining of the lungs). 
 
 

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Appendix VII FLIPI, IPI, and MIPI Tables and MIPI calculator  
International Prognostic Index (IPI) (Shipp, 1993) 
Risk Factors 
0 points 
1 point 
Age 
≤60 yrs. 
>60 yrs. 
Tumor Stage 
1 or 2 
3 or 4 
Serum LDH 
≤1 x normal 
> 1 x normal 
Performance Status 
0 or 1 
2 - 4 
Number of extranodal sites 
≤1 
>1 
Total number of risk factors = sum of the number of points for each prognostic factor. 
 
 
Follicular Lymphoma International Prognostic Index (FLIPI) (Solal-Celigny, 2004): 
Risk Factors 
0 points 
1 point 
Age 
˂60 yrs. 
≥60 yrs. 
Tumor Stage 
1 or 2 
3 or 4 
Serum LDH 
≤1 x normal 
> 1 x normal 
Hemoglobin 
≥ 12 
< 12 
Number of nodal groups 
≤4 
˃4 
Total number of risk factors = sum of the number of points for each prognostic factor 
 
MIPI Calculator: Please click on link below:  
  
 
MCL International Prognostic Index (MIPI) (Hoster, 2008): 
Points 
Age (years) 
ECOG PS 
LDH/ULN 
WBC, 109 /L 
0 
< 50 
0-1 
< 0.67 
< 6.700 
1 
50-59 
 
0.67-0.99 
6.700-9.999 
2 
60-69 
2-4 
1.00-1.49 
10.000-14.999 
3 
≥70 
 
≥1.50 
≥15.000 
For each prognostic factor, 0 to 3 points were given to each factor and points were summed up to a 
maximum of 11. Patients with 0 to 3 points in summary were classified as low risk, patients with 4 to 5 
points as intermediate risk, and patients with 6 to 11 points as high risk.