Conditions: Metastatic Colorectal Cancer
Keywords: Colorectal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Digestive System Diseases Gastrointestinal Diseases Intestinal Diseases Rectal Diseases Colonic Diseases
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This study will be looking at the objective response rate (ORR) as measured by RECIST in in patients with mismatch repair-proficient (MMR-p), advanced colorectal cancer that treated with CY/GVAX in combination with Pembrolizumab.

Detailed description:

Arms:
arm 1: During each 21 day cycles, Cyclophosphamide (CY) is administered on Day 1 at 200 mg/m2 followed by Pembrolizumab at 200mg, the colon cancer vaccine (GVAX) is administered on Day 2 at 5E8 colon cancer cells + 5E7 GM-CSF secreting cells for the first 4 cycles of treatment. After cycle 4, cyclophosphamide and GVAX will be administered with every 4th cycle.

Interventions: intervention 1: CY intervention 2: GVAX intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: CY is administered intravenously at 200 mg/m2 intervention 2: GVAX is administered intradermally at 5E8 colon cancer cells + 5E7 GM-CSF secreting intervention 3: Pembrolizumab is administered intravenously at 200 mg

Protocol document:
Prot_SAP_000.pdf: 
TITLE: A Phase 2 Study of GVAX Colon Vaccine (with Cyclophosphamide) and 
Pembrolizumab in Patients with Mismatch Repair-Proficient (MMR-p) Advanced 
Colorectal Cancer 
Johns Hopkins #: 
IRB00114053, J16154 
Merck Protocol #: 
MK-3475-485 
Principal Investigator: 
Nilofer Azad, MD 
1650 Orleans Street, Room 4M10 
Baltimore, Maryland 21287 
 
Lead Associate Investigator: 
Mark Yarchoan, MD 
1650 Orleans St. CRB1 4M 
Baltimore, MD 21287 
 
 
Regulatory Specialist: 
Jennifer Durham, PhD 
Statistician: 
Chiung-Yu Huang, PhD
Lead Study Coordinator:
Christina Rodriguez 
Lead Research Nurse: 
Anna Ferguson, RN 
Merck Supplied Agent: 
Pembrolizumab (KEYTRUDA®, MK-3475) 
JHU Supplied Agent: 
GVAX Colon Vaccine (Allogeneic SW 837 and SW 620 
cell lines admixed with GM-CSF Producing Bystander 
K562 cell line) 
Commercial Agent:
Cyclophosphamide
IND:  
BB IND 13520 
IND Sponsor: 
Lei Zheng, MD, PhD 
1650 Orleans St, Room 488 
Baltimore, MD 21287 
 


Phase 2 Study of GVAX (with CY) and pembrolizumab in MMR-p advanced colorectal cancer 
J16154/Version 5 / January 17, 2018 
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Protocol Type / Version # / Version Date: 
Original/ Version 1.0 / November 10, 2016 
Original/ Version 1.1 / December 16, 2016 
Amendment 1/ Version 2 / March 28, 2017 
Amendment 2/ Version 3 / September 1, 2017 
Amendment 3/ Version 4 / October 20, 2017 
Amendment 4/ Version 5 / January 17, 2018 


 
 
 
 
Phase 2 Study of GVAX (with CY) and pembrolizumab in MMR-p advanced colorectal cancer 
J16154/Version 5 / January 17, 2018 
 
 
 
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TRIAL DESIGN 
 
 
 This is an open-label phase 2 trial evaluating the GVAX Colon Vaccine with 
Cyclophosphamide and Pembrolizumab in Patients with Mismatch Repair-Proficient 
(MMR-p) Advanced Colorectal Cancer  
 Each treatment cycle = 21 days 
 Patients will receive pembrolizumab on day 1 of each cycle 
 Patients will also receive cyclosphophamide on day 1, and GVAX on day 2, for each of 
the first four cycles, and then every fourth cycle thereafter 
 For all patients, imaging scans will be performed at baseline and at least every 12 weeks 
thereafter, irrespective of the treatment schedule. 
 
 
 
 


 
 
 
 
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TABLE OF CONTENTS 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Primary Objectives ...................................................................................................6 
1.2 
Secondary Objectives ...............................................................................................6 
1.3 
Exploratory Objectives ............................................................................................6 
1.4 
Primary Endpoint .....................................................................................................6 
1.5 
Secondary Endpoints ...............................................................................................7 
1.6  
Exploratory endpoints ..............................................................................................7 
1.7 
Study Design ............................................................................................................7 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Disease Type ............................................................................................................9 
2.2 
Vaccine Therapy (GVAX) .......................................................................................9 
2.3 
Anti-PD-1/PD-L1 therapy (Pembrolizumab (MK-3475 or Keytruda)) .................12 
2.4 
Preclinical and Clinical Trial Data .........................................................................14 
2.5 
Rationale ................................................................................................................14 
3. 
PATIENT SELECTION ....................................................................................................15 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................17 
3.3 
Inclusion of Women and Minorities ......................................................................19 
4. 
TREATMENT PLAN ........................................................................................................19 
4.1 
Agent Administration .............................................................................................19 
4.2 
General Concomitant Medication and Supportive Care Guidelines ......................20 
4.3  
Prohibited and Restricted Therapies ......................................................................24 
4.4  
Dosing Criteria .......................................................................................................24 
4.5 
Definition of an Overdose for this Protocol ...........................................................24 
4.6 
Contraception, Use in Pregnancy, Use in Nursing ................................................25 
4.7 
Dose Limiting Toxicity ..........................................................................................26 
4.8 
Duration of Therapy ...............................................................................................29 
4.9 
Off Treatment Evaluation and Retreatment Criteria ..............................................30 
4.10 
Duration of Follow Up ...........................................................................................31 
4.11 
Criteria for Removal from Study Treatment ..........................................................31 
5. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................32 
5.1  
Dose Modifications ................................................................................................32 
5.2  
Dosing Delays ........................................................................................................32 
6. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................35 
6.1 
Definitions..............................................................................................................36 
6.2 
Relationship ...........................................................................................................37 
6.3 
Expectedness ..........................................................................................................39 
6.4 
Handling of Expedited Safety Reports ..................................................................39 
6.5  
Reporting................................................................................................................39 
7. 
PHARMACEUTICAL INFORMATION ..........................................................................41 
7.1  
Cyclophosphamide (Cytoxan®, CY) ......................................................................41 
7.2  
GVAX ....................................................................................................................43 


 
 
 
 
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7.3 
Pembrolizumab ......................................................................................................46 
8. 
CORRELATIVE/SPECIAL STUDIES .............................................................................48 
8.1 
Tumor Tissue Studies ............................................................................................48 
8.2  
Whole Blood Peripheral Blood Lymphocytes (PBLs)...........................................48 
8.3  
Serum and Plasma Marker Studies ........................................................................48 
8.4 
Diagnostic Tissue Samples ....................................................................................48 
9. 
STUDY CALENDAR .......................................................................................................50 
10. 
MEASUREMENT OF EFFECT........................................................................................52 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................52 
11. 
 DATA REPORTING / REGULATORY REQUIREMENTS ..........................................53 
11.1 
Data Management ..................................................................................................53 
11.2 
Safety Meetings .....................................................................................................53 
11.3   Monitoring .............................................................................................................53 
12. 
STATISTICAL CONSIDERATIONS...............................................................................54 
12.1   Overview ................................................................................................................54 
12.2   Sample Size and Accrual .......................................................................................55 
12.3 
Statistical analysis ..................................................................................................56 
REFERENCES ..............................................................................................................................59 
APPENDIX A: Performance Status Criteria .................................................................................63 
APPENDIX B: Guidance for Identification and Treatment of IRAEs (Version 5.0, Date: 
18-Dec-2014) .....................................................................................................................64 
APPENDIX C: Adverse Event of Clinical Interest (ECI) Reporting Form ...................................65 
APPENDIX D: Serious Adverse Event (SAE) Reporting Form ...................................................68 
APPENDIX E: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ...............................................................................71 
APPENDIX F: Immune Related Response Criteria ......................................................................75 
 
 
 
 
 


 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To determine the objective response rate (ORR) of GVAX colon vaccine in 
combination with pembrolizumab in patients with mismatch repair-proficient 
(MMR-p), advanced colorectal cancer who have progressed after at least two 
lines of prior therapy. 
 
1.2 
Secondary Objectives 
 
1.2.1 To assess the safety and tolerability of the combination GVAX/pembrolizumab 
in subjects with MMR-p, advanced colorectal cancer  
 
1.2.2 To assess the progression free survival (PFS) of subjects with MMR-p, 
advanced colorectal cancer who receive GVAX in combination with 
pembrolizumab using immune related response criteria. 
 
1.2.3 To assess the duration of response among subjects who demonstrate an 
objective response to treatment with GVAX in combination with 
pembrolizumab. 
 
1.2.4 To determine the overall survival (OS) of subjects with MMR-p, advanced 
colorectal cancer who receive GVAX in combination with pembrolizumab. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To evaluate the effects of combination therapy with pembrolizumab and 
Cy/GVAX on multiple immune pathways including suppressive pathways 
(including PD-L1, PD-L2, LAG3, BTLA, TIM3, IDO1, CTLA-4, and Tregs), 
activation 
pathways 
(including 
CD137, 
OX40, 
CD40, 
CD40L), 
cytokines/chemokines or their receptors (including CCL12, CXCR4, CCL2, 
CCL5, CCR2, CCR5), and tumor infiltrating lymphocytes. 
 
1.3.2  To assess tumor burden dynamics through measurements of circulating tumor 
biomarkers including carcinoembryonic antigen (CEA) as well as other 
exploratory circulating biomarkers in serial collections of sera and plasma at 
baseline and throughout treatment.  
 
1.3.3  To assess the baseline characteristic of the subjects enrolled and to correlate 
these molecular and clinicopathologic criteria with treatment response and 
toxicity.  
 
1.3.4  To assess changes in peripheral blood lymphocytes (PBL) to explore the 
association of lymphocyte activation markers with clinical responses. 
 
1.4 
Primary Endpoint 
 


 
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1.4.1 ORR, defined as the proportion of patients achieving a complete response (CR) 
or partial response (PR) based on the Response Evaluation Criteria in Solid 
Tumors (RECIST 1.1) at any time during the study, of GVAX in combination 
with pembrolizumab in patients with MMR-p, advanced colorectal cancer. 
 
1.5 
Secondary Endpoints  
 
 
1.5.1 Adverse events as graded by NCI CTCAE active version 
 
1.5.2 Progression free survival 
 
1.5.3 Duration of response  
 
1.5.4 Overall Survival 
 
1.6  
Exploratory endpoints 
 
1.6.1 Intratumoral changes in pre- and post-treatment core biopsy specimens will be 
studied 
using 
analyses 
such 
as 
immunohistochemistry 
(IHC) 
and 
transcriptional analysis (Merck's nanostring panels) 
o Immune suppressive pathways including PD-L1, PD-L2, LAG3, 
BTLA, TIM3, IDO1, CTLA-4, and Tregs 
o Immune activation pathways including CD137, OX40, CD40, CD40L 
o Cytokines/chemokines or their receptors including CCL12, CXCR4, 
CCL2, CCL5, CCR2, CCR5.  
o T cell receptor (TCR) repertoire (and compared to PBL) 
 
1.6.2 Biomarker marker changes (including standard protein biomarkers such as 
CEA) and correlation to evaluate for prognostic or predictive factors 
 
1.6.3 Clinicopathologic characteristics (including but not limited to age, sex, 
histology, grade, tumor mutations) and biomarkers of response (OS, PFS, and 
best overall response) or toxicity. 
 
1.6.4 Measure pre- and post-treatment changes in PBLs including effector, helper, 
and regulatory T cells through cell phenotyping analysis and gene expression 
profiling in association with clinical responses. We will also measure specific 
T cell responses as a parameter of immune response to treatment with 
immunotherapy.  
 
1.7 
Study Design 
 
This is an open-label, single-arm phase II study of Cy/GVAX in combination with 
pembrolizumab in subjects with MMR-p, advanced colorectal cancer who have 
progressed on at least two lines of prior therapies. Subjects with microsatellite repair 
deficiency (MMR-d; MSI) are not eligible for this study. 
 
Therapy is administered on days 1 and 2 of a 21 day cycle. On day 1, participants will 
receive their first dose of cyclophosphamide (Cy) 200 mg/m2 and pembrolizumab 200 


 
Phase 2 Study of GVAX (with CY) and pembrolizumab in MMR-p advanced colorectal cancer 
J16154/Version 5 / January 17, 2018 
 
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mg, both administered intravenously (IV). On day 2, participants will receive GVAX, 
administered as 8-9 intradermal injections for a final dose of 5x108 colon cancer cells 
+ 5x107 GM-CSF secreting cells. Participants may continue therapy every 21 days 
until there is disease progression. After completing four cycles of therapy, patients 
will continue pembrolizumab with every cycle of therapy and cyclophosphamide and 
GVAX will be administered every 4th cycles of therapy.  
  
Due to the expectation that some patients may experience delayed clinical responses 
to therapy, patients with disease progression by radiographic imaging or laboratory 
parameters during a 12 week evaluation period but without rapid clinical deterioration 
or significant change in performance status that requires additional immediate therapy 
may continue to receive treatment on study. In this setting, a repeat scans will be 
obtained at weeks 6 and 12, and every 12 weeks thereafter from time of initial 
radiographic progression. This extra scan at 6 weeks after initial radiographic 
progression will allow earlier recognition of true progression and will ensure that the 
treatment is stopped adequately if not working. Subjects who meet the above criteria 
and continue to receive treatment on study despite disease progression by 
radiographic imaging must discontinue treatment upon documentation of disease 
progression on the second scan (week 6). The date of progression will be backdated 
to the time of first RECIST criteria progression. Tumor assessments will be made 
using RECIST 1.1 and immune-related response criteria (irRC). All patients will be 
followed by this protocol for at least 30 days after their last dose of study drug or 
until initiation of a new anti-cancer treatment, whichever occurs first. 
 
NOTE: For patients who progress and remain on study, at the time of the next 
restaging, stable disease with clinical stability as determined by their treating 
physican/team can remain on study. Specifically, these patients do not have to have 
regression to <20% growth from baseline. If they do not have 20% increase from the 
last restaging scan, they may remain on study. 
 
Patients who are discontinued from the study due to an unacceptable drug-related AE 
will be followed until the resolution of the AE to Grade 0-1 or stabilization or until 
initiation of a new therapy for their cancer, whichever occurs first. Patients who 
discontinue from treatment will be contacted every three months to monitor overall 
survival. Information about other cancer therapies after discontinuation from the 
study treatment will be collected.  
 
At the end of the study, subjects will be required to enroll in a long-term follow-up 
protocol, an FDA requirement for genetically modified products, in which they will 
be followed for at least five years (or until death) after receiving the last dose of any 
investigational agent through this protocol for disease progression, survival, and 
potential long term toxicity of gene therapy. The subjects will be asked to enroll in 
the study entitled, “Long-Term Follow-Up of Patients who Received the Allogeneic 
Colon Cancer Cell Vaccine Administered with a GM-CSF Producing Bystander Cell 
Line.” 
 
2. BACKGROUND 
 


 
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2.1 
Disease Type 
 
Despite the existence of excellent screening and preventative strategies, colorectal 
carcinoma remains a major public health problem in industrialized countries and a rising 
health problem in developing countries. About 102,480 new cases of colon cancer and 
40,340 cases of rectal cancer are expected to occur in the United States in 2013, with 
about 50,830 deaths, accounting for approximately 9% of cancer deaths. Colorectal 
carcinoma is the third leading cause of death from cancer in both males and females, 
comprising 9% of all cancers diagnosed in men and women. It also is the third most 
common malignancy in both men (after prostate and lung cancers) and women (after 
breast and lung cancers) [1]. Surgical resection of the primary colorectal lesions 
combined with adjuvant chemotherapy and radiation, when indicated, remain the 
mainstay of therapy. Unfortunately, approximately 30% of these patients will be 
diagnosed with metastatic disease at initial presentation, and an additional 25-30% of 
patients will subsequently develop metastatic disease. Among these patients, 
approximately 20% will have disease confined to the liver, which is the dominant site of 
metastatic involvement [2]. Despite recent advances in earlier detection and 
improvements in chemotherapy, the median survival for all patients with metastatic 
colorectal carcinoma ranges from 11-20 months with five-year survival < 5% [3-8].  
 
2.2 
Vaccine Therapy (GVAX) 
 
Immunotherapy is a potentially effective therapeutic approach to the treatment of 
colorectal carcinoma for several reasons. First, immune-mediated tumor killing acts by 
mechanisms distinct from standard chemotherapy or radiation therapy and may represent 
a non-cross resistant treatment modality. Second, the immune system is capable of 
recognizing a diverse array of potential antigens while orchestrating selective and 
specific cytotoxic responses. This may be particularly important in the killing of a 
heterogeneous tumor population while avoiding normal tissue toxicity. Third, preclinical 
animal models using a vaccine approach for immunotherapy have been able to eliminate 
small burdens of established tumors, a situation that corresponds to a state of minimal 
residual disease commonly found after resection of all gross disease [9-14]. Fourth, 
completed Phase I and II trials evaluating irradiated, GM-CSF secreting allogeneic 
pancreatic cancer tumor vaccines have demonstrated both clinical and immunologic 
response [15-17].  
 
The use of whole-cell vaccines is promising because it delivers a range of peptide 
antigens without the need for specific knowledge of the relevant target antigens. 
Preclinical studies show that among tumor cells genetically modified to express various 
cytokines, GM-CSF is the cytokine most effective in inducing anti-tumor immunity [18]. 
GM-CSF is an important growth and differentiation factor for dendritic cells, which are 
potent antigen-presenting cells. The use of allogeneic tumor cells for vaccine 
development over autologous tumor cells is attractive for several reasons. Autologous 
tumor cells are not always available and the production of an autologous vaccine is 
technically difficult, costly, and inefficient. Supporting the use of allogeneic tumor cells 
is the characterization of tumor-associated antigens in melanoma, which revealed that 
regardless of human leukocyte antigen (HLA) type, 50% of tumors share common 
antigens [19, 20]. In addition, both preclinical and human data support that the antigen-


 
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presenting cells important in GM-CSF based vaccination are host-derived suggesting that 
the vaccine cells and the host do not have to be HLA compatible [21, 22]. 
 
Phase I Study of an Allogeneic GM-CSF-Secreting Tumor Vaccine in Patients with 
Resected Pancreatic Cancer 
 
This study was the first clinical trial to test the hypothesis that GVAX can prime a 
systemic immune response in patients with resected pancreatic adenocarcinoma [15]. 
Fourteen patients with stage II or III disease received an initial vaccination 8 weeks 
following resection. This was a dose escalation study in which 3 patients each received 1 
X 107, 5 X 107, and 1 X 108 vaccine cells. An additional 5 patients received 5 X 108 
vaccine cells. Study patients were jointly enrolled in an adjuvant chemoradiation protocol 
for 6 months. Following the completion of adjuvant chemoradiation, patients were re-
assessed and those who were still in remission were treated with 3 additional vaccinations 
given one month apart at the same original dose that they received for the first 
vaccination. Toxicities were limited to grade I/II local reactions at the vaccine site, and 
self-limited systemic rashes, including one documented case of Grover's syndrome. 
Systemic GM-CSF levels were evaluated as an indirect measure of the longevity of 
vaccine cells at the immunizing site. As was observed in pre-clinical studies, GM-CSF 
levels peaked at 48 hours following vaccination. In addition, serum GM-CSF levels could 
be detected for up to 96 hours following vaccination. The vaccine sites were also 
evaluated as a measure of the local immune reaction to the vaccine. Eleven of 14 patients 
demonstrated a similar local inflammatory response to what has been observed in pre-
clinical models and autologous GM-CSF vaccine clinical trials. Post-vaccination DTH 
responses to autologous tumor cells have been used in previously reported vaccine 
studies as a surrogate to identify and characterize specific immune responses that are 
associated with vaccination. In the pancreatic cancer vaccine trial, post-vaccination DTH 
responses to autologous tumor cells were observed in 1 of 3 patients receiving 1X 108 and 
in 2 of 5 patients receiving 5X108 vaccine cells. 
 
Follow-up Phase II Study Integrating the Whole Cell Vaccine with Chemoradiation 
for Resected Pancreatic Adenocarcinoma  
 
The follow-up phase II study of 60 patients with resected pancreatic adenocarcinoma 
based on the results of their phase I experience was completed [17]. The highest dose of 
vaccine from the phase I study (5 X 108 vaccine cells) was used. The common toxicities 
associated with the vaccine in this study included: local vaccine site skin reactions and 
systemic rashes similar in severity (grade 1-2) to what was observed in the phase I trial. 
The results from this study include the following: 
  The administration of the whole cell vaccine is safe and well-tolerated. Treatment 
related side effects included transient vaccine injection site reactions. There has been 
no incidence of anaphylaxis secondary to the vaccine reported thus far. 
  Systemic GM-CSF levels were evaluated as an indirect measure of the longevity of 
vaccine cells at the immunizing site. As was observed in the phase I study, GM-CSF 
levels peaked at 48 hours following the first and second vaccination but peaked 
earlier following the 3rd and 4th vaccination with diminution in amplitude. Serum 
GM-CSF levels following vaccine 5 peaked again at 48 hours and returned to vaccine 
1 serum levels. The results would suggest the possibility that the potency of an 


 
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allogeneic vaccine is diminished with repeated monthly vaccinations, but returns to 
pre-treatment levels with an extended time interval between boosts.  
  Post-Immunotherapy induction of mesothelin-specific CD8+ T cells with higher 
avidity and increased mesothelin epitope recognition (T cell repertoire expansion) 
correlates with disease free survival (DFS). 
 
Phase I and II Trials of Combining GM-CSF Secreting Allogeneic Vaccines in 
Sequence with Immune Modulating Doses of Cyclophosphamide (CY)  
 
Immune tolerance remains a major barrier to effective vaccine therapies. In particular, 
regulatory T cells (CD4+CD25+) have been shown to play a role in inducing CD8+ T cell 
tolerance. Manipulating the regulatory T cells may result in more effective vaccine 
strategies. In mouse models, immune modulating doses of CY in combination with GM-
CSF based cell vaccines have been shown to improve tumor rejection from 0% to 10 - 
30% in the HER-2/neu transgenic mouse model. The addition of CY allowed the 
activation of high-avidity RNEU420-429-specific CD8+ T cells in the mice, which rejected 
tumor. This effect was abrogated by CD4+CD25+ T cells derived from neu-N transgenic 
mice suggesting that CY before vaccination may block T regulatory cells allowing for 
recruitment of latent high-avidity neu-specific CD8+ T cells [23]. 
 
A feasibility study of the GM-CSF-secreting, allogeneic vaccine administered alone or in 
sequence with CY in patients with stage 4 pancreatic cancer, has been completed. This 
study consisted of two cohorts: Cohort A- 30 patients administered a maximum of six 
doses of vaccine using our two pancreatic cancer cell lines (2.5x108 of each cell line) 
intradermally at 21 day intervals; Cohort B- 20 patients administered CY 250 mg/m2 IV 
one day prior to each vaccination (administered as in Cohort A). Results from this study 
represent the first demonstration that integrating immunomodulatory doses of CY with a 
GM-CSF-secreting vaccine in patients with advanced pancreatic cancer is safe and 
feasible to administer. These data suggest that the vaccine given in sequence with CY 
results in anti-tumor activity, where median survivals in Cohort A and Cohort B were 2.3 
months and 4.3 months respectively in a patient population that had received > 2 prior 
chemotherapies. In addition, mesothelin-specific CD8+ T cell responses can be detected 
in stage 4 patients treated with the vaccine and may correlate with time to progression 
and overall survival [24].  
 
A phase I dose ranging study was completed that evaluated the safety and 
immunogenicity of administering an allogeneic HER2-positive granulocyte-macrophage 
colony-stimulating factor (GM-CSF) secreting tumor vaccine in combination with low-
dose CY and doxorubicin in patients with metastatic breast cancer. Patients received 
three monthly immunizations with a booster vaccine 6-8 months from study entry. This 
study found that low dose CY can augment the magnitude of vaccine-induced humoral 
immunity, but the therapeutic window for enhancing immune responses was narrow. 
Specifically, 200 mg/m2 of CY augmented the magnitude of HER2-specific humoral 
immunity, whereas doses above 200 mg/m2 were more likely to suppress both delayed 
type hypersensitivity and antibody responses. The addition of CY did not potentiate 
vaccine-related toxicity [25]. Thus, these findings provide the scientific rationale to 
continue to test combinations of vaccine with other more potent immune modifying 
agents. 


 
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Safety and Feasibility Study of an Allogeneic Colon Cancer Cell Vaccine 
Administered with a GM-CSF Secreting Bystander Cell line in Combination with 
Cyclophosphamide in Patients with Metastatic Colon Cancer 
 
Nine patients were treated in this dose-escalating safety and feasibility study. Prior to 
treatment, six patients underwent curative metastasectomy for hepatic metastases of 
colorectal adenocarcinoma and the other three had nonresectable metastatic colorectal 
adenocarcinoma. The investigational colon cancer vaccine consists of three components: 
a) SW837 cell line derived from a primary colorectal adenocarcinoma, b) SW620 cell 
line derived from a lymph node metastasis of colorectal adenocarcinoma, and c) 
K562/GM-CSF cell line, which is a K562 cell line derived from a CML patient in a blast 
crisis and subsequently transfected with a plasmid vector encoding human GM-CSF. A 
classical ‘3+3’ dose escalation design was adopted in this trial. Three patients were 
treated at dose level 1 (5x107 colon cancer cells + 4 x 107 K562). No dose limited 
toxicities (DLT) were observed in the first 3 patients, therefore six patients were treated 
at dose level 2 (5x108 colon cancer cells + 2 x 108 K562). No DLTs were observed at 
dose level 2. Patients received up to four monthly vaccinations. Patients received an 
immunomodulatory dose of cyclophosphamide 200mg/m2 intravenously one day prior to 
each vaccine administration.  
 
Local reactions at vaccination sites including erythema, induration, pruritis, and 
tenderness were observed with every vaccination in all patients, similar to those reported 
in patients who received GM-CSF producing tumor vaccine of other disease types. 
Minimal systemic toxicities were observed. The most common side-effects are transient, 
low grade fever, chill, nausea and headache. Fever and chill are likely attributive to the 
vaccine treatment; and nausea is likely attributive to the cyclophosphamide treatment. 
Headache may be attributive to ondansetron, which was given as an optional anti-emetic 
prophylactic treatment prior to the administration of cyclophosphamide. There has been 
no incidence of anaphylaxis secondary to the vaccine reported thus far. Grade 3 
lymphopenia was transiently observed in one patient, presumably attributive to the 
cyclophosphamide treatment. Thus, the higher dose level comprised of 2.5 x 108 cells per 
colon tumor cell lines and 2 x 108 GM-CSF-producing K562 cells is considered to have 
an acceptable degree of safety. In addition, cyclophosphamide at 200 mg/m2 
intravenously was well tolerated. 
 
2.3 
Anti-PD-1/PD-L1 therapy (Pembrolizumab (MK-3475 or Keytruda)) 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [26]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the 
ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with 
improved prognosis and long-term survival in solid malignancies such as ovarian, 
colorectal and pancreatic cancer, hepatocellular carcinoma, malignant MEL and RCC. 
TILs can be expanded ex vivo and re-infused, inducing durable objective tumor responses 
in cancers such as melanoma [27, 28]. 
 


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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in various tumors [29-32]. 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 [29]. Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor. High expression of PD-L1 on tumor cells (and to 
a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in 
various cancer types, including renal cell carcinoma (RCC) [33], pancreatic carcinoma 
[34], hepatocellular carcinoma [35], ovarian carcinoma [36]. Furthermore, PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with malignant 
melanoma [37]. The observed correlation of clinical prognosis with PD-L1 expression in 
multiple cancers suggests that the PD-1/PD-L1 pathway plays a critical role in tumor 
immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved 
in the United Stated for the treatment of patients with unresectable or metastatic non-
small-cell lung cancer (NSCLC) and melanoma. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 


 
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2.4 
Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure [IB] for Preclinical and Clinical Data 
 
2.5 
Rationale 
PD-1 checkpoint inhibitors have shown durable responses in a wide variety of tumors. 
However, in colorectal cancer, single agent pd-1 blockade with pembrolizumab has little 
or no activity in the majority of patients. A small subset of advanced colorectal 
carcinoma (<5%) is MMR-deficient (MMR-d) colorectal carcinoma. MMR-d, also 
referred to as microsatellite instability (MSI), is biologically marked by genomic 
instability with the potential of high numbers of neo-antigens and well described 


 
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increases in tumor-infiltrating lymphocytes (TILs) compared to other subtypes. In 
exploratory clinical trials, single agent pembrolizumab has been shown durable objective 
responses in many patients with MMR-d cancers. However, MMR-p colorectal cancer is 
the largest subtype of colorectal cancer, estimated to be between 90-95% of advanced 
disease. How to overcome the ineffectiveness of pembrolizumab in MMR-p colorectal 
cancer is therefore an important objective.  
The preclinical/clinical researchers at Johns Hopkins with GVAX in pancreatic cancer 
and colon cancer have suggested that GVAX may prime an immune checkpoint inhibitor 
insensitive cancer into a sensitive one. We recently reported the results of a novel study 
of GVAX given as both neo-adjuvant and adjuvant therapy, either alone or with immune 
modulating doses of cyclophosphamide (Cytoxan, Cy) to deplete regulatory T cells 
(Tregs) [38]. Pathological examination of PDA tumor tissue resected just two weeks 
following a single neoadjuvant dose of GVAX identified the formation of novel vaccine-
induced, immunologically active, tertiary lymphoid aggregates, organized lymph node-
like structures that are not observed in tumor tissue resected from unvaccinated patients. 
Our study showed for the first time that a vaccine-based immunotherapy can reprogram 
an immunologically quiescent tumor microenvironment (TME) into an immunologically 
active TME.  However, activated T cells secrete interferon-, which in turn upregulates 
the PD-1/PD-L1 pathway. These data support an emerging concept that vaccines are 
required to induce a T cell response that is capable of infiltrating the TME. However, 
vaccination is just the first step toward establishing an effective antitumor immune 
response, converting the TME into an environment similar to what is observed in MMR-d 
colon cancer exhibiting infiltrating but immunosuppressed T cells prior to 
immunotherapy treatment. Thus, we hypothesize that treatment with GVAX primes the 
TME for anti-PD-1/PD-L1-targeted therapy [39]. 
To support this hypothesis, we showed in a preclinical model of PDA that combining 
anti-PD-1 and anti-PD-L1 antibodies with GVAX+Cy enhances the infiltration of 
effector T cells into PDA tumors as well as the cure rate in PDA tumor-bearing mice 
[40]. Others have showed the synergistic effect of anti-PD-1 antibody and colon GVAX 
in colon tumor-bearing mice [41]. We found that GVAX treatment can also induce the 
membranous expression of PD-L1 in colon tumors in the mouse model. Therefore, we 
propose a clinical trial concept to examine the objective response rate of the combination 
of pembrolizumab and GVAX in MMR-p, advanced colorectal cancer. 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
3.1.1 Pathologically confirmed, mismatch repair-proficient adenocarcinoma of 
colorectum, who have received at least two prior lines of therapy in the 
metastatic setting. 
 
 
 
 
 
3.1.1.1 Mismatch repair proficiency can be assessed for eligibility by 
immunohistochemistry (intact expression of MLH1, MSH2, PMS2, and 
MSH6) or by molecular testing in a CLIA-certified laboratory for 
microsatellite instability (0 or 1 microsatellites unstable) 
 


 
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3.1.2 Measurable disease by RECIST v1.1.  
 
3.1.3 Age >18 years 
 
3.1.4 ECOG performance status 0-1 (Appendix A) 
 
3.1.5 Estimated life expectancy of greater than 3 months 
 
3.1.6 Adequate hematologic, renal, and liver function as defined below: 
 
Absolute neutrophil count 
> 1,500 cells/mm3 
Hemoglobin 
> 9g/dL (transfusion allowed but must 
demonstrate stability after transfusion) 
Platelets 
> 75K/mm3 
Serum creatinine 
≤ 2.0mg/dL 
AST and ALT  
≤ 3 x ULN 
Total bilirubin 
≤ 1.5 x ULN* 
 
*Subjects with Gilbert’s Syndrome should have direct bilirubin within normal 
institutional limits 
 
3.1.7 Women of childbearing potential (WOCBP) must have a negative urine or 
serum pregnancy test for the patient to be eligible for trial enrolment. In a case 
of a positive HCG test, a vaginal ultrasound must be used to confirm a lack of 
pregnancy.  
 
3.1.8 WOCBP must be willing to use either two adequate barrier methods or a 
barrier method plus a hormonal method of contraception to prevent 
pregnancy, or to abstain from heterosexual activity (complete abstinence) 
throughout the study, starting with visit 1 through 120 days after the last dose 
of study therapy. Approved contraceptive methods include for example; 
intrauterine device, diaphragm with spermicide, cervical cap with spermicide, 
male condoms, female condoms with spermicide, or oral contraceptives. 
Spermicides alone are not an acceptable method of contraception. Non-
pregnant, non-breast-feeding women may be enrolled if they are considered 
highly unlikely to conceive. Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age 
and has not had menses for greater than 2 years will be considered 
postmenopausal), or 3) amenorrheaic for <2 years without a hysterectomy and 
oophorectomy and with a documented FSH value in the postmenopausal 
range, or 4) not heterosexually active for the duration of the study, or 5) 
heterosexually active and willing to use 2 methods of birth control (which is 
also required for the female partners of male patients). 
Male patients must agree to use an adequate method of contraception, or to 
abstain from heterosexual activity (complete abstinence), starting with the first 
dose of study drug through 120 days after the last dose of study therapy. 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent 


 
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document. 
 
3.2.10 Willing to undergo tumor biopsy at baseline and during treatment (during 
week 6 or 7). Please note that tumor biopsy is not needed in subjects where 
the tumor is not accessible or if tumor biopsy is considered not in patient’s 
best interest. 
 
3.2 
Exclusion Criteria 
 
 3.2.1 Has a known additional malignancy that is progressing or requires active 
treatment.  Exceptions include basal cell carcinoma of the skin or squamous 
cell carcinoma of the skin that has undergone potentially curative therapy or in 
situ cervical cancer. 
 
3.2.2 Has known central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
 
3.2.3  Patients with malignant small bowel obstruction within the last 6 months, on 
parenteral nutrition, clinically significant ascites (palpable on physical exam 
and/or causing symptoms) or ascites requiring fluid removal more than twice 
in the last 6 weeks. 
 
3.2.4 Has active autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
 
3.2.5 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to the 
first dose of trial treatment. 
 
3.2.6 Has an active infection requiring systemic therapy. 
 
3.2.7 Has a known history of active TB   (Bacillus Tuberculosis) 
 
3.2.8 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
 
3.2.9 Has known history of Hepatitis B or Hepatitis C  
 
3.2.10 Has history of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease or active, non-infectious pneumonitis.  
 
3.2.11 Must not require supplemental oxygen or have a pulse oximetry < 92% on 
room air. 
 
3.2.12 Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the 


 
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subject’s participation for the full duration of the trial, or is not in the best 
interest of the subject to participate, in the opinion of the treating investigator. 
 
3.2.13 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
3.2.14 Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening 
visit through 120 days after the last dose of trial treatment. Women of 
childbearing potential must have a negative urine HCG (refer to Section 
3.1.7) 
 
3.2.15 Is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an 
investigational device within 4 weeks of the first dose of treatment. 
 
3.2.16 Has had prior chemotherapy, targeted small molecule therapy, or radiation 
therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
Grade 1 or at baseline) from adverse events due to a previously administered 
agent. 
 
 
 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
 
 
 
3.2.17 Patients who have had surgery within 4 weeks of dosing of investigational 
agent, excluding minor procedures (dental work, skin biopsy, etc), celiac 
plexus block, and biliary stent placement. 
 
3.2.18 Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior 
to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to agents administered more than 4 weeks earlier. 
 
3.2.19 Has received a live vaccine within 30 days of planned start of study therapy. 
 
 
 
 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
 
3.2.20 Has received prior therapy with any other systemic immunotherapy treatment, 
including but not limited to: IL-2, interferon, anti-PD-1 antibodies, anti-PD-
L2 antibodies, anti-CD137 antibodies, anti-OX-40 antibodies, anti-CD40 
antibodies, anti-CTLA-4 antibodies, therapeutic anticancer vaccines, cellular 
immunotherapies including chimeric antigen receptor–modified T cells, or bi-
specific CD3 antibodies.  
 
3.2.21 Patients receiving growth factors including, but not limited to, granulocyte-
colony stimulating factor (G-CSF), GM-CSF, erythropoietin, within 14 days 
of study drug administration. Use of such agents while on study is also 
prohibited. 


 
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3.2.22 Hypersensitivity to pembrolizumab or any of its excipients. 
 
3.2.23 Patient has a known or suspected hypersensitivity to GM-CSF, hetastarch, 
corn, dimethyl sulfoxide, fetal bovine serum, trypsin (porcine origin), yeast or 
any other component of GVAX vaccine. 
 
3.2.24 Patient is unwilling or unable to follow the study schedule for any reason. 
 
3.2.25 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Patients with a history of 
allogeneic hematopoietic stem cell transplant will also be excluded. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  
 
4. TREATMENT PLAN 
 
4.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and 
potential risks are described in Section 6. Appropriate dose modifications are 
described in Section 5. No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Table 1: Study Regimen 
 
Agent 
Premedications, 
Precautions 
Dose 
Route 
Cyclophosphamide 
Subjects may be 
pre-medicated with 
anti-emetics 
200 mg/m2 in 
100 mL NS 
IV infusion over 
30 minutes 
GVAX 
Lidocaine-based 
topical anesthetic 
(approximately 2.5 
grams per site, at 
least 1 hour prior to 
vaccination) 
5x108 (colon 
cancer cells) + 
5x107 (GM-CSF 
secreting cells) 
8-9 Intradermal 
injections 
Pembrolizumab 
No prophylactic 
pre-medications 
unless indicated by 
previous experience 
in an individual 
subject 
200 mg 
IV over 30 
minutes 
Pembrolizumab should be administered after cyclophosphamide, with a minimum of 
30 min wait time between infusions. Infusion times are approximate (+/- 10 min) and 
may need to be adjusted based on subject tolerability. 


 
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Please see Section 5.2 for guidance regarding dosing delays. 
 
4.1.1 GVAX GVAX is administered through a total of 8-9 intradermal injections. 
Because the spatial distribution of vaccine cells among three or more lymph 
node regions primes a more potent anti-tumor immune response distributed 
equally among the right and left thighs, and the non-dominant arm. In the 
event that the specified limb is contraindicated, the dominant arm may be 
used. 
No pre-medications will be administered except a lidocaine-based topical 
anesthetic (may include but is not limited to EMLA or ELA-MAX) cream, 
which will be applied to the injection site at least 1 hour prior to vaccination 
to diminish the discomfort associated with intradermal injections. The patient 
must be observed in the clinic for at least 60 minutes after the first vaccine 
and 30 minutes for subsequent vaccinations. Acute reactions will be managed 
using standard therapy for acute drug reactions as per institutional standard of 
care and reported to the sponsor. 
4.1.2 Cyclophosphamide (CY, CytoxanR) Cy is a FDA-approved and widely used 
chemotherapy agent. Subjects may be pre-medicated prior to administration 
with anti-emetics per institutional guidelines. Acute reactions will be managed 
using standard therapy for acute drug reactions as per institutional standard of 
care and reported to the sponsor. 
4.1.3 Pembrolizumab (KEYTRUDA®, MK-3475) 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. It is FDA-approved for treating metastatic melanoma and metastatic 
PDL1 positive non-small cell lung cancer. Pembrolizumab will be 
administered IV over 30 minutes at 200 mg. Antiemetic medications should 
not be routinely administered prior to dosing except as indicated by patient’s 
prior reaction. Acute reactions will be managed as described in Section 4.2.3.1 
below. 
 
4.2 
General Concomitant Medication and Supportive Care Guidelines 
 
In general, concomitant medications and therapies deemed necessary for the 
supportive care and safety of the subject are allowed, provided their use is 
documented in the subject records and on the appropriate case report form. If toxicity 
occurs, the appropriate treatment will be used to ameliorate signs and symptoms 
(including antiemetics for nausea and vomiting, anti-diarrheals for diarrhea and anti-
pyretics and anti-histamines for drug fever). All supportive measures for optimal 
medical care will be given during the period of study.  
 
4.2.1 Cyclophosphamide (Cy) 
 
Cyclophosphamide is commonly used in chemotherapy to treat a variety of 
cancer diseases. Although cyclophosphamide is administrated at low doses, 
subjects may still experience the side effects below, but generally the side 


 
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effects tend to be milder than standard dose cyclophosphamide. Side effects 
that have reported with cyclophosphamide, when it is given at a standard dose, 
include: 
 Common toxicities: leucopenia/neutropenia, low appetite, nausea, 
vomiting, fatigue, and hair loss.  
 Less common toxicities: hyponatremia, early menopause, hematuria, and 
pain due to inflammation in the bladder, liver, lungs, or veins 
 Rare but clinical important toxicities: hives, blurry vision, numbness 
and tingling of the mouth and throat, pulmonary fibrosis. Treatment with 
Cytoxan can also increase the risk of other cancers (bladder and skin cancers, 
leukemia). 
 
Acute reactions will be managed using standard therapy for acute drug 
reactions as per institutional guidelines 
 
4.2.2 GVAX  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
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Local skin reactions at vaccine sites may be treated with cold packs, topical 
lotions (e.g. aloe vera or vitamin E). Pruritus can be managed with topical or 
systemic benadryl. Significant local inflammation leading to severe pain may 
be treated with oral analgesics. Local ulceration should be managed with local 
wound care, with or without antibiotics, and should be evaluated on a case-by-
case basis. 
 
4.2.3 Pembrolizumab (KEYTRUDA®, MK-3475) 
 
Pembrolizumab is a humanized monoclonal Ab. Subjects should be closely 
monitored for potential adverse reactions during antibody infusion and 
potential adverse events throughout the study.  
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated 
within 24-72 hours if clinically indicated and monitored as necessary to 
determine if event meets toxicity criteria. 
 
4.2.3.1 Infusion Reactions 
 
Pembrolizumab infusion reactions may consist of fever, chills/rigor, nausea, 
pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness or hypertension. Severe reactions may include 
acute respiratory distress syndrome, myocardial infarction, ventricular 
fibrillation, and cardiogenic shock. Patients should be closely monitored for 
such reactions. Guidelines for patients who experience an infusion related or 
allergic reaction during or after infusion with pembrolizumab are shown 
below. 
 
 
 


 
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Table 2: Guidance on Infusion and Hypersensitivity Reactions 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h (± 30 
minutes) prior to infusion of pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or equivalent dose 
of antihistamine). 
 
Acetaminophen 500-1000 mg po (or equivalent 
dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 
 
 
4.2.3.2 Immune-Related Adverse Events (IRAEs)  
 
Blocking PD-1 function may permit the emergence of auto-reactive T cells 
and 
resultant 
clinical 
autoimmunity. 
Rash/pruritis, 
diarrhea/colitis, 
pneumonitis, hepatitis, and hypothyroidism were drug-related, presumptive 
autoimmune events, now termed IRAEs.  
 
For the purposes of this study, an IRAE is defined as an AE of unknown 
etiology, associated with drug exposure and is consistent with an immune 
phenomenon. Efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an AE an IRAE. 
Serological, immunological, and histological (biopsy) data should be used to 
support the diagnosis of an immune-mediated toxicity. Suspected IRAEs must 


 
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be documented on an AE or SAE CRF. Identification and treatment of IRAEs 
can be found in Appendix B. 
 
4.3  
Prohibited and Restricted Therapies 
 
Patients may not use any of the following agents during the study: 
 
 Any non-study anticancer or immunotherapy treatments (investigational or 
non-investigational) 
 
 Any other cancer immunotherapy treatments, including but not limited to: IL-
2, interferon, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 
antibodies, anti-CD137 antibodies, anti-OX-40 antibodies, anti-CD40 
antibodies, anti-CTLA-4 antibodies, therapeutic anticancer vaccines, cellular 
immunotherapies including chimeric antigen receptor–modified T cells, or bi-
specific CD3 antibodies. 
 
 Systemically active steroids can be used but should be reported to the 
Principal Investigator and IND Sponsor. Steroid treatment should be titrated 
down to physiologic dosing  prior to resuming study-related treatments (See 
Section 5.2 for dosing delays for steroids) 
 
 Filgrastim (Neupogen® or G-CSF) or sargramostim (Leukine® or GM-CSF) 
 
 Prophylactic vaccines (e.g., influenza, pneumococcal, Td/Tdap) within 28 
days prior to or after dosing combination immunotherapy 
 
 Mistletoe 
 
4.4  
Dosing Criteria 
 
Dosing will be delayed for the following laboratory criteria:  
 
 AST, ALT > 3.0 x ULN  
 Total bilirubin >2.0 (patients with diagnosed Gilbert’s Syndrome, direct bilirubin 
should be within normal institutional limits) 
 Hemoglobin < 8 g/dL 
 ANC < 1000/uL  
 Platelets < 75 x 103/uL 
 
4.5 
Definition of an Overdose for this Protocol 
 
Overdose of pembrolizumab is defined as: 
The patient has taken (accidentally or intentionally) a dose of pembrolizumab of 
≥1000mg (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab 
should be discontinued and the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 


 
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If an adverse experience(s) is associated with (“results from”) the overdose of test 
drug or vaccine, the adverse experience(s) is reported as a serious adverse experience, 
even if no other criteria for serious are met. 
If a dose of test drug or vaccine 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 experience must be reported 
within 24 hours to the Sponsor and Merck Global Safety. Merck Global Safety (GS) 
contact information can be found in Section 6.5.1. 
4.6 
Contraception, Use in Pregnancy, Use in Nursing 
 
4.6.1 Contraception 
 
The investigational agents may have adverse effects on a fetus in utero. Furthermore, 
it is not known if the investigational agents have transient adverse effects on the 
composition of sperm. Non-pregnant, non-breast-feeding women may be enrolled if 
they are considered highly unlikely to conceive. Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years 
of age and has not had menses for greater than 2 years will be considered 
postmenopausal), or 3) amenorrheaic for <2 years without a hysterectomy and 
oophorectomy and with a documented FSH value in the postmenopausal range, or 4) 
not heterosexually active for the duration of the study, or 5) heterosexually active and 
willing to use 2 methods of birth control (which is also required for the female 
partners of male patients). The 2 birth control methods can be 2 barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy, used throughout the 
study starting with Visit 1through 120 days after the last dose of study medication. 
Male patients enrolled in this study must also agree to use an adequate method of 
contraception starting with Visit 1 through 120 days after the last dose of study drug. 
 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide. 
Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including 
oral, subcutaneous, intrauterine, or intramuscular agents). 
 
Patients should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order 
to participate in the study, they must adhere to the contraception requirement 
(described above) for the duration of the study. If there is any question that a patient 
will not reliably comply with the requirements for contraception, that patient should 
not be entered into the study. 
 
4.6.2 Use in Pregnancy 
 


 
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The investigational agents may have adverse effects on a fetus; therefore, women 
with a positive pregnancy test at screening will not be eligible for enrollment. If a 
patient inadvertently becomes pregnant while on treatment with combination 
immunotherapy, the patient will immediately be removed from the study. The site 
will contact the patient at least monthly and document the patient’s status until the 
pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor and to Merck Global Safety without delay. The outcome must 
be reported to the Sponsor within 24 hours and to Merck Global Safety 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). If a male 
patient’s partner becomes pregnant on study the pregnancy must be reported to the 
Sponsor and to Merck Global Safety as described in Section 6.5.1. 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 and to 
Merck Global Safety. 
 
4.6.3 Use in Nursing Women 
 
It is unknown whether the investigational agents are 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, patients who are breast-feeding are not 
eligible for enrollment. 
 
4.7 
Dose Limiting Toxicity 
 
 
Unless otherwise specified below, unacceptable toxicities are defined as: 
 Treatment-related ≥ grade 4 AEs, or  
 Treatment-related grade 3 AEs that do not improve to ≤ grade 2 under 
supportive therapy within 3 weeks. 
 Death within 30 days of receiving investigational agent that is considered 
related to the agent as a study stopping criterion 
 
Hematologic toxicity 
The only adverse hematologic events that will be considered dose limiting are: 
 Grade 4 anemia related to study therapy 
 Grade 4 neutropenia that lasts > than 7 days or febrile neutropenia 
 Grade 4 thrombocytopenia that lasts greater than 7 days or has clinically 
significant bleeding 
 
Electrolyte aberrations 
 Unexpected Grade 3 or greater laboratory abnormalities should be repeated 
within 24-72 hours if clinically indicated and monitored as necessary to 
determine if event meets toxicity criteria. 
 Patients may continue therapy without interruption for any electrolyte 
abnormality that can be corrected with intervention to < grade 2. 
 
Diarrhea/Colitis 


 
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Grade 1 
Asymptomatic pathologic 
or radiographic findings 
only 
Consider endoscopy to confirm 
Grade 2 
Abdominal pain; mucus or 
blood in stool 
Endoscopy is indicated to confirm the 
etiology of the patient’s symptoms. 
Hold 
therapy, 
start 
lomotil 
and 
budesonide 
9mg 
daily 
and 
start 
systemic steroids. Therapy may be 
resumed only when patient returns to ≤ 
grade 1. If symptoms are not controlled 
within 7 days of initiating budesonide, 
contact Dr. Azad or Dr. Yarchoan. 
Grade 3 
Abdominal 
pain, 
fever, 
change in bowel habits 
with ileus; peritoneal signs 
Endoscopy is indicated to confirm the 
etiology of the patient’s symptoms. 
Hold 
therapy, 
start 
lomotil 
and 
budesonide 
9mg 
daily 
and 
start 
systemic steroids. Continue steroids 
until symptoms improve to grade 1, 
then taper. Therapy may be resumed 
only when patient returns to ≤ grade 1. 
If symptoms are not controlled within 7 
days of initiating steroids, contact Dr. 
Azad or Dr. Yarchoan. Patients should 
be taken off study if symptoms are not 
controlled within 14 days. 
Grade 4 
Life-threatening 
consequences (perforation, 
bleeding, 
ischemia, 
necrosis, toxic megacolon) 
Permanently discontinue therapy 
 
 
 
Hepatitis 
Grade 1 
ALT/AST > ULN – 
2.5 x ULN; Bilirubin > 
ULN – 1.5 x ULN 
Maintain 
treatment, 
but 
increase 
frequency of liver function testing 
Grade 2 
ALT/AST > 2.5 – 5.0 
x ULN; Bilirubin > 
1/5 – 3.0 x ULN 
Maintain treatment, increase frequency 
of liver function testing, consider 
systemic steroids until liver function 
tests return to ≤ grade 1. 
Grade 3 
ALT/AST > 5.0 – 20.0 
x ULN; Bilirubin > 3.0 
– 10.0 x ULN 
Permanently 
discontinue 
therapy. 
Hepatology consultation is indicated to 
confirm the etiology of the patient’s 
symptoms. Start systemic steroids. Rule 
out infectious causes of hepatitis.  
Grade 4 
AST/ALT 20.0 x 
ULN; Bilirubin > 10.0 
x ULN 
Permanently discontinue therapy. 


 
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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. 
 
Pneumonitis 
Grade 1 
Asymptomatic; clinical or 
diagnostic observations 
only; 
intervention 
not 
needed 
Hold MK-3475 but may continue 
Cy/GVAX. Monitor symptoms every 2-
3 days. Consider pulmonary consult 
and/or systemic steroids. May resume 
MK-3475 
when 
symptoms 
near 
baseline. 
Grade 2 
Symptomatic; 
medical 
intervention 
indicated 
limited instrumental ADLs 
Hold MK-3475 but may continue 
Cy/GVAX. Monitor symptoms every 2-
3 days. Obtain pulmonary consult and 
initiate 
systemic 
steroids 
(1/2 
mg/kg/day prednisone or equivalent). 
Consider 
hospitalization 
and 
bronchoscopy. Hold MK-3475 and 
continue 
systemic 
steroids 
until 
symptoms near baseline. If symptoms 
persist for 3 weeks or re-develop upon 
re-challenge, permanently discontinue 
MK-3475. 
Grade 3 
Severe symptoms; limiting 
self-care 
ADL; 
oxygen 
indicated 
Permanently discontinue therapy and 
admit to the hospital. Obtain pulmonary 
and ID consults, and treat with systemic 
steroids (1/2 mg/kg/day prednisone or 
equivalent) 
and 
prophylactic 
antibiotics. Recommend bronchoscopy 
and consideration of lung biopsy. 
Consider 
addition 
of 
additional 
immunosuppressant (eg anti-  tumour 
necrosis factor alpha, IVIG, etc.) 
Grade 4 
Life-threatening respiratory 
compromise; 
urgent 
intervention indicated (e.g. 
tracheostomy 
or 
intubation). 
 
 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Type 1 
diabetes 
mellitus (if 
new onset) or 
Hyperglycem
ia 
T1DM or  
3-4 
Hold therapy for new 
onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia 
associated with 
evidence of beta cell 
failure. 
May resume therapy when 
patients are clinically and 
metabolically stable. 


 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Hypophysitis 2-4 
Toxicity resolves to 
Grade 0-1. Therapy can 
be continued while 
endocrine replacement 
therapy is instituted 
Toxicity 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. 
Hyperthyroid
ism  
3 
Toxicity resolves to 
Grade 0-1 
Toxicity 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 
Hypothyroidi
sm 
 
Therapy can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy can be continued 
while thyroid replacement 
therapy is instituted. 
Infusion 
Reaction 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Renal Failure 
or Nephritis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity 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 
Toxicity2 
3 or 
Severe 
Toxicity resolves to 
Grade 0-1 
Toxicity 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 
 
The proportion of unacceptable toxicities will be monitored. If the toxicity levels are 
unacceptable (high probability that it is >45% of subjects), then enrollment will be 
suspended until further review and consideration by the IND Sponsor and MEC.  
 
4.8 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue 
indefinitely until one of the following criteria applies: 
 


 
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 
Continued radiographic evidence of disease progression on two subsequent 
imaging scans 6 weeks apart, 
 
 
Clinical progression or deterioration per Section 4.10, 
 
 
Intercurrent illness that prevents further administration of treatment, 
 
 
Unacceptable adverse event(s) as described in Section 4.7, 
 
 
Patient decides to withdraw from the study, or 
 
 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator, or 
 
 
Achieved a complete response to therapy, and received 6 weeks of therapy 
beyond the date when the initial complete response was declared without 
evidence of disease recurrence, or 
 
 
Completed 24 months of study medication or 35 administrations of 
Cy/GVAX/pembrolizumab, whichever is later. Note: 24 months of study 
medication is calculated from the date of first dose. Subjects who stop therapy 
after 24 months may be eligible for up to one year of additional study treatment 
if they progress after stopping study treatment provided they meet the initial 
study requirements. See Section 4.9 below. 
 
4.9 
Off Treatment Evaluation and Retreatment Criteria 
 
If a patient is discontinued from study medication after completion of 24 months of 
treatment, a mandatory Off Treatment Evaluation should be performed 30 days (+/- 7 
days) after the last treatment as described in the Study Calendar (Section 9). Patients 
should continue to be monitored for disease status by radiologic imaging and tumor 
marker(s) every 12 weeks (+/- 2 weeks). In addition, we will also continue to collect 
peripheral blood, serum, and plasma samples every 12 weeks (+/- 2 weeks) as 
described in the Study Calendar (Section 9). Patients will also be monitored for AEs 
up to the Off Treatment Evaluation or to resolution of drug-related AEs to ≤ Grade 1, 
whichever occurs later. SAEs that occur within 90 days of the last treatment or before 
initiation of a new antineoplastic treatment should also be followed and recorded.  
 
Retreatment Criteria 
 
Patients who stop therapy with SD or better may be eligible for up to one year of 
additional therapy with Cy/GVAX/pembrolizumab if they progress after stopping 
therapy and they meet the following criteria: 
 
EITHER: 
 
 
Stopped initial treatment with Cy/GVAX/pembrolizumab after attaining an 
investigator determined confirmed CR according to RECIST 1.1 
o Was treated for at least 24 weeks with Cy/GVAX/pembrolizumab before 


 
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discontinuing therapy 
o Received at least two treatments with Cy/GVAX/pembrolizumab beyond the 
date when the initial CR was declared 
 
OR: 
 
 
Subject had SD, PR or CR and stopped Cy/GVAX/pembrolizumab treatment after 24 
months of study therapy for reasons other than disease progression or intolerability 
 
AND: 
 
 
Experienced an investigator-determined confirmed radiographic disease progression 
after 
stopping 
their 
initial 
treatment 
with 
Cy/GVAX/pembrolizumab 
 
 
Did 
not 
receive 
any 
anti-cancer 
treatment 
since 
the 
last 
dose 
of 
Cy/GVAX/pembrolizumab 
 
 
Meets 
the 
initial 
study 
requirements 
as 
detailed 
in 
Section 
3.1 
 
 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication. 
 
Subjects who restart treatment should resume at the same dose and cycle interval 
which they were receiving prior to discontinuation. Study visit requirements are 
outlined in the Study Calendar (Section 9). 
 
 
4.10 Duration of Follow Up  
 
Patients will be followed for 30 days after their last dose of study drug or until death, 
whichever occurs first. SAEs that occur within 90 days of the last infusion of MK-
3475 or before initiation of a new antineoplastic treatment should also be followed 
and recorded. Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
Patients who discontinue from treatment should be contacted every three months to 
monitor overall survival. Information of other cancer therapies after discontinuation 
from the study treatment will be collected. 
 
At the end of the study, subjects will be required to enroll in a long-term follow-up 
protocol, an FDA requirement for genetically modified products, in which they will 
be followed for  at least 5 years (or until death) after receiving the last dose of any 
investigational agent for disease progression, survival, and potential long term 
toxicity of gene therapy. The subjects will be asked to enroll in the study entitled, 
“Long-Term Follow-Up of Patients who Received the Allogeneic Colon Cancer Cell 
Vaccine Administered with a GM-CSF Producing Bystander Cell Line.” 
 
4.11 Criteria for Removal from Study Treatment 
 


 
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Patients will be removed from study treatment when any of the criteria listed in 
Section 4.8 applies. The reason for study removal and the date the patient was 
removed must be documented in the Case Report Form. 
 
Patients with disease progression by radiographic imaging or laboratory parameters 
during the 12-week evaluation but without rapid clinical deterioration or significant 
change in performance status that requires additional immediate therapy may 
continue to receive treatment on study. Subjects that meet the above criteria and 
continue on study therapy must discontinue treatment upon documentation of disease 
progression on the second scan six weeks later, with the date of progression being 
backdated to the first RECIST 1.1 progression time point.  
 
NOTE: For patients who progress and remain on study, at the time of the next 
restaging, stable disease with clinical stability as determined by their treating 
physician/team can remain on study. Specifically, these patients do not have to have 
regression to <20% growth from baseline. If they do not have 20% increase from the 
last restaging scan, they may remain on study. 
 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
 
5.1  
Dose Modifications 
 
Dose reduction or dose increase of CY, GVAX, and pembrolizumab will not be 
permitted in individual patients. 
 
5.2  
Dosing Delays 
 
5.2.1 All scheduled cycles within a course are to be given approximately 3 weeks 
apart. If necessary, a cycle may be delayed for up to 1 week. In this case, 
subsequent cycles should continue so that a subject can still receive all cycles 
given that the cycles are a minimum of 3 weeks apart and they have not 
experienced an AE necessitating discontinuation. If delayed more than 1 week, 
the Principal Investigator must be contacted for further instructions on 
continued treatment. Additional delays or modifications to the treatment 
schedule must be approved by the Principal Investigator or IND Sponsor. 
 
If a delay occurs between Day 1 and 2 in a cycle: 
 Pembrolizumab-related infusion reactions must resolve to baseline prior to 
administration of GVAX. 
 Resume Day 2 treatment and assessment schedule without repeating Day 1 
study treatments if the delay is within 72 hours. 
 If the delay is longer than 72 hours, repeat Day 1 and Day 2 (if applicable) 
study treatments/assessments with a minimum of 1 week from the 
previous Day 1 treatment. This includes steroid treatment requiring at least 
a 14 day washout prior to resuming study-related treatments. 
 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic 
toxicities, non-hematological toxicity ≥ Grade 3 including laboratory 


 
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abnormalities, and severe or life-threatening AEs as per Table 5. 
 
Table 5: Pembrolizumab Dose Delay and Discontinuation Criteria 
 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken 
to 
pembrolizum
ab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of pneumonitis 
 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids 
(initial dose of 0.5- 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 


 
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34
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants 
with T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.   
 
 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as appropriate  
 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 Initiate thyroid 
replacement hormones (eg, 
levothyroxine or 
liothyroinine) per standard 
of care 
 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Nephritis and 
Renal dysfunction 
Grade 2 
Withhold  
 Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other immune-
related AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
 Based on type and severity 
of AE administer 
corticosteroids  
 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM).   
 


 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the Sponsor. With Sponsor and Merck agreement, 
subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue treatment in 
the trial only if asymptomatic and controlled. 
 
In the case that a participant develops intolerance or side effect that is attributable to one agent 
(for example, intolerance only to Cy/GVAX or intolerance only to pembrolizumab), the 
participant may, at his or her discretion, continue to receive the other active agent on study as 
otherwise indicated as long as they have received at least 1 full dose of both Cy/GVAX and 
pembrolizumab.  
 
6. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Active version for 
adverse 
event 
reporting 
that 
can 
be 
found 
at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected, recorded, and followed as appropriate.  
 
The PI has the primary responsibility for continuous internal monitoring for safety, protocol 
compliance, and identification, grading, coding, and required reporting of all anticipated and 
unanticipated adverse events and protocol problems. Although this responsibility is usually 
shared among the PI, research nurse, and data manager, the PI is ultimately responsible for 
grading and attribution of all events. 
 
All adverse events experienced by subjects will be collected and reported from the first dose 
of the investigational agent, throughout the study, and will only be followed for 90 days 
unless related to the investigational agent. All Serious Adverse Events (SAEs) will be 
collected for 90 days after the end of treatment. 
 
Subjects who have an ongoing adverse event related to the study procedures and/or 
medication(s) may continue to be periodically contacted by a member of the study staff until 
the event is resolved or determined to be irreversible by the investigator. 
 
Patients who experience a Grade 2 or higher irAE should be discussed with the IND Sponsor. 
In addition, irAEs listed in Section 6.1.3 must be reported as an Event of Clinical Interest 
(ECI) within 24 hours to the Sponsor and to Merck Global Safety even if no Serious Adverse 
Event Criteria are met. 
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will be 
recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as adverse events. A grade 1 or 2 clinical laboratory abnormality should be 
reported as an adverse event only if it is considered clinically significant by the investigator. 
 


 
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6.1 
Definitions 
 
6.1.1 Adverse Event (AE) 
 
Adverse event is defined as any undesirable sign, symptom or medical condition 
occurring after starting the study drug (or therapy) even if the event is not 
considered to be related to the study. An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or 
the abnormal results of an investigation (e.g., laboratory findings, 
electrocardiogram). Medical conditions/diseases present before starting the 
study treatment are only considered adverse events if they worsen after starting 
the study treatment (any procedures specified in the protocol). Adverse events 
occurring before starting the study treatment but after signing the informed 
consent form will not be recorded. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms or 
require therapy. 
 
6.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event is an undesirable sign, symptom or medical condition 
which:  
• Results in death  
• Is life threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe)  
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see note below for exceptions) > 24 hours 
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect (note: reports of congenital 
anomalies/birth defects must also be reported on the Pregnancy Supplemental 
Form)  
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention [eg, medical, surgical] to prevent one of the other 
serious outcomes listed in the definition above.). Examples of such events 
include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.) 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose 
 
Events not considered to be serious adverse events are hospitalizations for the:  
• Admissions as per protocol for a planned medical/surgical procedure or to 
facilitate a procedure 
• Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)  


 
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• Medical/surgical admission for purpose other than remedying ill health state 
and was planned prior to entry into the study. Appropriate documentation is 
required in these cases  
• Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of 
housing, economic inadequacy, care-giver respite, family circumstances, 
administrative). 
 
6.1.3 Adverse Events of Clinical Interest (ECI) for pembrolizumab 
 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported within 24 hours to the Sponsor and 
within 2 working days to Merck Global Safety using the form found in 
Appendix C. (Attn: Worldwide Product 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: 
 An overdose of Merck's product, as defined in Section 4.5, that is not 
associated with clinical symptoms or abnormal laboratory results.  
 An elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater 
than or equal to 2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is less than 2X the upper limit of normal, 
as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying 
etiology. 
6.2 
Relationship 
 
The relationship of an AE to the administration of the study drug is to be assessed by 
the investigator according to the following definitions:  
 


 
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 No (unrelated, not related, no relation):  The time course between the 
administration of study drug and the occurrence or worsening of the adverse event 
rules out a causal relationship and another cause (concomitant drugs, therapies, 
complications, etc.) is suspected.  
 
 Yes (related): The time course between the administration of study drug and the 
occurrence or worsening of the adverse event is consistent with a causal relationship 
and no other cause (concomitant drugs, therapies, complications, etc.) can be 
identified.  
 
The following factors should also be considered:  
 The temporal sequence from study drug administration - The event should occur 
after the study drug is given. The length of time from study drug exposure to event 
should be evaluated in the clinical context of the event.  
 Underlying, concomitant, intercurrent diseases - Each report should be evaluated 
in the context of the natural history and course of the disease being treated and any 
other disease the subject may have.  
 Concomitant medication - The other medications the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
might be recognized to cause the event in question.  
 Known response pattern for this class of study drug - Clinical and/or preclinical 
data may indicate whether a particular response is likely to be a class effect.  
 Exposure to physical and/or mental stresses - The exposure to stress might induce 
adverse changes in the recipient and provide a logical and better explanation for the 
event.  
 
The pharmacology and pharmacokinetics of the study drug - The known 
pharmacologic properties (absorption, distribution, metabolism, and excretion) of the 
study drug should be considered. 
 
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported 
during the study, which will be recorded in the CRF. The assessment will be based on 
the National Cancer Institute’s CTCAE (Version 4.03) and graded as shown below: 
 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the 
highest level experience by the subject. 


 
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6.3 
Expectedness 
 
Unexpected adverse event: An adverse event, which varies in nature, intensity or 
frequency from information on the investigational drug/agent provided in the 
Investigator’s Brochure, package insert or safety reports. Any adverse event that is 
not included in the informed consent is considered “unexpected”.  
 
Expected (known) adverse event: An adverse event, which has been reported in the 
Investigator’s Brochure. An adverse event is considered “expected”, only if it is 
included in the informed consent document as a risk. 
 
6.4 
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the Sponsor will notify investigators of all SAEs 
that are unexpected (i.e. not previously described in the Investigator Brochure), and 
definitely, probably, or possibly related to pembrolizumab, cyclophosphamide, or 
GVAX. This notification will be in the form of an expedited safety report (ESR) that 
is to be faxed to the investigators and the study coordinators within 48 hours. Upon 
receiving such notices, the investigator must review and retain the notice with the 
Investigator’s Brochure and where required by local regulations, the investigator will 
submit the ESR to the appropriate IRB. The investigator and IRB will determine if 
the informed consent requires revision. The investigator should also comply with the 
IRB procedures for reporting any other safety information. Where required, 
submission of ESRs by the investigator to Health Authorities should be handled 
according to local regulations.  
 
6.5  
Reporting 
 
6.5.1  General 
 
All adverse events (both expected and unexpected) will be captured on the 
appropriate study-specific case report forms (CRFs).  
 
In addition, all serious adverse events, regardless of causality to study drug, will 
be reported promptly to the IND Sponsor (Dr. Lei Zheng, 
) within 24 hours of recognition of the adverse event 
using the form found in Appendix D. If this falls on a weekend or holiday, an 
email notification is acceptable but must be followed by an SAE reporting form 
on the next business day. 
 
All serious adverse events, regardless of causality to study drug and/or 
administration will be forwarded to Merck’s Global Safety (“Merck GS”) group 
within 24 hours of learning of the event.  
 
After the initial SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department in regards to the 
subject’s condition. 
  


 
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All SAE(s) will be followed until: 
•         Resolution 
•         The condition stabilizes 
•         The event is otherwise explained 
•         The subject is lost to follow-up 
 
Within 24 hours of receipt of follow-up information, a follow-up SAE report will be 
submitted to the IND Sponsor, Merck GS. 
 
Non-serious Events of Interest will be forwarded to Merck GS and will be handled 
in the same manner as SAEs.  
 
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 who has provided written consent to provide 
information regarding pregnancy, that occurs during the trial or within 120 days 
of completing the trial. All 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 to Merck GS. 
SAE reports and any other relevant safety information are to be forwarded to 
Merck GS facsimile number: 
. 
 
6.5.2  Institutional Review Board (IRB) and Institutional Biosafety Committee (IBC) 
 
All serious adverse events will be reported to the IRB and IBC per institutional 
standards. Follow-up information will be given to the IRB and IBC as soon as 
relevant information is available, per institutional standards. 
 
6.5.3  Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the sponsor. 
 
6.5.3.1 Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:  
The Sponsor is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 
related to the investigational agent. Such reports are to be telephoned or faxed 
(
 to the FDA within 7 calendar days of first learning of the event.  
 
15 Calendar-Day Written Report:  
The Sponsor is required to notify the FDA of any serious adverse event that is 
unexpected and possibly related to the investigational agent in a written IND 
Safety Report.  


 
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Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32. All safety reports previously filed 
with the IND concerning similar events should be analyzed. The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports.  
 
Written IND safety reports with Analysis of Similar Events are to be submitted 
to the FDA within 15 calendar days of first learning of the event.  
 
6.5.3.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the Sponsor shall within 60 
days of the anniversary date that the IND went into effect submit a brief report 
of the adverse events and progress of the investigation. Please refer to Code of 
Federal Regulations, 21 CFR § 312.33 for a list of the elements required for the 
annual report. All IND annual reports will be submitted to the FDA by the 
Sponsor-Investigator. 
 
6.5.4 Recombinant DNA Advisory Committee (RAC) 
 
Unexpected SAEs believed to be related to GVAX will be reported to RAC by 
email if fatal or life-threatening within 7 calendar days or by written report if 
related and unexpected to GVAX within 15 calendar days. SAEs that are 
unrelated or related and expected with GVAX will be reported to RAC in the 
Annual Report. Follow-up information will be submitted to the RAC as soon as 
relevant information is available. 
 
7. PHARMACEUTICAL INFORMATION 
 
7.1  
Cyclophosphamide (Cytoxan®, CY) 
 
7.1.1 
Agent Accountability 
The IND Sponsor or the Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, 
storage, handling, distribution and usage of investigational product in accordance 
with the protocol and any applicable laws and regulations. 


 
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7.1.2 
Mode of Action 
 
CY is a synthetic antineoplastic drug chemically related to the nitrogen mustards. CY 
is biotransformed principally in the liver to active alkylating metabolites by a mixed 
function microsomal oxidase system. These metabolites interfere with the growth of 
susceptible rapidly proliferating malignant cells. The mechanism of action is thought 
to involve cross-linking of tumor cell DNA. 
 
7.1.3 
Description 
 
CY (CYTOXAN®; cyclophosphamide for injection, USP) is a sterile, white powder 
containing cyclophosphamide monohydrate and is supplied in vials for single-dose 
use. 
 
7.1.4 
Packaging and Labeling Information 
 
CY is commercially available. 
 
7.1.5 
Preparation 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Add 
the diluent to the vial and shake it vigorously to dissolve. If the powder fails to 
dissolve immediately and completely, it is advisable to allow the vial to stand for a 
few minutes. Use the quantity of diluent shown below to constitute the product: 
 
Dosage Strength 
CYTOXAN Contains 
Cyclophosphamide Monohydrate 
Quantity of Diluent 
 
500 mg 
534.5 mg 
25 mL 
1 g 
1069.0 mg 
50 mL 
2 g 
2138.0 mg 
100 mL 
 
CY may be prepared for parenteral use by infusion using any of the following methods: 
1. CY constituted with 0.9% sterile sodium chloride may be infused without further 
dilution. 
2. CY constituted with 0.9% sterile sodium chloride may be infused following further 
dilution in the following: 
 
 Dextrose Injection, USP (5% dextrose) 
 Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile 
sodium chloride) 
 5% Dextrose and Ringer’s Injection 
 Lactated Ringer’s Injection, USP 
 Sodium Chloride Injection, USP (0.45% sterile sodium chloride) 
 Sodium Lactate Injection, USP (1/6 molar sodium lactate) 
 
7.1.6 
Storage 


 
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Store vials at or below 77° F (25° C). 
 
7.1.7 
Stability 
 
CY (prepared for either direct injection or infusion) is chemically and physically 
stable for 24 hours at room temperature or for 6 days in the refrigerator; it does not 
contain any antimicrobial preservative and thus care must be taken to assure the 
sterility of prepared solutions. 
 
7.1.8 
Route of Administration 
 
CY is administered by IV injection over 30 minutes. 
 
7.1.9 
Subject Care Implications 
 
During treatment, the subject’s hematologic profile (particularly neutrophils and 
platelets) should be monitored regularly to determine the degree of hematopoietic 
suppression. 
 
The rate of metabolism and the leukopenic activity of CY reportedly are increased by 
chronic administration of high doses of phenobarbital. The physician should be alert 
for possible combined drug actions, desirable or undesirable, involving CY even 
though CY has been used successfully concurrently with other drugs, including other 
cytotoxic drugs. CY treatment, which causes a marked and persistent inhibition of 
cholinesterase activity, potentiates the effect of succinylcholine chloride. If a subject 
has been treated with CY within 10 days of general anesthesia, the anesthesiologist 
should be alerted. 
 
CY may interfere with normal wound healing. 
 
7.1.10 Returns and Reconciliation 
 
N/A 
 
7.2  
GVAX 
 
7.2.1 
Agent Accountability 
 
The IND Sponsor or the Sponsor’s representative shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, 
storage, handling, distribution and usage of investigational product in accordance 
with the protocol and any applicable laws and regulations. 
 
7.2.2 
Mode of Action 
 
GM-CSF secreting whole cell vaccines recruit and activate tumor specific T-cells and 
induce a cytotoxic response through two mechanisms: 1. they deliver a range of 
peptide antigens (without the need for specific knowledge of the relevant target 


 
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antigens), and 2. GM-CSF is an important growth and differentiation factor for 
dendritic cells, which are potent antigen-presenting cells. 
 
7.2.3 
Description 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
7.2.4 
Storage 
 
 
 
7.2.5 
Preparation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.6 
Stability 
 
 
 
7.2.7 
Route of Administration 
 
 
 


 
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7.2.8 
Subject Care Implications 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.9 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies, 
the amount dispensed to, and returned by the subjects and the amount remaining at 
the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 


 
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investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
7.3 
Pembrolizumab 
 
7.3.1 Agent Accountability 
 
The sponsor/investigator shall take responsibility for and shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and 
any applicable laws and regulations. 
 
7.3.2 Mode of Action 
 
Pembrolizumab is a highly selective humanized monoclonal antibody designed to 
block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Pembrolizumab is an IgG4/kappa isotype with a stabilizing sequence alteration in the 
Fc region.  
 
7.3.3 Description 
 
 
 
 
 
 
 
 
 
Packaging and Labeling Information 
 
 
  
7.3.5 
Preparation 
Refer to Procedures Manual for preparation instructions. 
 
7.3.6 
Storage 
 
 
 
  
 
 
 
 


 
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7.3.7 
Stability 
 
Refer to Procedures Manual for Stability information. 
 
7.3.8  
Route of Administration 
 
The reconstituted product is intended for IV administration.  
 
7.3.9  
Patient Care Implications 
 
Based on results from the nonclinical studies, there are currently no specific safety 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.10 
Agent Ordering 
 
 
 
 
  
 
 
 


 
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7.3.11  
Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to, and returned by the 
subjects and the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
8. CORRELATIVE/SPECIAL STUDIES 
 
Sample collection, processing, and storage instructions will be provided in the Laboratory 
Manual. The specimens below will be stored and evaluated in Dr. Zheng’s laboratory. 
 
8.1 
Tumor Tissue Studies 
 
Tumor biopsies will be performed on subjects with accessible tumor at baseline and 
during treatment (during week 6 or 7). However, tumor biopsy will not be performed 
either at baseline and/or during treatment if the tumor is not accessible or if biopsy is 
considered not in patient’s best interest. An additional biopsy at the time of response 
and/or progression is optional. Tumor samples will be collected by core biopsy from 
accessible tumor tissue. A maximum of 6 core biopsies (or fine needle aspirates, if 
cores are considered unsafe) will be obtained from each subject.  
Attempts will be made to obtain archived tissue samples from all subjects  
 
8.2  
Whole Blood Peripheral Blood Lymphocytes (PBLs) and Circulating Tumor 
Cells (CTCs) 
 
Up to 180 cc of whole blood will be collected for isolation of PBL at baseline (C1D1) 
and at every 6 weeks (with every other cycle of treatment) up to and including C5D1. 
After C5D1, blood will then be collected every 12 weeks (every 4th cycle; C9D1) and 
at the off study visit. In addition, up to 20 cc of whole blood may be 
collected/aliquoted for circulating tumor cell analyses.  
 
8.3  
Serum and Plasma Marker Studies 
 
Whole blood for serum (20 cc) and plasma (20 cc) will be collected at baseline 
(C1D1) and at every 6 weeks (with every other cycle of treatment) up to and 
including C5D1. After C5D1, blood with then be collected every 12 weeks (every 4th 
cycle; C9D1) and at the off study visit to identify potential therapeutic targets, 
biomarkers, circulating DNA analyses, and predictors of response and autoimmune 
toxicity through proteomic approaches.  
 
8.4 
Diagnostic Tissue Samples 
 


 
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Tissue, fluid, or blood may be collected from standard of care procedures used to treat 
or diagnoses immune related toxicities.  
 


 
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9. STUDY CALENDAR 
 
 
Screening 
Cycles 1-4 
Week 6 Week 12
Cycles 5 and Above21 
Off 
Treatment16 Off Study19 
Day 1 
Day 2 
Every Cycle Every 4th cycle
Visit Window1 
-14 to -1 
+/- 3 
 
+/-7 
+/-7  
+/-7 
+/-7 
+/-7 
+/- 7 
TREATMENT 
Cyclophosphamide 
 
X 
 
 
 
 
X21 
 
 
GVAX 
 
 
X 
 
 
 
X21 
 
 
Pembrolizumab 
 
X 
 
 
 
X 
 
 
 
CLINICAL ASSESSMENTS/TESTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
 
Concurrent medications 
X 
X 
 
 
 
X 
 
X 
X 
Physical Exam3 
X 
X 
 
 
 
X 
 
 
X 
Vital Signs and pulse ox4 
X 
X 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
X 
Performance Status 
X 
X 
 
 
 
X 
 
 
X 
CBC with differential 5,6 
X 
X 
 
 
 
X 
 
X 
X 
Complete Metabolic Profile5-7 
X 
X 
 
 
 
X 
 
X 
X 
TSH5, 8 
X 
X 
 
 
 
X 
 
X 
X 
Serum or Urine Preg9 
X 
X 
 
 
 
X 
 
 
 
Urinalysis and microscopic 
exam5 
X 
 
 
 
 
 
 
 
 
INR and pTT5 
X 
 
 
 
 
 
 
 
 
MRI brain with contrast 
X20 
 
 
 
 
 
 
 
 
Adverse event evaluation10 
 
X 
 
 
 
X 
 
X 
X 
Vaccine Site Assessment11 
 
X 
 
 
 
X 
 
X 
X 
ASSESSMENT OF RESPONSE AND CORRELATIVE STUDIES 
Archival tumor sample 
X 
 
 
 
 
 
 
 
 
CEA5,6 
X 
X 
 
X 
X 
X 
 
X 
X 
Tumor measurements12 
X 
 
 
 
X 
 
X 
X17
X 
Research Blood13 
 
X15 
 
 
 
 
X15 
X18
X 
Tumor Biopsy14 
X 
 
 
X 
 
 
 
 
X 
 
1) Longer delays to be approved by the sponsor 
2) Includes history of lung disease, HIV, hepatitis B or C infection, and complete cancer history, 
including primary site of cancer, gross location of primary tumor, secondary sites of cancer, 
histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, and prior 
cancer therapy regimens. 
3) Complete physical exam will be completed at baseline; focused physical examinations will be 
conducted thereafter. Exams, concomitant medication, AE assessments can be made up to 3 days 
prior to infusion. 
4) Temperature, respiration rate, blood pressure, pulse, and pulse ox should be taken prior to the 
administration of each of the drugs: CY, GVAX, and pembrolizumab. Vitals will also be 
collected post-GVAX. 
5) Labs may be collected within a window of up to 4 days prior to dosing. Unexpected Grade 3 
or greater laboratory abnormalities should be repeated within 24-72 hours if clinically indicated 
and monitored as necessary to determine if event meets toxicity criteria. 
6) Screening bloodwork does not need to be repeated if performed within 7 days of C1D1 
7) Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
8) Free T3/T4 to be checked reflexively if TSH is abnormal 
9) Serum or urine pregnancy for women of childbearing potential 


 
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10) Baseline adverse event evaluation may be performed either at the screening visit or at C1D1 
prior to the administration of therapy. 
11) Not applicable for first cycle, but applicable for day 1 of all subsequent cycles 
12) Tumor measurement will be performed with contrast CT chest/abdomen/pelvis. Noncontrast 
CT chest/abdomen/pelvis or CT Chest and MRI Abdomen/pelvis will be performed in subjects 
with contrast allergies. Baseline scans may be performed within 28 days prior to first treatment. 
If patients remain on study after initial progression, a repeat CT scan will be obtained at 6 weeks 
after progression (+/- 7 day window), 12 weeks after progression (+/- 7 days), and every 12 
weeks thereafter (+/- 7 days). If the off study visit occurs early, scans do not need to be repeated 
if one has been performed within 6 weeks. 
13) Baseline serum and plasma collection should be performed at C1D1 prior to the 
administration of therapy. Please see section on correlative studies (section 8). 
14) Only for subjects with tumor that is safely accessible for biopsy, a biopsy should be 
performed prior to initiation of therapy, and again at 6-7 weeks after initiation of therapy, and 
(optional) at the time of progression. Refer to section on correlative studies. Optional tumor 
biopsies may be performed at the time of clinical response as well. 
15) Follow-up peripheral blood collection will be performed at every other cycle of 
immunotherapy, (e.g. at C1D1, C3D1, C5D1) prior to the administration of therapy, up to and 
including C5D1 and then only on cycles where the patient receives GVAX therapy (e.g. every 4th 
cycle). 
16) Patients will undergo the Off Treatment Evaluation if they completed 24 months of study 
medication (Section 4.9). 
17) Patients should continue to be monitored for disease status by radiologic imaging and tumor 
marker(s) every 12 weeks (+/- 2 weeks). 
18) Peripheral blood, serum, and plasma samples should continue to be collected every 12 weeks 
(+/- 2 weeks). 
19) 30 days after their last dose of study drug or within 7 days prior to initiation of a new anti-
cancer treatment, whichever comes first. Patients who discontinue from treatment should be 
contacted every three months to monitor overall survival.  Information of other cancer therapies 
after discontinuation from the study treatment will be collected. SAEs that occur within 90 days 
of the last infusion of pembrolizumab or before initiation of a new antineoplastic treatment 
should also be followed and recorded. 
20) MRI brain with contrast performed in the 8 weeks prior to day 1 can be used to fulfill these 
criteria. 
21) After cycle 4, cyclophosphamide and GVAX will be administered with every 4th cycle (12 
weeks), restarting with cycle 8. Similar to cycles 1-4, pembrolizumab will administered on cycle 
day 1. For cycles that include cyclophosphamide and GVAX, cyclophosphamide will also be 
administered on day 1 and GVAX on day 2.  The treatment window for cycles beyond 4 is +/- 7 
days. 
 
 


 
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10. MEASUREMENT OF EFFECT 
 
10.1 Antitumor Effect – Solid Tumors 
 
10.1.1 Definitions 
 
Evaluable for toxicity. All subjects are evaluable for toxicity after receiving first 
dose of combined immunotherapy. 
 
Evaluable for objective response. All patients who have received at least two 
doses of immunotherapy and have had their disease re-evaluated with imaging 
will be considered evaluable for response. Response criteria will be classified by 
RECIST and irRECIST criteria (Appendix E and F) 
 
10.1.2 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 14 days before the beginning of 
the treatment. Subjects will be evaluated for anti-tumor effect by follow-up 
imaging (CT chest/abdomen/pelvis with IV contrast; noncontrast CT 
chest/abdomen/pelvis or CT Chest and MRI Abdomen/pelvis will be performed in 
subjects with contrast allergies, intolerance, elevated creatinine, or other 
contraindication). All subsequent scans (post-treatment) will be compared to the 
same pretreatment scan that was used prior to initiating of study treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by 
clinical exam. 
 
CT Chest/Abdomen/Pelvis: This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness.  
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement. Furthermore, the availability of MRI is variable globally. As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up should be the 


 
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same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence. It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body 
scans should be performed with breath-hold scanning techniques, if possible. 
 
10.1.3  Overall Survival (OS)  
 
OS is defined as the duration of time from start of study treatment to time of 
death. Individuals will be censored at the date of the last study visit if no event 
occurs. 
 
 
11.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event guidelines and instructions for AE reporting can be found in Section 6 
(Adverse Events: List and Reporting Requirements). 
 
11.1 Data Management 
 
All information will be collected on study-specific case report forms (CRFs) by study 
staff. These data will be reviewed for completeness and accuracy by the Principal 
Investigator.  
 
11.2 Safety Meetings 
 
Scheduled meetings will take place weekly and will include the protocol principal 
investigator, study coordinator(s), research nurse (s), and sub-investigators (as 
appropriate). During these meetings matters related to the following will be 
discussed: safety of protocol participants, validity and integrity of the data, 
enrollment rate relative to expectation, characteristics of participants, retention of 
participants, adherence to protocol (potential or real protocol violations), data 
completeness, and progress of data for objectives. 
 
Quarterly teleconferences will be scheduled to include the Investigator and Merck 
representatives. During these meetings, the Investigator shall provide Merck with study 
progress updates. The Investigator will provide a summary of key points from the 
weekly meetings with a focus on safety of the protocol participants, enrollment status, 
and progress of data for objectives. In addition, Merck will provide safety and 
applicable program updates to the Sponsor. 
 
11.3  Monitoring 
 


 
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This is a DSMP Level III study under the Johns Hopkins Sidney Kimmel 
Comprehensive Cancer Center (SKCCC). Data monitoring of this protocol will occur 
on a regular basis with the frequency dependent on the rate of subject accrual and the 
progress of the study. The protocol will be monitored internally by the Principal 
Investigator. The protocol will be monitored externally by the SKCCC CRO in 
accordance with SKCCC guidelines. Additional data and safety monitoring oversight 
will also be performed by the SKCCC Safety Monitoring Committee (SMC - as 
defined in the DSMP) and a Medical Expert Committee (MEC) as detailed below. 
  
The Medical Expert Committee (MEC) for this clinical study contains three medical 
oncologists from other disciplines who are not affiliated with this clinical trial 
protocol. The MEC will review safety data on at least a semi-annual basis. The MEC 
will provide a written summary of each assessment to the IND Sponsor after each 
meeting. In turn, the study team will forward these summaries to the JHU and other 
participating site IRBs and JHU SKCCC SMC. The operating plan of the MEC will 
be as follows:  
 Meetings will be held at least semi-annually, and potentially more frequently if 
needed.  
 Meetings will be conducted in-person or via video/teleconference, with a 
participant sign-in sheet collected at each meeting.  
 Approximately one week prior to each MEC meeting, the study team will submit 
the following items to MEC personnel for review and discussion at the meeting 
(The PI may join the MEC meeting in order to answer any questions the MEC 
might have):  
o A summary of the clinical trial’s progress to date;  
o The latest IRB-approved consent document;  
o A summary of all adverse events, serious adverse events, deaths, and 
withdrawals to date; 
  
Note that the MEC reserves the right to halt trial accrual or all study activity if, after 
review, serious safety concerns warrant this action. If the MEC halts study accrual or 
all study activity, then the study team must notify the JHU SKCCC SMC, JHU IRB, 
JHU IBC, RAC and the FDA immediately. 
  
Dr. Lei Zheng will be holding the IND for this study. He will comply with all 
regulated reporting requirements to the FDA. 
 
12. STATISTICAL CONSIDERATIONS 
 
12.1  Overview 
 
The proposed study is an open-label, single-arm phase II study of GVAX in 
combination with pembrolizumab in patients with metastatic colorectal cancer who 
have progressed at least two lines of therapies. Subjects with microsatellite instability 


 
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(MSI) would not be eligible for this study. The primary objective of the trial is to 
determine whether the combination of GVAX with pembrolizumab administered in 
this patient population yields a clinically compelling antitumor activity measured as 
objective response rate (ORR, assessed by RECIST 1.1). Secondary endpoints 
include safety, duration of response (DOR), progression-free survival (PFS), overall 
survival (OS), and immunologic correlates. The study is planned with 25 evaluable 
subjects based on a two-stage design that allows early termination for lack of 
efficacy. A safety run-in phase will be included to ensure that the combination of 
GVAX and pembrolizumab is safe. The study will be continuously monitored for 
adverse events after the safety run-in phase.  
  
At the beginning of the study, GVAX plus pembrolizumab will be tested in the first 6 
patients in the safety run-in portion of the study. These subjects will be monitored for 
unacceptable toxicities (defined in Section 4.7) through Cycle 1 of treatment before 
continuation with further accrual. The study will continue without pause to complete 
the accrual goal for the first stage if no more than 1 of the first 6 subjects experiences 
unacceptable toxicities (as defined as dose –limiting toxicities in cycle one in section 
4.7) in the run-in. If 2 of the 6 subjects experience unacceptable toxicities, the study 
will be paused for a review. If 3 or more of the first 6 subjects experience 
unacceptable toxicities with the combination therapy during the run-in, the study will 
be discontinued. The probability of observing 2 or more patients with DLT among the 
first 6 subjects is greater than 64% if the true incidence rate is greater than 33%. 
 
12.2  Sample Size and Accrual 
 
Approximately 25 patients with metastatic colorectal cancer who have progressed at 
least two lines of therapies will be enrolled according to this single-arm, Phase 2 trial, 
with ORR as the primary endpoint. Enrollment will be carried out in 2 stages so that 
the study can terminate early if GVAX in combination with pembrolizumab is not 
sufficiently effective. A recently published phase III study showed that TAS-102 
resulted in an ORR of 1.6% (95% confidence interval 0.7-3%) and the agent had an 
overall survival benefit vs. placebo in a similar patient population [42]. Simon’s 
minimax two-stage design will be employed to test the null hypothesis that the true 
ORR is 3% or less (not considered clinically compelling for this combination). In the 
first stage, 15 subjects will be accrued. If none of these 15 subjects respond, the study 
will be terminated. Otherwise, 10 additional subjects will be accrued to target a total 
of 25 treated and response evaluable subjects. If 3 or more responses are observed in 
these 25 subjects, we will conclude the combination of pembrolizumab with GVAX 
is promising and warrant further investigation. The study could also be terminated 
early as soon as 3 responses with the combination treatment are confirmed. The 
probability of stopping the trial early for futility is 63% if the true ORR is 3% or less. 
This design yields 89% power at a one-sided type I error rate of 5% when the true 
response rate is 20%. Subjects who are withdrawn from the study prior to receiving 
one cycle of the combination treatment of cyclophosphamide, GVAX, and 


 
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pembrolizumab for reasons other than disease progression will be replaced. The study 
may enroll 28-30 subjects to ensure 25 would be evaluable for the primary efficacy 
endpoint. 
 
More than 300 colorectal cancer patients seek primary oncology care at JHH and an 
additional 200 patients or more come to JHH for consultation each year. The majority 
of these patients have MMR-p metastatic disease. We estimate that approximately a 
third of the colorectal cancer patients seen at JHH would be potentially eligible for 
enrollment for the proposed study. We expect to enroll 2-3 patients per month. We 
estimate that we could reach the accrual goal within 1 year. 
 
12.3 Statistical analysis  
    
12.3.1 
Analysis of Primary Endpoint 
 
The objective response rate defined as the proportion of response evaluable subjects 
who have a complete response (CR) or partial response (PR) using RECIST 1.1 
criteria at any time during the study. The evaluable population includes all subjects 
who have completed at least two dose of combination therapy and have received at 
least one follow-up scan. It is known that this crude proportion underestimates the 
true ORR due to the adaptive nature of Simon’s two stage design. Thus we will also 
report the bias-reduced estimator for ORR due to Whitehead [43] and the adjusted 
95% confidence intervals that account for the adaptiveness of the study design [44]. 
 
12.3.2 
Analysis of Secondary Efficacy Endpoints 
 
Overall survival is defined as the duration of time from start of study treatment to 
time of death. For subjects lost to follow-up or whose vital status is unknown, every 
effort will be made to determine the date such subjects were last known to be alive. 
Such efforts may include phone calls, certified mail, and the checking of public 
records. Subjects who are alive or lost to follow-up as of the data analysis cutoff date 
will be right-censored. The censoring date will be determined from the date the 
subject was last known to be alive. 
 
Progression-free Survival (PFS) is defined as the time from cycle 1, day 1 of 
immunotherapy until first documented local progression or death due to any cause. 
Disease progression will be assessed using RECIST (version 1.1). RECIST evaluation 
will be performed by the radiology staff designated for completing RECIST reads for 
GI Oncology clinical trials conducted at the SKCCC at Johns Hopkins University.  
Due to the expectation that some patients may experience delayed clinical responses 
to therapy, patients with disease progression by radiographic imaging or laboratory 
parameters during a 12 week evaluation period but without rapid clinical deterioration 
or significant change in performance status that requires additional immediate therapy 
may continue to receive treatment on study. Subjects that meet the above criteria and 


 
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continue on study therapy must discontinue treatment upon documentation of disease 
progression on the second scan. The date of progression will be backdated to the time 
of first RECIST criteria progression. Tumor assessments will be made using RECIST 
1.1 and immune-related response criteria (irRC). Local Progression-Free Survival 
(LPFS) is defined as the duration of time from start of treatment to time of first 
documented local progression or death due to any cause, whichever occurs first. 
Individuals will be censored at the date of the last scan for PFS and LPFS if no event 
occurs. 
 
Duration of response (ROR) will be calculated for subjects who achieve a best overall 
response of CR or PR with GVAX in combination with pembrolizumab. For such 
subjects, duration of response is defined as the number of weeks from the start date 
of PR or CR (whichever response is recorded first) and subsequently confirmed to the 
first date that recurrent or progressive disease or death is documented. In such cases, 
recurrent or progressive disease will be assessed relative to the smallest tumor 
measurements recorded since the start of study treatment. The primary analysis of 
duration of response will be based on the time point responses, best overall response, 
and PD status that are determined by the review of the investigator.  
 
OR, PFS, LPFS, and DOR will be summarized descriptively using the Kaplan-Meier 
method. Analysis of PFS, LPFS, and DOR will be restricted to evaluable individuals 
who complete at least two doses of combination therapy and have at least one follow-
up scan, while the analysis of OS will be performed on all evaluable patients as well 
as all the individuals who complete at least one dose of pembrolizumab/GVAX. 
Median event-free survival will be reported and the associated 95% confidence 
interval will be estimated using the method of [45]. 
  
12.3.3 
Analysis of Safety Endpoints 
  
The safety analysis will be performed in all subjects who receive any amount of study 
drug. A baseline measurement and at least 1 laboratory or other safety-related 
measurement obtained after at least 1 dose of study treatment may be required for 
inclusion in the analysis of a specific safety parameter (e.g., lab shifts from baseline). 
A complete list of all AE data will be provided along with an assessment of NCI 
CTCAE grade and relationship to study drug. The incidence of AEs will be tabulated 
by subgroups of interest (e.g. grade 3 or higher, organ class, relationship to study 
drug). For analyses at the individual level, the highest grade and relationship to study 
drug will be assumed if multiple events have occurred. Toxicity will be tabulated by 
type and grade and will be summarized with descriptive statistics. Other safety data 
will be assessed in terms of physical examination, clinical chemistry, hematology, 
vital signs, and ECGs. Negative binomial regression and Cox proportional hazards 
models will be used to assess the rate of AE and time to first toxicity, respectively. 
     
 


 
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12.3.4 
Biomarker Analysis 
 
Intratumoral changes in pre- and post-treatment core biopsy specimens at week 6 and 
at the time of progression, if available, will be studied using immunohistochemistry 
(IHC) and transcriptional analysis. The immune parameters include suppressive 
pathways (including PD-L2, LAG3, BTLA, TIM3, IDO1, CTLA-4, and Tregs), 
activation 
pathways 
(including 
CD137, 
OX40, 
CD40, 
CD40L), 
cytokines/chemokines or their receptors (including CCL12, CXCR4, CCL2, CCL5, 
CCR2, CCR5). Change standard protein biomarkers such as CEA will be evaluated 
after each pembrolizumab/GVAX treatment. Descriptive statistics for both pre and 
post administration of each immunotherapy and the differences in immune parameters 
will be computed. Plots will be used to show the changes in immune response over 
time both for each individual and for each arm. Continuous variables will be 
summarized with means or medians and standard deviations. Dichotomous and 
categorical variables will be summarized using proportions with exact 95% 
confidence intervals and counts. For each immunotherapy, comparisons in the pre and 
28 day post-immunotherapy responses will be compared using paired t-tests (or 
Wilcoxon signed-rank tests if appropriate) for continuous variables and McNemar's 
tests for dichotomous variables. Associations between immune parameters will be 
explored graphically (e.g. scatterplots, boxplots) and numerically (e.g. correlations, χ2 
tests). Regression techniques (linear, logistic, linear mixed effects models) will be 
used to explore the differences between the treatment arms cross-sectionally as well 
as longitudinally. The associations between immune parameters and clinical 
outcomes (OS and DFS) will be evaluated using univariate and multivariate Cox 
regression models. Analyses will be performed using data from all evaluable patients 
and from the subgroup of patients who receive at least one immunotherapies. 
Sensitivity analyses will be carried out to evaluate the extent to which results of data 
analyses can be affected by early dropouts. The significance level is set at 0.05 for all 
tests in this phase 2 study.   
 
 
 
 
 
 
 
 
 
 


 
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REFERENCES 
 
1. The American Cancer Society. Cancer Facts and Figures. 2013. 
2. Cohen AM, Minsky BD, Schilsky RL. Cancer of the Colon and Rectum. In DeVita VT, 
Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th edition. 
Philadelpia: Lippincott 1144-1234; 1997. 
3. Piedbois P, Rougier P, Buyse M, et al. Efficicay of intravenous continuous infusion of 
fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin 
Oncol 16: 301-8; 19987 
4. Piedbois P, Buyse M, Rustum D, et al. Modulation of fluorouracil by leukovorin in 
patients with advanced colorectal caner: evidence in terms of response rate. J Clin Oncol 
10: 896-903; 1992. 
5. Giachetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of 
oxaliplatin added to chronomodulated fluorouracil-leukovorin as first line treatment of 
metastatic colorectal cancer. J Clin Oncol 18: 136-47; 2000. 
6. De Gramont, Figer A, Seymour M, et al. Leukovorin and fluorouracil with or whithout 
oxaliplatin as first line treatment in advanced colorectal cancer. J Clin Oncol 18: 239-42; 
2000. 
7. Van Cutsem E, Findlay M, Osterwalder B, et al. Capecitabine, an oral fluoropyrimidine 
carbamate with substantial activity in advanced colorectal cancer: results of a randomized 
phae II study. J Clin Oncol 18: 1337-1345. 
8. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leukovorin for 
metastic colorectal cancer. NEJM 2000; 343: 905-914..  
9. Fearon ER, Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, Karasuyama H, 
Vogelstein B, Frost P. Interleukin-2 production by tumor cells bypasses T helper function 
in the generation of an antitumor response. Cell 1990; 60:397-403. 
10. Golumbek PT, Lazenby AJ, Levitsky HI, JaffeeEM, Karasuyama H, Baker H, Pardoll 
DM. Treatment of established renal cancer by tumor cells engineered to secrete 
interleukin-4. Science 1991; 254:713-716. 
11. Gansbacher B, Zier K, Daniels B, Cronin K, Bannerji R, Gilboa E. Interleukin 2 gene 
transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp 
Med 1990; 172:1217-1224. 
12. Dranoff G, Jaffee EM, Lazenby A, Golumbek P, Levitsky HI, Brose K, Jackson V, 
Hamada H, Pardoll DM, Mulligan RC. Vaccination with irradiated tumor cells 
engineered to secrete murine granulocyte-macrophage colony stimulating factor 
stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci 
USA 1993; 90:3539-3543. 
13. Porgador A, Tzehoval E, Katz A, Vedai E, Revel M, Feldman M, Eisenback L. 
Interleukin 6 gene transfection into Lewis lung carcinoma tumor cells suppresses the 
malignant phenotype and confers immunotherapeutic competence against parental 
metastatic cells. Cancer Res 1992; 52:3679-3686. 
14. Colombo MP, Ferrari G, Stoppacciaro A, Parenza M, Rodolfo M, Mavilio F, Parmiani G. 
Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a 
murine adenocarcinoma in vivo. J Exp Med 1991; 173:889-897. 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
J16154/Version 5/ January 17, 2018 
 
 
 
60
15. Simmons JW, Jaffee EM, Weber C, Levitsky HI, Nelson WG, Carducci MA, Lazenby 
AJ, Cohen L, Finn CC, Clift SM, Hauda KM, Beck LA, Leiferman KM, Ownes AH, 
Piantadosi S, DranoffG, Mulligan RC, Pardoll DM, Marshall FF. Bioactivity of 
Autologous Irradiated Renal Cell Carcinoma Vaccines Generated by ex Vivo 
Granulocyte-Macrophage Colony-stimulating Factor Gene Transfer. Cancer Res 
1997;57:1537-1546. 
16. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, 
Coleman J, Grochow L, Donehower RC, Lillemoe KD, O'Reilly S, Abrams RA, Pardoll 
DM, Cameron JL, Yeo CJ. Novel allogeneic granulocyte-macrophage colony-stimulating 
factor-secreting tumor vaccine for pancreatic cancer: A phase I trial of safety and 
immune activation. J Clin Onc 19: 145-156; 2001. 
17. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, et al. A lethally 
irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor 
vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune 
activation. Ann Surg. 2011: 253: 328-35. 
18. Dranoff G, Jaffee E, Lazenby A, et al (1993). Vaccination with irradiated tumor cells 
engineered to secrete murine granulocyte-macrophage colony-stimulating factor 
stimulates potent, specific, and long-lasting anti-tumor immunity. ProcNatlAcadSci U S 
A. 90(8):3539-3543. 
19. Cox AL, Skipper J, Chen Y, et al (1994). Identification of a peptide recognized by five 
melanoma-specific human cytotoxic T cell lines.Science. 264(5159):716-719. 
20. Kawakami Y, Eliyahu S, Delgado CH, et al(1994).Cloning of the gene coding for a 
shared human melanoma antigen recognized by autologous T cells infiltrating into 
tumor.ProcNatlAcadSci U S A. 91(9):3515-3519. 
21. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H (1994). Role 
of bone marrow-derived cells in presenting MHC class I-restricted tumor 
antigens.Science.264(5161):961-965. 
22. Huang AY, Bruce AT, Pardoll DM, Levitsky HI (1996). In vivo cross-priming of MHC 
class I-restricted antigens requires the TAP transporter. Immunity.4(4):349-355. 
23. Ercolini AM, Ladle BH, Manning EA, et al (2005). Recruitment of latent pools of high-
avidity CD8(+) T cells to the antitumor immune response. J Exp Med. 201(10):1591-
1602. 
24. Laheru D, Lutz E, Burke J, et al (2008). Allolgeneic GM-CSF Secreting Tumor Vaccine 
(GVAX) Alone Or in Sequence with Cyclophosphamide for Metastatic Pancreatic 
Cancer: A Pilot Study of Safety, Feasability and Immune Activation. Clin. Cancer Res. 
14(5):1455-63. 
25. Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary 
MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, 
Davidson NE, Jaffee EM. Timed sequential treatment with cyclophosphamide, 
doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-
secreting breast tumor vaccine: A chemotherapy dose-ranging factorial study of safety 
and immune activation. J Clin Oncol 27:5911-5918, 2009. 
26. Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29): 4531-8. 
27. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
J16154/Version 5/ January 17, 2018 
 
 
 
61
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol 2005;23(10): 2346-57. 
28. Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous 
CD4+ T cells against NY-ESO-1. N Engl J Med 2008;358(25): 2698-703. 
29. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236: 219-42. 
30. Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on 
dendritic cells enhances T cell activation and cytokine production. J Immunol 
2003;170(3): 1257-66. 
31. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8(8): 793-800. 
32. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002;2(2): 116-
26. 
33. Yoshimura K, Laird LS, Chia CY, et al. Live attenuated Listeria monocytogenes 
effectively treats hepatic colorectal cancer metastases and is strongly enhanced by 
depletion of regulatory T cells. Cancer Res 2007;67(20): 10058-66. 
34. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. 
Clin Cancer Res 2007;13(7): 2151-7. 
35. Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with 
tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. 
Clin Cancer Res 2009;15(3): 971-9. 
36. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-
infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc 
Natl Acad Sci U S A 2007;104(9): 3360-5. 
37. Fourcade J, Kudela P, Sun Z, et al. PD-1 is a regulator of NY-ESO-1-specific CD8+ T 
cell expansion in melanoma patients. J Immunol 2009;182(9): 5240-9. 
38. Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, Solt S, Dorman A, Wamwea 
A, Yager A, Laheru D, Wolfgang CL, Wang J, Hruban RH, Anders RA, Jaffee EM, 
Zheng 
L. 
Immunotherapy 
converts 
nonimmunogenic 
pancreatic 
tumors 
into 
immunogenic foci of immune regulation. Cancer immunology research. 2014a;2(7):616-
31. PMCID: PMC4082460 
39. Lutz E, Kinkead H, Jaffee EM, Zheng L. Priming the Pancreatic Cancer Tumor 
Microenvironment for Checkpoint-inhibitor Immunotherapy. OncoImmunology 2014b; 
11:e962401.  
40. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz 
E, Liu L, Yao S, Anders AA, Laheru D, Wolfgang CL, Edil BH, Schulick RD, Jaffee 
EM, Zheng L. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T 
cell infiltration into pancreatic tumors. Journal of Immunotherapy 2015;38(1):1-11. 
41. Li B, VanRoey M, Wang C, Chen TH, Korman A, Jooss K. Anti-programmed death-1 
synergizes with granulocyte macrophage colony-stimulating factor--secreting tumor cell 
immunotherapy providing therapeutic benefit to mice with established tumors. Clin 
Cancer Res. 2009 Mar 1;15(5):1623-34. 
42. Mayer, R.J., Van Cutsem, E., Falcone, A., Yoshino, T., Garcia-Carbonero, R., 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
J16154/Version 5/ January 17, 2018 
 
 
 
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Mizunuma, N., Yamazaki, K., Shimada, Y., Tabernero, J., Komatsu, Y. and Sobrero, A., 
2015. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. New 
England Journal of Medicine, 372(20), pp.1909-1919. 
43. Whitehead J. On the bias of maximum likelihood estimation following a sequential test. 
Biometrika 1986; 73(3):573–581 
44. Koyama, T. and Chen, H., 2008. Proper inference from Simon's two‐stage designs. 
Statistics in Medicine, 27(16), pp.3145-3154. 
45. Brookmeyer, R., and Crowley, J. (1982), ‘‘A Confidence Interval for the Median 
Survival Time,’’ Biometrics, 38, 29–41. 
 
 
 


 
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APPENDIX A: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX B: Guidance for Identification and Treatment of IRAEs (Version 5.0, Date: 
18-Dec-2014)  
 
 
 
 
 
 
 
 


 
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APPENDIX C: Adverse Event of Clinical Interest (ECI) Reporting Form 
 
 


 
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66
Adverse Event of Clinical Interest (ECI) Reporting Form 
 
Please notify: IND Sponsor within 24 hours (
,  
Merck within 24 hours (
  
 
Protocol Title: 
 
 
A Phase 2 Study of GVAX Colon Vaccine (with Cyclophosphamide) and 
Pembrolizumab in Patients with Mismatch Repair-Proficient (MMR-p) Advanced 
Colorectal Cancer 
Protocol Number 
J16154 
(MK-3475-485) 
 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Dr. Nilofer Azad 
Date: 
 
 
 
Report Type: 
 
Initial     
Follow-up     
Final Follow-up     
Addendum to: 
 
 
 
Section A: Subject Information 
Subject ID: 
Subject Initial: 
 
Subject Gender: 
Male 
Female 
 
Section B: Event Information 
Event diagnosis or symptoms: 
 
Date of First Dose: 
 
Action taken with the study 
drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Pembrolizumab 
CY 
 
 
GVAX 
Date of Last Dose Prior to Event: 
 
Pembrolizumab 
CY 
 
 
GVAX 
Number of Total Doses: 
 
Pembrolizumab 
CY 
 
 
GVAX 
Event Onset Date: 
 
 
 
 
 
Event End Date: 
 
 
 
Date Event Discovered: 
 


 
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67
Relationship to: 
Pembrolizumab
CY 
GVAX 
Underlying Disease 
Unrelated 
 
 
 
 
Related 
 
 
 
 
Section C: Brief Description of the Event: (please include relevant procedures and laboratory values)  
 
Section D: Relevant Medical History 
 
Section E: Concomitant Drug (Not related to ECI) 
Name of the Drug 
Start Date
Stop Date
Route 
Dose
Frequen
cy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 
 


 
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APPENDIX D: Serious Adverse Event (SAE) Reporting Form 
 
 


 
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Serious Adverse Event Reporting Form 
 
Please notify: Dr. Zheng within 24 hours (
  
Merck within 24 hours (
) 
 
Protocol Title: 
 
 
A Phase 2 Study of GVAX Colon Vaccine (with Cyclophosphamide) and 
Pembrolizumab in Patients with Mismatch Repair-Proficient (MMR-p) 
Advanced Colorectal Cancer 
Protocol Number: 
J16154 
(MK-3475-485) 
Signature of PI: 
 
 
 
Principal Investigator: 
 
Dr. Nilofer Azad 
Date: 
 
 
 
Report Type: 
Initial   
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all that 
apply): 
Death   
Life-threatening 
 Hospitalization or Elongation of 
Existing Hospitalization 
 Persistent or Significant Disability 
 Congenital Anomaly 
 Other Important Medical Event 
 Cancer 
 Overdose 
 
Hospital Admission 
Date:  
 
 
 
Hospital Discharge Date: 
Date Event 
Discovered: 
Section A: Subject Information 
Subject ID: 
Subject Initial: 
 
Subject Gender: 
Male 
Female 
 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Date of First Dose: 
Action taken with the study drug: 
 
None 
Interrupted 
Discontinued 
Delayed 
 
Pembrolizumab 
CY 
GVAX 
Date of Last Dose Prior to Event: 
 
Pembrolizumab 
CY 
GVAX 
Number of Total Doses: 
Pembrolizumab 
CY 
GVAX 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
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70
Event Onset Date: 
Event End Date: 
Relationship to: 
Pembrolizumab 
CY 
GVAX 
Underlying Disease 
Unrelated 
 
 
 
 
Related 
 
 
 
 
Section C: Brief Description of the Event: 
 
Section D: Relevant Medical History 
 
Section E: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date
Stop Date
Route 
Dose
Freque
ncy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section F: Comments 
 
Additional Documents: 
 Please specify 
 
 
 
 
 
 
 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
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APPENDIX E: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
 
RECIST version 1.1 will be used in this study for assessment of tumor response. While either CT 
or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.  
Disease Parameters 
 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
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included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase.   
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 


 
Phase 2 Study of GVAX (with CY) and  pembrolizumab in MMR-p advanced colorectal cancer 
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73
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 


 
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Reference 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 
J. Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 


 
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APPENDIX F: Immune Related Response Criteria 
 
For all patients who experience disease progression on study, the date noted for of disease 
progression is the time of the scan where it is originally detected, and not the following date of 
the confirmatory scan.  
Definitions of measurable and non-measurable disease  
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane 
perpendicular diameters. Both its longest diameter and its longest perpendicular must be greater 
than or equal to 10 mm. Lymph nodes must have a short-axis line-length of ≥ 15 mm. Malignant 
lymph nodes must be measurable in 2 perpendicular diameters. Both its longest diameter and its 
longest perpendicular must be greater than or equal to 15 mm. The quantitative endpoint will be 
defined as the product of the longest diameter with its longest perpendicular.  
Non-measurable disease: Non-measurable lesions are those that are not suitable for quantitative 
assessment over time. These include: 
1) Neoplastic masses that are too small to measure, because their longest uninterrupted diameter 
or longest perpendicular are less than 10 mm. 
2) Neoplastic masses whose boundaries cannot be distinguished. This includes masses which 
cannot be demarcated from surrounding tissue because of inadequate contrast, masses with 
overly complex morphology, or those with highly heterogeneous tissue composition.  
3) Other types of lesions that are confidently felt to represent neoplastic tissue, but difficult to 
quantify in a reproducible manner. These include bone metastases, leptomeningeal 
metastases, malignant ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, ill-defined abdominal masses, etc. 
For irRC, only target lesions selected at baseline and measurable new lesions are taken into 
account.  
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five 
cutaneous index lesions) is calculated.  
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable 
lesions (≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral 
lesions) are added together to provide the total time-point tumor burden. 
 
 


 
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Overall response using irRC: 
 Complete Response (irCR): Complete disappearance of all tumor lesions (whether 
measureable or not, and no new lesions). CR must be confirmed by repeated, consecutive 
assessments made no less than 4 weeks from the date first documented.  
 Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive 
assessment at least 4 weeks after first documentation.  
 Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD.  
 Progressive Disease (irPD): At least 25% increase in SPD relative to nadir (minimum 
recorded tumor burden) Confirmation by a repeat, consecutive assessment no less than 4 
weeks from the data first documented.  
Please note other key differences between irRC and the original WHO criteria: 
New measurable lesions will be incorporated into the SPD  
New non measurable lesions do not define progression but preclude irCR 
Non-index lesions contribute to defining irCR (complete disappearance required). 
See the Investigators Imaging Operations Manual (IIOM) for more details. 
REFERENCE 
IrRC for the current protocol is adopted from the following reference: 
Wolchok, JD, Hoos, A, O’Day S, et al., Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clinical Cancer Research, 2009 
Dec 1;15(23):7412-20. Epub 2009 Nov 24.