In-Situ Cancer Vaccine: Phase IIA, Open-Label Study to Assess the Safety of AlloStim® Immunotherapy Alone and in Combination With Cryoablation as Third Line Therapy for Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
Sponsor: Mirror Biologics, Inc.

 
 
 
CLINICAL STUDY PROTOCOL 
 
IN-SITU CANCER VACCINE: PHASE I/IIB OPEN-LABEL STUDY TO 
ASSESS THE SAFETY OF ALLOSTIM® IN COMBINATION WITH 
CRYOABLATION AS THIRD LINE THERAPY FOR METASTATIC  
COLORECTAL CANCER  
PROTOCOL #ITL-019-CORK-CRYVAC 
IND Number: 
13936 
Drug Development Phase: 
Phase IIA 
Investigational Products: 
AlloStim®  
Investigational Treatment: 
AlloStim® and targeted tumor cryoablation 
Indication: 
Metastatic colorectal cancer third line therapy  
Sponsor: 
 
Immunovative Therapies, Ltd. 
Malcha Technology Park 
Building 1, First Floor 
Jerusalem, Israel 96951 
Original Protocol Date: 
December 23, 2014  v.2  
Amendment 1.0 Date: 
September 16, 2015 
Amendment 2.0 Date: 
September 24, 2015 
Amendment 3.0 Date: 
November 24, 2015 
Amendment 4.0 Date: 
March 23, 2016 
Amendment 5.0 Date: 
June 14, 2016 
Amendment 6.0 Date: 
October 25, 2016 
Amendment 7.0 Date: 
May 18, 2017 
Amendment 8.0 Date: 
September 12, 2017 
 

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CONFIDENTIAL INFORMATION: 
The information in this document contains commercial information and trade secrets that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. In any 
event, persons to whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied which is indicated as privileged or confidential. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY CONTACTS  
 
This study is to be performed in accordance with Good Clinical Practice (GCP), the ethical principles 
that have their origin in the Declaration of Helsinki, Title 21 of the Code of Federal Regulations §§ 
50, 56, and 312, and the International Conference on Harmonization E6 guidelines.  
 
Investigators: 
Dr. Madappa N. Kundranda 
Banner MD Anderson Cancer Center 
2946 E. Banner Gateway Drive 
Gilbert, AZ, USA 85234  
Phone: +1-480-256-3623  
Fax:     +1-480-256-4003 
E-mail: Madappa.Kundranda@bannerhealth.com 
 
Sponsor: 
 
 
Immunovative Therapies, Ltd. 
Malcha Technology Park 
Building 1, First Floor 
Jerusalem, Israel 96951 
Phone:+972-2-6506288 
Fax:    +972-2-6505088 
info@immunovative.com 
 
Study Chairman: 
 
 
Dr. Michael Har-Noy 
Immunovative Therapies Ltd. 
Malcha Technology Park 
Building No. 1, First Floor 
Jerusalem, Israel 96951 
U.S. Phone: +1-760-216-7494 
E-mail: harnoy@immunovative.com 
 
 
 
Institutional Review Board: 
 
Western Institutional Review Board®  
1019 39th Avenue SE Suite 120  
Puyallup, WA 98374-2115 
Phone:+1-360-252-2500 
Fax:    +1-360-252-2498 
 
 
 
 
 
 
 
 
 
 
 

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1. PROTOCOL APPROVAL SIGNATURE PAGE 
 
SPONSOR: IMMUNOVATIVE THERAPIES, LTD. 
I have read and understand the contents of this clinical protocol for study No. ITL-019-
CORK-CRYVAC dated September 12, 2017 and I agree to meet all obligations of 
Immunovative Therapies, Ltd. as detailed in all applicable regulations and guidelines. In 
addition, I will inform the Principal Investigator and all other Investigators of all relevant 
information that becomes available during the conduct of this study. 
 
Approved By: 
Print Name:      DR. MICHAEL HAR-NOY 
Signature:         ____________________________      Date:  _____________________ 
Title:                 Chief Executive Officer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.  PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol for study No. ITL-019-
CORK-CRYVAC dated September 12, 2017 and will adhere to the study requirements as 
presented, including all statements regarding confidentiality. In addition, I will conduct the 
study in accordance with current Good Clinical Practices and applicable US FDA regulatory 
requirements: 
 
Print Name:      ____________________________ 
Signature:         ____________________________      Date:  _____________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. PROTOCOL ABSTRACT 
Sponsor: 
Immunovative Therapies, Ltd. 
Investigational Product: 
AlloStim® 
Study Phase: 
Phase IIA 
Study Title: 
In-Situ Cancer Vaccine: Phase IIA, Open-Label Study to Assess the Safety of AlloStim® in 
Combination with Cryoablation as Third Line Therapy for Metastatic Colorectal Cancer 
Protocol Number:  
ITL-019-CORK-CRYVAC 
Study Phase: 
Phase IIA 
Indication:  
Metastatic colorectal cancer third line therapy  
CryoVaxTM:  
CryoVaxTM is the name provided by the Sponsor to protocols that incorporate an in-situ 
vaccination step. This protocol includes an in-situ cancer vaccine step, which combines a 
percutaneous ablation of a single metastatic tumor lesion with intralesional immunotherapy 
serving as an adjuvant. In this protocol, the ablation step is conducted using a percutaneous 
cryoablation procedure (CA). The ablation of the selected tumor lesion causes release of 
tumor-specific antigens into the microenvironment (antigen source) and the intralesional 
immunotherapy serves as an adjuvant to promote maturation of dendritic cells (DC) that 
engulf and process released tumor antigens. The mature DC migrate to the draining lymph 
nodes to elicit a Th1-type tumor-specific immune response. The combination of ablation and 
intralesional immunotherapy thus creates an in-situ, patient-specific, anti-tumor vaccine.  
Some subjects enrolled in this study are scheduled to undergo cryoablation, while other 
subjects are scheduled to receive IV doses to try to create an in-vivo, patient-specific, anti-
tumor in-situ vaccine. 
T-StimTM:  
T-StimTM cells are an intermediate product in the process of making the study drug called 
AlloStim®. T-StimTM is ex-vivo differentiated and expanded memory CD4 T-cells that 
uniquely function as both Th1 cells (produce IFN-gamma and not IL-4) and natural killer 
cells (contain granzyme B and perforin and lyse tumor cells and not normal cells in-vitro). T-
StimTM cells are derived from the blood of normal donors (allogeneic) and are intentionally 
mismatched to the recipients. The T-StimTM production process involves first purifying CD4+ 
T-cells from buffy coat material collected from known normal screened blood donors. The 
CD4+ cells are cultured in the presence of Dynabeads® ClinExVivo™ CD3/CD28 beads for 9 
days. After the 9-day culture process, the CD4+ cells expand approximately 50-fold and 
differentiate into T-StimTM memory CD4 cells with Th1 and NK-like properties. The T-
StimTM cells are harvested from the culture, washed, the beads are removed and the cells are 
aliquoted into individual dose vials. The dose vials are stored frozen in liquid nitrogen. 
Frozen T-StimTM doses are stable for at least 18 months. T-StimTM cells are produced in 
Jerusalem, Israel under cGMP and are certified USP sterile and low endotoxin (validated gel 
clot method) before release. All blood donors are screened pursuant to 21 CFR 1271 and 
tested to be free from blood-borne infectious diseases pursuant to US regulations (HIV1, 

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HIV2, HTLV1, HTLV2, HBV, HCV, syphilis, and additionally screened for CMV. Each 
batch is also tested to meet pre-determined identity and functional requirements prior to 
release.  
AlloStim®:  
AlloStim® is formulated T-StimTM cells that have been activated by adding CD3/CD28-
conjugated microbeads and packaged in a syringe. AlloStim® is prepared by thawing frozen, 
QC released T-StimTM cells and incubating the cells for 4 hours with Dynabeads® 
ClinExVivo™ CD3/CD28. The beads are mixed with the cells at a 2:1 bead to cell ratio. After 
4 hours, the cells with the beads attached are harvested, washed and suspended in formulation 
buffer containing PlasmaLyteA® supplemented with 1% human serum albumin. The 
formulated cells with the beads still attached are then loaded in a syringe for infusion or 
injection. A sample from the syringe lot is tested for bacterial contamination with a Rapid 
Microbiological Method (RMM) with results at 24 -48 hours. AlloStim® syringes are 
packaged in validated temperature-controlled containers and shipped by specialized courier 
service to the study site at least 48 hours prior to the protocol required treatment day for each 
enrolled subject. The syringe lots are quarantined at the study site until notification of RMM 
release. The cells are stable for at least 72 hours in this final formulation. AlloStim® is 
available in the following dosage forms:  
• 1 ml formulation buffer containing 1 x 107 cells with 2 x 107 beads attached in a 3 ml 
syringe for intradermal injections (ID) and intratumoral (IT) injection,  
• 3 ml formulation buffer containing 3 x 107 cells with 6 x 107 beads attached in a 10 ml 
syringe for intravenous injection (IV) and intratumoral (IT) injection, 
• 5 ml of formulation buffer containing 5 x 107 cells attached to 1 x 108 beads in a 10 ml 
syringe for intravenous infusion (IV).  
Note: some cohorts call for a 0.5 ml intradermal dose.  For these cohorts, a 1 ml syringe will 
be provided and the clinic is instructed to administer only 0.5 ml and discard the remaining 
0.5 ml. 
Study Purpose:  
This is a Phase IIa open label, study designed to compare AlloStim+cryoablation vs AlloStim 
alone 
Brief Description of the Protocol: 
This is a single center, open label study comparing CryoVaxTM personalized anti-tumor 
vaccine protocol combining the cryoablation of a selected metastatic lesion with intra-lesional 
immunotherapy with AlloStim® alone. The treatment schedules both have the following steps: 
(1) priming with intradermal AlloStim®; (2) vaccination combining cryoablation with 
intratumoral AlloStim® or intravenous AlloStim® dosing in the place of cryoablation; (3) 
activation with intravenous AlloStim®; and (4) booster with intravenous AlloStim®. All 
subjects are followed for safety during the dosing period and until 28 days following the last 
dose (Safety Evaluation Period”).  All subjects are continued to be followed for survival after 
the Safety Evaluation Period. 
Dosing Schedule A-1: Treatment With Cryoablation  
The priming step: Subjects will receive an ID injection of AlloStim® (0.5 ml) on Days 0, 7, 
and 14 all in different locations. 
The vaccination step: Subjects will receive cryoablation and intratumor (IT) injection of 
AlloStim® (1 ml) on Day 21.  
The activation step: Subjects will receive an IV infusion of AlloStim® (3ml) on Day 28. 

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The booster step: Subjects will receive two (optional) IV booster infusions of AlloStim® 
(3ml), one on Day 56, a second on Day 84. 
 
Dosing Schedule A-2: AlloStim® without cryoablation 
The priming step: Subjects will receive an ID injection of AlloStim® (1 ml) on Days 0, 3, 7, 
10 and 14. 
The vaccination step: Subjects will receive an IV injection of AlloStim® (3 ml) of on Day 21. 
The activation step: Subjects will receive an IV infusion of AlloStim® (3ml) on Day 28. 
The booster step: Subjects will receive three (optional) IV booster infusions of AlloStim® 
(3ml), one on Day 49, a second on Day 77. 
 
Two types of toxicity are assessed for determination of whether a Dose Limiting Toxicity 
(DLT) has occurred. An acute dose limiting toxicity (ADLT) is assessed within 48h of a dose 
administration during the priming, vaccination and activation steps of each protocol.  
Cumulative dose limiting toxicity (CDLT) is assessed during the complete Safety Evaluation 
Period including any ADLT that occurs in the booster dosing.  
An ADLT is defined as the occurrence of any of the following within 48h of dosing: 
• Any ≥ Grade 3 local injection site reaction;  
• Any ≥ Grade 3 infusion related symptoms of duration > 2 days; 
• Any ≥ Grade 4 infusion reaction of any duration 
For any Grade 1-2 acute toxicity, the study drug administration schedule can continue to the 
next scheduled dose. If an ADLT is observed, the subject will be followed until the toxicity is 
resolved or the subject is stable.  No further dosing for that subject will occur after an ADLT 
event. 
A CDLT event is defined as the occurrence of any of the following within the Safety 
Evaluation Period: 
• Any ≥ Grade 3 graft vs. host disease 
• Any toxicity ≥ Grade 3 that is probably or definitely related to the study drug; 
• Any toxicity not present at baseline that occurs at ≥ Grade 4 
• Any autoimmune toxicity ≥ Grade 3 not present at baseline 
All adverse events (AEs) and serious adverse events (SAEs), regardless of attribution to the 
study drug, will be coded, graded and become part of the final safety report for each cohort.  
The Data Safety Monitoring Board (DSMB) will review the safety data on each cohort and 
recommend whether to advance enrollment to the next cohort. 
The development of any Grade 4 or greater toxicity in any subject at any time will prompt a 
review of safety data by the Sponsor, PI and the DSMB prior to accrual of any additional 
subjects. It is recognized that Grade 4 events and death can occur in this population due to 
disease progression. Therefore, dosing will continue for currently enrolled subjects at the 
occurrence of a grade 4 event according to protocol unless the PI determines the Grade 4 or 
greater event is definitely or probably related to the study drug. If attribution is assigned to 
the study drug dosing will be suspended pending review by the DSMB.   
In accordance with the 3+3 design, three subjects will be accrued into the first dosing 
schedule. If during the priming, vaccination and activation steps no ADLT are observed in 
any of the three subjects, accrual into the next cohort is allowed. If an ADLT occurs in two of 
the three subjects, no further dose frequency escalation is allowed. If ADLT occurs in one of 

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the three subjects, three additional subjects will be accrued into the same cohort. If no ADLT 
occurs within the additional three subjects, accrual into the next cohort can begin. If an ADLT 
is observed in any of the additional three subjects, no further dose escalation is permitted.  
The development of any DLT toxicity in ≥ 33% of the accumulated number of subjects in any 
and all dosing schedules during the Safety Evaluation Period will result in protocol 
discontinuation.  
At the completion of the Safety Evaluation Period for all cohorts, the safety evaluation of Part 
1 will be considered completed and all enrollment will be closed.  Efficacy evaluation will 
continue monthly for each subject until death or loss to follow-up.  
 
Objectives:  
Primary Objectives 
1. To evaluate the safety and anti-tumor effect of AlloStim® with or without  
cryoablation  
Exploratory Objectives 
1. To assess the longitudinal changes in tumor burden by RECIST and compare these 
changes with the histopathological analysis of corresponding biopsies. 
2. To assess whether immune response correlates with RECIST or histopathology and 
Overall Survival (OS). 
Study Population:  
Adult patients ≥18 years and ≤80 years with adequate performance status (ECOG <2) and 
adequate organ function with metastatic, histologically confirmed adenocarcinoma of the 
rectum or colon presenting with metastatic disease and has been previously treated with two 
lines of active chemotherapy with or without bevacizumab and also present with a liver tumor 
lesion safely accessible for percutaneous cryoablation. 
Total Number of Subjects: 
Part 1 will accrue 3 subjects in A-1 and 3 subjects in A-2 and continue with an additional up 
to 25 subjects in the favored protocol.  
Study Duration:  
Part 1 is projected to last 30 to 72 weeks. It is projected that approximately one subject will 
be accrued every two weeks. Part 2 is projected to last an additional 72-104 weeks   Subjects, 
as long as they are available for follow-up, will be followed monthly for 12 months following 
last dose administration for survival and quarterly thereafter.  
Inclusion Criteria: 
Each subject must meet the following criteria to be enrolled in this study: 
1. Adult males and female subjects aged 18-80 years at screening visit 
2. Pathologically confirmed diagnosis of colorectal adenocarcinoma  
3. Presenting with metastatic disease:  
o Primary can be intact or previously resected 
o Metastatic lesion(s) in liver must be non-resectable 
o Extrahepatic disease acceptable 
4. At least one liver lesion able to be visualized by ultrasound and determined to be 

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safely assessable for percutaneous cryoablation (if schedule includes cryoablation) 
5. Previous treatment failure of two previous lines of active systemic chemotherapy:  
o Previous chemotherapy must have included an oxaliplatin-containing (e.g. 
FOLFOX) and an irinotecan-containing (e.g. FOLFIRI) regimen  
o With or without bevacizumab 
o Administered in adjuvant setting or for treatment of metastatic disease    
o If KRAS wild type, must have at least one prior anti-EGFR therapy 
o Treatment failure can be due to disease progression or toxicity 
o Disease progression on second line therapy must be documented 
radiologically and must have occurred during or within 30 days 
following the last administration of treatment for metastatic disease  
6. ECOG performance score: 0-1 
7. Adequate hematological function: 
o Absolute granulocyte count ≥ 1,200/mm3  
o Platelet count ≥ 100,000/mm3  
o PT/INR ≤ 1.5 or correctable to <1.5 at time of interventional procedures 
o Hemoglobin ≥ 9 g/dL (may be corrected by transfusion) 
8. Adequate Organ Function: 
o Creatinine ≤ 1.5 mg/dL  
o Total bilirubin ≤ 1.5 times upper limit of normal (ULN) 
o Alkaline phosphatase ≤ 2.5 times ULN * 
o Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN * 
o Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN* 
*≤ 5 ULN if liver involvement) 
9. EKG without clinically relevant abnormalities 
10. Female subjects: Not pregnant or lactating  
11. Patients with child bearing potential must agree to use adequate contraception  
12. Study specific informed consent in the native language of the subject.  
Exclusion Criteria: 
Subjects with any of the following will be excluded from the participation in the study: 
1. Bowel obstruction or high risk for obstruction 
2. Moderate or severe ascites requiring medical intervention   
3. Clinical evidence or radiological evidence of brain metastasis or leptomeningeal 
involvement  
4. Symptomatic asthma or COPD  
5. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in 
pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room 
air  
6. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation 
procedure (if schedule includes cryoablation) 
7. Regorafenib prior to the Study Period 
8. Previous treatment with TAS102  
9. Any of the following mood disorders: active major depressive episode, history of 

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suicidal attempt or ideation  
10. Taking anticoagulant medication for concomitant medical condition (unless can be 
safely discontinued for invasive cryoablation, biopsy and intratumoral injection 
procedures) 
11. Prior allogeneic bone marrow/stem cell or solid organ transplant 
12. Chronic use (> 2 weeks) of greater than physiologic doses of a corticosteroid agent 
(dose equivalent to > 5 mg/day of prednisone) within 30 days of the first day of study 
drug treatment  
o Topical corticosteroids are permitted 
13. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple 
sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes 
allowed 
14. Prior experimental therapy  
15. History of blood transfusion reactions 
16. Known allergy to bovine products   
17. Progressive viral or bacterial infection  
o All infections must be resolved and the subject must remain afebrile for seven 
days without antibiotics prior to being placed on study 
18. Cardiac disease of symptomatic nature  
19. History of HIV positivity or AIDS 
20. Concurrent medication known to interfere with platelet function or coagulation (e.g., 
aspirin, ibuprofen, clopidogrel, or warfarin) unless such medications can be 
discontinued for an appropriate time period based on the drug half-life and known 
activity (e.g., aspirin for 7 days) prior to cryoablation and biopsy procedures  
21. History of severe hypersensitivity to monoclonal antibody drugs or any 
contraindication to any of the study drugs 
22. Psychiatric or addictive disorders or other condition that, in the opinion of the 
investigator, would preclude study participation. 
23. Subjects that lack ability to provide consent for themselves. 
Endpoints: 
Primary endpoint: Safety  
Exploratory Endpoints: Correlation of immune response with tumor burden by RECIST, 
histopathology and OS. 
Safety Assessments:  
The following evaluations will be used to assess the safety of the investigational product:  
• Physical examination, vital signs and laboratory evaluations (including a CBC with 
differential and comprehensive metabolic panel (CMP), coagulation factors, C-
reactive protein (CRP), total IgG and IgM, erythrocyte sedimentation rate, serum 
lipase, and autoimmune blood screens). 
• Adverse Events (AEs) recording according to the National Cancer Institute (NCI) 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.  
• Interrogation of subject, caregivers and family regarding any changes in health 
condition, in person or by telephone. 
 

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Radiology Assessment:  
All subjects will undergo a CT scan of the head, chest, abdomen and pelvis with and without 
contrast (contrast can be withheld if medically indicated) at baseline and at Day 91 at same 
time as biopsy.  
As it is difficult to determine if subjects are responding or progressing after immunotherapy 
by standard radiological methods and RECIST criteria, the analysis of the CT scans is 
conducted as an experimental end-point. It is known that after immunotherapy that subjects 
can develop new lesions, experience lymphadenopathy and interval size increases in tumors. 
These changes would normally be documented as progression. However, in immunotherapy, 
the changes could represent “pseudo-progression”. In some cases, the changes could indicate 
actual progression, but a response can still occur months after immunotherapy. Other times, 
immunotherapy can cause a stable disease condition that results in increased survival. 
 
The changes in the images will be analyzed by RECIST and other accepted and novel 
experimental methods in order to retrospectively determine a method that best correlates with 
survival outcomes. The CT scans are scheduled on the same day as biopsy procedures in 
order to correlate the radiological images with pathological response. It is believed that 
patterns of necrosis, fibrosis and immune cell infiltration patterns with HU numbers on the 
radiographic images may provide correlates that could distinguish immune response from 
progression or be predictive of a survival response. Radiographic images can be reviewed by 
the site radiologists according to established methods. At the discretion of the PI, select 
subjects may be further evaluated by MRI or PET in order to attempt to distinguish between 
radiological “pseudo-progression” due to an immune response and actual progression. 
Histopathology Assessment:  
Subjects will undergo mandatory tumor biopsies of a target lesion at baseline, during 
intratumoral injections (Schedule A-1) and at Day 91. The intratumoral procedures use a 
trocar that will have already been inserted into the tumor to conduct the intratumoral injection 
and thus these biopsies will not add an additional interventional procedure on day 21 
Schedule A-1  
Additional biopsies will be conducted only if subjects separately consent.  Failure to consent 
for the additional biopsy procedures will not disqualify subjects. 
The harvested tissue will be prepared in paraffin blocks and read centrally by a pathologist 
appointed by the Sponsor.  The amount of tumor burden estimated from the pathological 
evaluation will be compared with the amount of burden shown on the CT images. The amount 
and type of immune cell infiltration (immunohistochemical analysis), existence of coagulative 
necrosis, necrotic tumor and fibrosis will also be documented and correlated to the 
radiological images.  
 
Immunological Monitoring Assessments:  
Research blood draws for monitoring of immunological response will be drawn at day 0 prior 
to study drug injection (baseline). A research blood draw is scheduled prior to study drug 
administration on Day 0, Day 28, Day 56 and Day 84 in Schedule A-1 and Day 0,21, 49 and 
77 in Schedule A-2.  
Immunological tests include: engraftment study (HLA), serum cytokines and polyclonal 

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Th1/Th2 balance. Seroconversion to IL-12 positivity will be evaluated as a possible 
biomarker that can predict response and extended survival. Development of a biomarker is 
important, as standard measures such as RECIST and tumor markers don’t necessarily 
correlate with immune response mechanisms.  
The Sponsor will prepare and label blood collection tubes for each research blood draw day. 
The collected research blood will be processed per Sponsor’s SOP at or near the site in a 
laboratory approved by the Sponsor. The laboratory will isolate and store PBMC, serum and 
plasma for subsequent immunological testing. These samples will be transported in bulk 
using a dry shipper to the Sponsor’s laboratory in Jerusalem for analysis. The research blood 
collection days are designed to obtain information on the mechanism of action of the drug. It 
is important that the minimum required amount of blood is collected and processed in 
accordance with the SOPs. The PI should consider placement of port or indwelling catheter in 
order to facilitate these blood draws.    
Clinical Laboratory Tests: 
Changes in laboratory levels are evaluated in order to determine if the study drug is related to, 
or might cause, any changes in serum chemistry, hematological function, liver or kidney 
function, or maintenance of immune self-tolerance (autoimmune tests). All subjects will be 
monitored for changes in laboratory values in CBC, CMP (including liver function test, 
kidney function tests) lipase, total IgG and IgM, erythrocyte sedimentation rate, and CRP at 
baseline and weekly during the Safety Evaluation Period. Coagulation studies (PT, PTT, and 
INR) are conducted at baseline and prior to interventional procedures (biopsy, cryoablation 
and intratumoral injections). An autoimmune panel will be assessed on day 0 (baseline, prior 
to drug administration) and on the last day of the Safety Evaluation Period.   
The laboratory reports should be de-identified and provided to the Sponsor. The Sponsor will 
provide graphs indicating the changing values of select markers. The graphs will be provided 
to the PI or designee for review and indication of clinical significant findings. 
Statistical Analysis:  
Safety analyses will be performed on the safety population, defined as all subjects in the 
Intent to Treat (ITT) population that received any dose of study medication. The number of 
AEs reported will be summarized. Subjects will be censored is still alive at data cut-off or if 
they withdraw consent. The incidence and percentage of subjects with at least one occurrence 
of a preferred term will be included, according to the most severe NCI-CTCAE Version 4.03 
grade.  
Causality (relationship to study drug) will be summarized separately. Duration of AE will be 
determined and included in the listings along with action taken and outcome. 
Laboratory results will be classified according to NCI-CTCAE Version 4.03. Incidence of 
laboratory abnormalities will be summarized; laboratory results not corresponding to an NCI-
CTCAE Version 4.03 terms will not be graded. Laboratory toxicity shifts from baseline to 
worst grade will also be provided. 
Any clinically significant results from physical examination and vital signs measurements 
will be tabulated.  
 
Survival 
Subjects will be followed for survival after the Safety Evaluation Period by monthly 
telephonic contact for first 12 months and quarterly thereafter.  

 
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4. GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations  Explanation 
aBMT 
Allogeneic Bone Marrow Transplantation  
ADLT 
Acute Dose Limiting Toxicity  
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AMA 
Anti-Mitochondrial Antibody 
ANA 
Anti-Nuclear Antibody 
APC 
Antigen Presenting Cells 
ART 
Anthracycline And Taxane Resistant 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen  
CA 
Cryoablation  
CBC 
Complete Blood Count 
CDLT 
Cumulative Dose Limiting Toxicity 
CE 
Covered Entities  
CFR 
Code of Federal Regulations  
cGMP 
Current Good Manufacturing Practices 
CM 
Clinical Monitor  
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CPT 
Cell Preparation Tube 
CRC 
Colorectal Cancer 
CRF 
Case Report Form 
CRO 
Contract Research Organization  
CRP 
C-Reactive Protein 
CT 
Computer Tomography 
CTCAE 
Common Terminology Criteria For Adverse Events  
CTL 
Cytotoxic T-Lymphocyte 
Da 
Dalton 
DCs 
Dendritic Cells 
DHHS 
Department Of Health And Human Services  
dL 
Deciliter 
DLT 
Dose Limiting Toxicity 
DPBS 
Dulbecco's Phosphate Buffered Saline 
DSM 
Data Safety Monitoring  

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Abbreviations  Explanation 
DSMB 
Data Safety Monitoring Board 
DTR 
Deep Tendon Reflexes 
eCRF 
Electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture  
e.g. 
For Example 
EGFR 
Epidermal Growth Factor Receptor 
EKG 
Electrocardiogram 
EPAR 
European Public Assessment Report 
FDA 
Food and Drug Administration 
H&P 
History And Physical Examination 
µg 
microgram 
g 
gram 
GCP 
Good Clinical Practice  
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
GMP 
Good Manufacturing Practice 
GVHD 
Graft Versus Host Disease 
GVT 
Graft Versus Tumor 
h 
Hour 
H-2 
Histamine Blocker 
HBV 
Hepatitis B Virus 
β-HCG 
Beta-Human Chorionic Gonadotropin  
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability And Accountability Act  
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HMW 
High Molecular Weight 
HRQoL 
Health-Related Quality of Life 
HSA 
Human Serum Albumin 
HTLV 
Human T-Lymphotropic Virus  
HVG 
Host Versus Graft 
HVT 
Host Versus Tumor 
IC/EC 
Inclusion Criteria /Exclusion Criteria 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
ID 
Intradermal Injection 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon-Gamma 
Ig 
Immunoglobulin 

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Abbreviations  Explanation 
IL 
Interleukin 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
irRC 
Immune-Related Response Criteria 
IT 
Intratumoral Injection  
ITT 
Intent To Treat  
IU 
International Unit 
IV 
Intravenous Infusion 
L 
Liter 
LFT 
Liver Function Test 
LKM 
Anti-Liver-Kidney Microsome Antibodies 
MCRC 
Metastatic Colorectal Cancer  
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
Milligrams 
ml 
Milliliter 
mm 
Millimeter 
MoAb 
Monoclonal Antibody 
N 
Number 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK 
Natural Killer Cells 
NS 
Normal Saline 
NSAID 
Nonsteroidal Anti-Inflammatory Drugs 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PDGF 
Platelet Derived Growth Factor 
PERRLA 
Pupils Equal Round Reactive To Light And Accommodation  
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
PHI 
Protected Health Information  
PI 
Principal Investigator 
PO 
Oral Route (Per Os) 
PP 
Per Protocol  
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QC 
Quality Control 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria In Solid Tumors 

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Abbreviations  Explanation 
RMM 
Rapid Microbiological Method 
RN 
Registered Nurse 
RPR 
Rapid Plasma Reagin 
RR 
Response Rate 
RT 
Room Temperature 
RTK 
Receptor Tyrosine Kinase 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SMA 
Anti Smooth Muscle Antibody  
SOP 
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Events 
TGF-β 
Transforming Growth Factor Beta 
Th1/Th2 
T Helper Cells (Type 1 And 2) 
TKO 
To Keep Open 
TNFα 
Tumor Necrosis Factor-Alpha  
TTP 
Time to Progression 
ULN 
Upper Limit Normal  
US 
United States 
USA 
United States Of America 
USP 
United States Pharmacopoeia 
v 
Version 
VEGF 
Vascular Endothelial Growth Factor 
VOD 
Veno-Occlusive Disease 
vs 
Versus 
w 
With 
w/o 
Without 
yo 
Year Old 
yr 
Year 

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5. TABLE OF CONTENTS 
1. 
PROTOCOL APPROVAL SIGNATURE PAGE ...................................................... IV 
2. 
PRINCIPAL INVESTIGATOR’S AGREEMENT ..................................................... V 
3. 
PROTOCOL ABSTRACT ..............................................................................................6 
4. 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..................14 
5. 
TABLE OF CONTENTS ..............................................................................................18 
6. 
INTRODUCTION ..........................................................................................................22 
6.1. 
INVESTIGATIONAL PRODUCTS .......................................................................................... 22 
6.1.1. 
AlloStim® .....................................................................................................22 
6.1.2. 
Cryoablation .................................................................................................22 
6.2. 
BACKGROUND TO THE DISEASE ........................................................................................ 23 
6.2.1. 
Colorectal Cancer.........................................................................................23 
6.2.2. 
First and Second Line Therapy ....................................................................25 
6.2.3. 
Biologic Agents ...........................................................................................26 
6.2.4. 
Bevacizumab ................................................................................................26 
6.2.5. 
Cetuximab and Panitumumab ......................................................................27 
6.2.6. 
KRAS Mutation Status ................................................................................27 
6.2.7. 
Regorafenib ..................................................................................................28 
6.2.1. 
TAS-102 .......................................................................................................29 
6.3. 
CANCER VACCINES AND RATIONALE FOR CRYOVAXTM .................................................. 31 
6.4. 
ALLOSTIM® RATIONALE IN METASTATIC COLORECTAL CANCER ................................... 33 
6.5. 
PRE-CLINICAL STUDIES ..................................................................................................... 34 
6.6. 
PREVIOUS HUMAN EXPERIENCE ....................................................................................... 34 
6.6.1. 
Clinical Toxicity data from the Phase I/II under the US IND .....................34 
6.6.1. 
Clinical Hold ................................................ Error! Bookmark not defined. 
6.7. 
EXPECTED BENEFITS FROM THE PROPOSED STUDY.......................................................... 39 
6.8. 
RATIONALE FOR THE STUDY ............................................................................................. 39 
6.8.1. 
Rationale for the Doses and the Dosing Regimen .......................................39 
7. 
STUDY OBJECTIVES ..................................................................................................41 
7.1. 
PRIMARY OBJECTIVES....................................................................................................... 41 
7.2. 
EXPLORATORY OBJECTIVES ............................................................................................. 41 
8. 
STUDY DESIGN ............................................................................................................42 
9. 
STUDY ENDPOINTS ....................................................................................................43 
9.1. 
PRIMARY ENDPOINT.......................................................................................................... 43 
9.2. 
EXPLORATORY ENDPOINT ................................................................................................ 44 

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10. SELECTION OF SUBJECTS ......................................................................................45 
10.1. 
NUMBER OF SUBJECTS ...................................................................................................... 45 
10.2. 
INCLUSION CRITERIA ........................................................................................................ 45 
10.3. 
EXCLUSION CRITERIA ....................................................................................................... 46 
11. STUDY PLAN AND PROCEDURES ..........................................................................47 
11.1. 
OVERALL STUDY PLAN ..................................................................................................... 47 
11.2. 
STUDY PROCEDURES ......................................................................................................... 48 
11.2.1. 
Physical Examination...................................................................................48 
11.2.2. 
Monitoring Vital Signs ................................................................................48 
11.2.3. 
Laboratory tests ............................................................................................49 
11.2.4. 
Tumor Assessment .......................................................................................49 
11.2.5. 
Immunological Research Assays .................................................................50 
11.2.6. 
Cytokines .....................................................................................................50 
11.2.7. 
Th1/Th2 Intracellular Staining .....................................................................51 
12. DESCRIPTION OF STUDY VISITS ...........................................................................51 
12.1. 
SCHEDULE DEVIATIONS .................................................................................................... 54 
12.2. 
SCREENING ASSESSMENTS FOR ALL SCHEDULES ............................................................. 54 
12.3. 
ELIGIBILITY DETERMINATION (SCREENING) FOR ALL SCHEDULES (STUDY SITE) ........... 55 
13. DISCONTINUATION CRITERIA ..............................................................................56 
13.1. 
EARLY DISCONTINUATION OF THE STUDY ....................................................................... 56 
13.2. 
EARLY DISCONTINUATION OF INDIVIDUAL SUBJECTS ..................................................... 56 
14. STUDY TREATMENT .................................................................................................57 
14.1. 
STUDY DRUG FORMULATIONS .......................................................................................... 57 
14.2. 
DRUG STORAGE AND RELEASE ......................................................................................... 57 
14.3. 
DRUG PREPARATION PRIOR TO ADMINISTRATION ........................................................... 57 
14.4. 
TREATMENT ADMINISTRATION ......................................................................................... 58 
14.4.1. 
Intradermal Injection ....................................................................................58 
14.4.2. 
Intravenous Infusions (IV) ...........................................................................58 
14.4.3. 
Intratumoral Injections (IT) .........................................................................59 
14.5. 
DRUG ACCOUNTABILITY .................................................................................................. 59 
14.6. 
CONCOMITANT TREATMENTS PROHIBITED AND RESTRICTED THERAPIES   
DURING THE STUDY .......................................................................................................... 59 
15. ADVERSE EVENTS .....................................................................................................60 
15.1.1. 
Clinical Laboratory Adverse Events ............................................................61 
15.1.2. 
Immune-Related Adverse Events ................................................................61 
15.1.3. 
Expected Adverse Events ............................................................................62 
15.2. 
SERIOUS ADVERSE EVENTS .............................................................................................. 65 

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15.2.1. 
Definition of an Unexpected Adverse Event ...............................................66 
15.2.2. 
Handling of Serious Adverse Events ...........................................................66 
15.2.1. 
Exceptions in the Reporting of Serious Adverse Events .............................67 
15.3. 
ADVERSE EVENTS REPORTING ......................................................................................... 68 
15.3.1. 
Reporting Requirements ..............................................................................68 
15.3.2. 
IND Safety Reports ......................................................................................68 
15.3.3. 
Reporting Adverse Events in the (e)CRFs ...................................................68 
15.3.4. 
SAE Contact Information ............................................................................69 
15.4. 
ALLOSTIM® INFUSION-RELATED ALLERGIC OR AUTOIMMUNE TOXICITY ....................... 69 
15.5. 
PRINCIPAL INVESTIGATOR/SPONSOR SAFETY REVIEW .................................................... 71 
15.6. 
DATA SAFETY MONITORING BOARD ................................................................................ 71 
15.7. 
STOPPING RULES ............................................................................................................... 72 
16. STATISTICAL METHODS .........................................................................................72 
16.1. 
GENERAL CONSIDERATIONS ............................................................................................. 72 
16.1.1. 
Demographics ..............................................................................................73 
16.1.2. 
Concomitant Medications or Treatments .....................................................73 
16.1.3. 
Primary Endpoint .........................................................................................73 
16.1.4. 
Adverse Events ............................................................................................73 
16.1.5. 
Secondary Endpoint (Part 2 only) ................................................................73 
16.1.6. 
Exploratory Endpoints .................................................................................74 
16.1.7. 
Missing and Spurious Data ..........................................................................74 
16.1.8. 
Determination of Sample Size .....................................................................74 
17. REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ..................................74 
17.1. 
DECLARATION OF HELSINKI ............................................................................................. 74 
17.2. 
INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES ................................................. 74 
17.3. 
ETHICAL CONDUCT OF THE STUDY ................................................................................... 75 
17.4. 
PROTOCOL AMENDMENTS ................................................................................................ 75 
17.5. 
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS ..................................... 75 
17.6. 
INFORMED CONSENT ......................................................................................................... 75 
17.7. 
CONFIDENTIALITY AND DISCLOSURE ............................................................................... 76 
17.8. 
MONITORING AND AUDITING STUDY DOCUMENTATION ................................................. 76 
17.9. 
STUDY REPORT, PUBLICATION POLICY AND ARCHIVING OF STUDY 
DOCUMENTATION ............................................................................................................. 77 
17.10. DATA CAPTURE ................................................................................................................. 77 
17.10.1. Case Report Forms .......................................................................................77 
Source/CRF 78 
Comment 
78 
17.10.2. Electronic Data Capture ...............................................................................79 

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17.11. STUDY DOCUMENTS ......................................................................................................... 80 
17.11.1. Curricula Vitae .............................................................................................80 
17.11.2. Financial Disclosure.....................................................................................80 
17.11.3. Archiving of Documents ..............................................................................80 
18. REFERENCES ...............................................................................................................81 
19. APPENDICES ................................................................................................................86 

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6. INTRODUCTION 
6.1. INVESTIGATIONAL PRODUCTS 
6.1.1. AlloStim®  
The active ingredient in AlloStim® is viable polyclonal CD4+ memory Th1-like T-cells 
with both cytolytic (granzyme B+, perforin+) and Th1 helper (IFN-+, IL-4-) properties. 
In its final formulation, AlloStim® is a combination biological drug (somatic cell therapy) 
and medical device (microbeads). Source cells are CD4+ T-cells positively selected from 
buffy coat material prepared from normal, screened, volunteer blood donors. These CD4+ 
T-cells are differentiated and expanded ex-vivo in a 9-day culture process in a bioreactor 
to become Th1-like memory cells (“T-StimTM”). The final formulation includes the T-
StimTM cells attached to non-biodegradable microbeads; the formulated combination is 
called AlloStim®. The microbeads have covalently bound mouse anti-human CD3 and 
CD28 mAbs (Dynabeads® ClinExVivo™ CD3/CD28, Dynal/Invitrogen, Oslo, Norway) 
which activate the somatic cells and serve to maintain this activated state upon infusion 
or injection. 
 
AlloStim® is produced under GMP in clean rooms in Jerusalem, Israel. The source blood 
is tested to be free from contamination with HIV1, HIV2, HTLV1, HTLV2, HBV, HCV, 
RPR, mycoplasma and CMV. Each batch is tested to assure it is USP sterile, low 
endotoxin and meets pre-defined functional and identity criteria.  
6.1.2. Cryoablation 
The cryoablation procedure is conducted with U.S. FDA approved medical devices and 
disposable probes as an out-patient procedure. Local and/or conscious sedation is 
allowed. These treatments are used to kill tumor cells. Cryoablation is a minimally 
invasive treatment that involves placing a probe into a known tumor percutaneously 
under image guidance (e.g. CT scan or Ultrasound). The cryoablation procedure should 
be conducted by a licensed interventional radiologist approved by the Sponsor.  Unlike 
normal ablation methods that seek to ablate all viable tumor and leave no tumor at the 
margins, the ablation procedure for this protocol should aim to ablate only a portion of 
the tumor and leave viable tumor margins. Effort should be made to ablate viable tumor 
and avoid necrotic areas of the tumor. Thus, the edge of the tumor, rather than the center 
is a preferred target. Intratumoral injection of study drug is best accomplished by first 
inserting a guide device with a gauge larger than the cryoprobe. Generally, a 14g guide is 
suggested. In this manner, biopsy tools and the cryoprobe can be inserted through the 
guide to reach the tumor. On site pathology or radiological confirmation that the guide is 
inserted within viable tumor is preferred. The ablation should occur with at least two 
freeze-thaw cycles each of at least 10 minutes.  The study drug should only be injected 
when the temperature is verified to be above 350 C.  The study drug is best delivered 
using a needle that has side ports to assure the drug is delivered within the ablated lesion 
and not injected through the lesion into the normal tissue. After the ablation, the guide 

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tract should be sealed with mesh material to prevent bleeding.  All subjects should be 
observed for at least 2 hours following the procedure for any signs of bleeding or other 
adverse events. Subjects should be monitored continuously for pulse, respiration, blood 
pressure and oxygen saturation during the procedure. The type of probes used, the 
location of the tumor, the amount of tumor ablated, the cooling and warming cycle times, 
vital signs and procedure notes should be documented in source medical records. 
6.2. BACKGROUND TO THE DISEASE 
6.2.1. Colorectal Cancer 
Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Metastasis 
is the main reason of death in CRC patients. CRC includes cancerous growths in the 
colon, rectum and appendix. The liver and the lung are common metastatic sites of 
colorectal cancer. The most common colon cancer cell type is adenocarcinoma, which 
accounts for 95% of cases. [1] 
 
For metastatic CRC (CRC) patients, the exposure to all active chemotherapeutic drugs, 
including 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, can increase survival.  These 
chemotherapy drugs are usually given in two lines of drug combinations: FOLFOX 
(leukovorin, 5-FU and oxaliplatin) and FOLFIRI (leukovorin, 5-FU and irinotecan). 
Leucovorin is a vitamin that improves the effectiveness of 5-FU. However, chemotherapy 
options are absent after progression on 5-FU, oxaliplatin, and irinotecan. 
 
Targeted biologic treatments for metastatic colorectal cancer are available to add to the 
chemotherapy regimens. These fall into three groups: inhibitors of vascular endothelial 
growth factor (VEGF), including bevacizumab and aflibercept, monoclonal antibodies 
against epidermal growth factor receptor (EGFR) on the surface of tumor cells, including 
cetuximab and panitumumab. However, these EGFR targets are not applicable to KRAS 
mutant disease. The only approved therapies for chemotherapy-refractory KRAS mutant 
disease are Regorafenib (a small molecule inhibitor of intracellular kinase involved in 
various signaling cascades) and TAS102 (oral chemotherapy, for both, non-mutated and 
mutated KRAS).   
 
This study targets subjects with mCRC. Untreated patients with mCRC have a median 
survival of approximately 6 months [2]. Chemotherapy regimens such as FOLFOX and 
FOLFIRI can extend survival for up to 20 months.  The use of anti-EGFR therapy in 
patients that progress after two lines of chemotherapy drug mixtures is an additional 6.4 
months [3]. However this survival advantage occurs only in patients that express a wild 
type KRAS gene (KRAS wt). Patients with a mutated KRAS (KRAS mutant) gene do not 
respond adequately to anti-EGFR therapy (e.g., cetuximab, panitumumab).  
 
Standard therapy for mCRC is currently based on the use of four chemotherapy drugs (5-
fluorouracil, irinotecan, oxaliplatin, and capecitabine) and three biologic agents 
(cetuximab, bevacizumab, and panitumumab).   The common combinations of these 
drugs are shown below: 

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Continuous-infusion 5-fluourouracil (5-FU)–based combinations with irinotecan 
 
Saltz (IFL):  Irinotecan 125 mg/m2 IV over 90 minutes on days 1, 8, 15, and 22 plus 
leucovorin (LV) 20 mg/m2 via IV bolus of days 1, 8, 15, and 22 plus 5-FU 
500 mg/m2 via IV bolus on days 1, 8, 15, and 22; repeat every 6 weeks 
[4]. 
 
Douillard   
Irinotecan 180 mg/m2 over 2 hours on day 1 plus LV 200 mg/m2 IV over 
2 hours prior to 5-FU on days 1 and 2, plus 5-FU 400 mg/m2 via IV bolus, 
then 600 mg/m2 via continuous infusion over 22 hours on days 1 and 2; 
repeat every 2 weeks [5]. 
 
FOLFIRI  
Irinotecan 180 mg/m2 over 90 minutes on day 1 + LV 200 mg/m2 over 2-
hour infusion during irinotecan plus bolus 5
- FU 400 mg/m2, then 2.4–3 
g/m2 via continuous infusion over 46 hours on days 1 and 2; repeat every 
2 weeks [6]. 
 
Oral capecitabine-based combinations with irinotecan 
 
XELIRI  
Irinotecan 250 mg/m2 IV on day 1 plus capecitabine 1,000 mg/m2 PO bid 
from day 1 PM through day 15 AM; repeat every 3 weeks [7]. 
 
CapIRI  
Capecitabine 1,000 mg/m2 PO bid on days 1–14 plus irinotecan 100 
mg/m2 on days 1 and 8; repeat every 22 days [8].  
 
Continuous-infusion 5-FU–based combinations with oxaliplatin 
 
FOLFOX6  
Oxaliplatin 100 mg/m2 IV over 2 hours on day 1 plus LV 200 mg/m2 IV 
over 2 hours on day 1 plus 5-FU 400 mg/m2 via IV bolus, then 2.4–3 g/m2 
via continuous infusion over 46 hours; repeat every 2 weeks [9]. 
 
FOLFOX4  
Oxaliplatin 85 mg/m2 IV over 2 hours on day 1 plus LV 200 mg/m2 IV 
over 2 hours on days 1 and 2, plus 5-FU 400 mg/m2 via IV bolus, then 600 
mg/m2 IV via continuous infusion over 22 hours on days 1 and 2; repeat 
every 2 weeks [10]. 
 
mFOLFOX Oxaliplatin 85 mg/m2 IV over 2 hours on day 1 plus LV 175 mg/m2 IV over 
2 hours on day 1 plus 5-FU 400 mg/m2 via IV bolus, then 2.4–3 g/m2 via 
continuous infusion over 46 hours; repeat every 2 weeks [11]. 
 
FUFOX  Oxaliplatin 60 mg/m2 IV over 2 hours on days 1, 8, 15, and 22 plus LV 500 
mg/m2 IV over 2 hours on days 1, 8, 15, and 22 plus 5-FU 2.6 g/m2 via 
continuous infusion over 24 hours on days 1, 8, 15, and 22; repeat every 36 
days [12]. 
 

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FOLFOX7  
Oxaliplatin 130 mg/m2 IV over 2 hours on day 1 plus LV 400 mg/m2 IV 
over 2 hours plus 5-FU 2.4 g/m2 via continuous infusion over 46 hours; 
repeat every 2 weeks for 6 cycles [13]. 
 
Bolus 5-FU–based combinations with oxaliplatin 
 
FLOX  
Oxaliplatin 85 mg/m2 IV over 2 hours on days 1, 15, and 29 plus LV 500 
mg/m2 IV over 2 hours on days 1, 8, 15, 22, 29, and 36 plus 5-FU 500 
mg/m2 1 hour after start of LV on days 1, 8, 15, 22, 29, and 36; repeat every 
8 weeks for 3 cycles [14]. 
bFOL  
Oxaliplatin 85 mg/m2 IV over 2 hours every 2 weeks plus LV 20 mg/m2 IV 
over 10–20 minutes on days 1, 8, and 15 plus 5-FU 500 mg/m2 via IV bolus 
on days 1, 8, and 15; repeat every 28 days [15].  
 
Oral capecitabine-based combinations with oxaliplatin 
 
XELOX  
Oxaliplatin 130 mg/m2 IV over 2 hours on day 1 plus capecitabine 
1,000 mg/m2 PO bid from day 1 PM through day 15 AM; repeat every 
3 weeks [16]. 
 
Capecitabine     1,000 mg/m2 PO bid on days 1–14 plus oxaliplatin 130 mg/m2 IV on 
day 1; repeat every 3 weeks for 8 cycles [17]. 
 
CapOx  
Oxaliplatin 70 mg/m2 IV on days 1 and 8 plus capecitabine 1,000 
mg/m2 PO bid on days 1–14; repeat every 22 days [18]. 
 
Combinations with bevacizumab 
 
TREE-2 study  mFOLFOX6 plus bevacizumab 5 mg/kg IV every 14 days vs bFOL 
plus bevacizumab 5 mg/kg IV every 14 days vs CapOx [XELOX] plus 
bevacizumab 5 mg/kg IV every 14 days [19].  
 
Combinations with cetuximab 
 
FOLFOX4 + cetuximab  FOLFOX4 + cetuximab 400 mg/m2 IV for week 1, then 250 
mg/m2 IV weekly thereafter [20]. 
CapOx + cetuximab 
 Cetuximab 400 mg/m² on day 1 followed by weekly 
cetuximab 250 mg/m² plus oxaliplatin 70 mg/m² on days 1 and 
8 plus capecitabine 1,000 mg/m² PO bid on days 1–14; repeat 
every 22 days [21].  
 
6.2.2. First and Second Line Therapy 
Subjects in this study are recruited at third line metastatic disease after failure of two 
lines of chemotherapy with one containing oxaliplatin and another irinotecan (with at 
least one line containing bevicuzumab).  
 

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Combination regimens of infusional 5-FU with either oxaliplatin (FOLFOX) or 
irinotecan (FOLFIRI) form the basis of current first and second line standards of care for 
mCRC.  The choice of first and second line therapies varies by physician preference and 
toxicity, as toxicity is increased with the three-drug combinations.  The most common 
first and second line combination therapies are: FOLFIRI, FOLFOX, CapeOx, 
FOLFOXIRI, and XELOX [22-25] [26].  
 
According to NCCN Clinical Practice Guidelines, mCRC is treated with FOLFOX as 
first line therapy and FOLFIRI or CapOx as second line therapy.  Patients diagnosed with 
mCRC are often treated for prolonged time periods and experience multiple sequelae 
from chemotherapy toxicity which adversely impacts quality of life.  Neurologic and 
hematologic toxicities limit treatment with oxaliplatin, and irinotecan therapy is limited 
by hematologic toxicity and diarrhea [27].   Thus failure of first and second lines of 
chemotherapy can be due to either disease progression or toxicity. 
 
6.2.3. Biologic Agents 
In an attempt to improve first and second line chemotherapy regimens, three biological 
agents have been recently FDA licensed for the treatment of mCRC. These agents target 
molecular pathways of mCRC tumorigenesis: Bevacizumab, a human monoclonal 
antibody (MoAb) that targets vascular endothelial growth factor (VEGF); cetuximab, a 
chimeric human:mouse MoAb aganst the epidermal growth factor receptor (EGFR); and 
panitumumab, a fully human MoAb that targets the extracellular domain of EGFR. 
6.2.4. Bevacizumab 
As of 2004, bevacizumab has been FDA approved for first-line treatment of mCRC in 
combination with irinotecan- or oxaliplatin-based chemotherapy regimens [28].  
Bevacizumab was initially approved after it was found to show a significant survival 
benefit when added to first-line IFL chemotherapy [29]   [30].  Yet in a phase III study of 
1401 mCRC patients randomized to first-line FOLFOX4 or XELOX with or without 
bevacizumab, PFS was extended in the bevacizumab group (9.4mo vs. 8.0mo, p=0.0023), 
but no significant difference was found in median OS (21.9mo vas 19.9mo, p=0.0769) or 
RR (47% vs. 49%, p=0.31)  [31].  What more, the PFS benefit was limited to the XELOX 
group only (9.3mo vs. 7.4mo, p=0.003).  In terms of toxicity, more patients in the 
bevacizumab arm discontinued treatment because of adverse events, including 
thromboembolic events and bowel perforations (30% vs. 21%).  Thus, it is unclear 
whether bevacizumab improves outcome with better chemotherapy regimens in the first-
line setting.  For patients in the refractory mCRC setting, bevacizumab plus FOLFOX has 
been found to significantly improve RR (22.6% vs. 8.6%, p<0.001), PFS (7.3mo vs. 
4.7mo, p<0.0001), and OS (12.9mo vs 10.8mo, p=0.0011) [32]. Maintenance 
bevacizumab after initial response to combination treatment is being investigated, yet this 
drug has little activity when used alone. Therefore, prior use of bevacizumab is optional 
in this protocol. 

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6.2.5. Cetuximab and Panitumumab 
The fact that approximately 80% of colorectal tumors stain positively for EGFR has led 
to relatively rapid FDA approval for cetuximab and panitumumab.  As of 2004, 
cetuximab has been FDA approved for use as monotherapy or combination therapy for 
pretreated chemotherapy-resistant disease.  In a head to head comparison of cetuximab 
versus bevacizumab in first-line treatment of KRAS mutant mCRC, neither strategy 
demonstrated a clearly superior outcome [33]. However, the association with longer 
overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line 
regimen for patients with KRAS wt mCRC [34].    In the refractory-setting FOLFIRI plus 
cetuximab improves RR (23% vs. 11%, p=0.007) and TTP (4.1mo vs. 1.5mo, p<0.0001) 
over FOLFIRI alone [35].   
 
Panitumumab was intially FDA approved in 2007 for use in EGFR-expressing mCRC 
after failure of fluoropyrimide-, oxaliplatin-, and irinotecan-based chemotherapy 
regimens, on the basis of a phase III trial that compared panitumumab plus best 
supportive care (BSC) vs. BSC alone   (Chamoto et al. 2003). In this phase III trial, 231 
patients were randomized to panitumumab plus BSC, and 232 to BSC alone.  After a 
median follow-up of 35 weeks, OS was similar in both groups, but patients in the 
panitumumab arm had a significantly greater PFS (8 weeks, 95%CI, 7.9-8.4wks) than the 
BSC alone arm (7.3 wks, 95% CI, 7.1-7.7wks)  p<0.001 (Chamoto et al. 2003).  A 
retrospective analysis of the panitumumab phase III approval trial showed a significantly 
greater effect on PFS for patients with wild-type KRAS than with mutant KRAS (12.3 vs. 
7.4 wks; p<0.0001) [36].  Investigators concluded that KRAS status should be 
determined when considering panitumumab monotherapy [37]. (see discussion of KRAS 
status and treatment response below). 
 
6.2.6. KRAS Mutation Status 
The oncogene KRAS is the most commonly mutated gene in various human cancers. 
Being constitutively activated, it can bypass the EGFR-driven signaling cascade and 
impair the clinical efficacy of EGFR inhibitors such as cetuximab, nimotuzumab, 
panutinumab and aflibercep. KRAS is currently considered a clinically useful biomarker, 
and it is common practice in the oncology community to test KRAS mutational status 
prior to initiating therapy with either cetuximab or panitumumab.  Roughly 40% of 
patients with mCRC have somatic activating KRAS mutations [38].  The mutant status of 
KRAS, a gene encoding the KRAS proto-oncogene downstream effector of EGFR, has 
been associated with poor prognosis and nonresponse to EGFR antagonists [38, 39]. 
Therefore, these agents are indicated for KRAS wt disease only. 
 
On October 2, 2007, the FDA expanded labeling and granted regular approval for single-
agent cetuximab for the treatment of patients with EGFR-expressing mCRC after failure 
of both irinotecan- and oxaliplatin-based chemotherapy regimens.  On July 17, 2009, the 
FDA ordered changes to the product labels of cetuximab (Erbitux, ImClone Systems) and 
panitumumab (Vectibix Amgen) due to retrospective subset analyses of trials in patients 

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with colorectal cancers having KRAS mutations which showed a lack of benefit 
associated with these monoclonal antibodies.    
Labeling changes have been implemented in the ‘indications and usage’, ‘clinical 
pharmacology’ and ‘clinical studies’ sections of both cetuximab and panitumumab 
product labels. See FDA website:   
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm172905.htm 
However, while approved for KRAS wt mCRC, not all patients with a KRAS wt 
genotype respond to EGFR-targeted agents. Recently, activating mutations of BRAF, 
which encode for a protein acting downstream of KRAS, were also shown to be 
responsible for resistance to EGFR inhibitors in chemorefractory mCRC. A recent 
publication confirms, as for KRAS, a high concordance of BRAF mutations in primary 
CRC and related metastatic sites [40]. Because the KRAS pathway is central to many 
nodes of receptor tyrosine kinase (RTK) signaling, the same hurdles are to be expected in 
inhibition of other RTKs. 
 
Accordingly, development of new therapeutic strategies for KRAS mutant as well as 
BRAF mutant tumors are therefore highly needed.   
 
This study targets the population of mCRC patients that have progressed after two lines 
of chemotherapy and are not eligible for targeted therapies in order to offer a new 
category of drug (immunotherapy) to a population of patients with unmet medical needs 
in an indication requiring more effective therapies. 
 
6.2.7. Regorafenib  
Regorafenib (Stivarga) is an oral multi-kinase inhibitor developed by Bayer which targets 
angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows 
anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. 
Regorafenib demonstrated to increase the overall survival of patients with mCRC and 
was approved by the US FDA on September 27, 2012 for use in third- or fourth-line 
therapy. 
 
Regorafenib was approved based on results from the CORRECT pivotal trial which 
randomized 760 patients; 505 to Regorafenib and 255 to placebo.  Regorafenib had a 
median benefit of 1.4 months compared to placebo (6.4 months vs 5.0 months, HR=0.77, 
p=0.0052). The subset analysis in the CORRECT trial, indicated that median OS in the 
KRAS mutant subset was 6.2 months compared to control of 5.1 months (1.1 month 
difference, HR=0.87 95%CI), whereas the KRAS wt subset had median OS of 7.3 
months compared to 5.0 months for placebo control (2.3 months difference, HR=0.65, 
95%CI).  There were no complete responses and only 1% of patients had a partial 
response.  
 
Based on the results of studies evaluating Regorafenib in metastatic colorectal cancer, the 
National Comprehensive Cancer Network (NCCN) has updated their guidelines 

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regarding the treatment of colon and rectal cancers. Regorafenib is recommended as a 
treatment option after first, second, or third progression on therapies containing 5-
fluorouracil/ leucovorin, irinotecan, oxaliplatin (e.g., FOLFOX and FOLFIRI), 
bevacizumab, and cetuximab or panitumumab (if KRAS wt.). Patients with KRAS 
mutant disease are recommended for consideration of regorafenib therapy in the third-
line setting after progression on FOLFOX/FOLFIRI (or other oxaliplatin and irinotecan 
combinations) with bevacizumab.   
 
However, due to the marginal survival benefit and high toxicity of Regorafenib , the 
NCCN guidelines also state that physicians can consider to enroll KRAS mutant patients 
who progress on FOLFOX and FOLFIRI with bevacizumab and maintain adequate 
performance status and end-organ function into clinical trials, including phase I trials 
[41].  The EMA European Public Assessment Report (EPAR) for Regorafenib states that 
the drug is indicated in adult patients with metastatic colorectal cancer who have been 
previously treated with or are not considered candidates for other available therapies, 
including patients with KRAS mutant tumors, though physicians are recommended to 
carefully evaluate benefits and risks when prescribing Regorafenib in patients with 
KRAS mutant tumors.   
 
Although Regorafenib is a recommended therapy for metastatic colorectal cancer after 
failure of standard therapies, it is important to note that it comes at a starting cost of 
$9,350 per 28-day cycle. A recent editorial questions the cost-effectiveness of 
Regorafenib therapy. The authors comment on the small incremental survival benefit, 
short PFS, and the potentially substantial adverse effects. They suggest that identification 
of the subset of patients most likely to derive significant clinical benefit from 
Regorafenib  therapy become a high priority [42].   
 
This protocol does not require prior Regorafenib for eligibility. This is based on the 
subset analysis of the CORRECT trial demonstrating little OS benefit for the KRAS 
mutant subset of patients and is consistent with NCCN guidelines recommending 
consideration of clinical trial options for third-line KRAS mutant mCRC. Subjects in this 
protocol that are progressing or not responding to experimental therapy can add 
Regorafenib after the Safety Evaluation Period as salvage therapy. 
 
6.2.1. TAS-102 
TAS-102 (Lonsurf®) is an oral drug that combines two agents, trifluridine  (FTD), a 
nucleoside metabolic inhibitor, and tipiracil (TPI), a thymidine phosphorylase inhibitor, 
developed by Taiho Oncology, Inc.  
 
The FDA approved the use of the drug on September 22, 2015 for patients with 
metastatic 
colorectal 
cancer 
following 
an 
international, 
multicenter, 
phase 
III RECOURSE trial.  The study enrolled 800 patients with mCRC from Japan, the 
United States, Europe, and Australia, randomly assigned in a 2:1 ratio to receive TAS-
102 or placebo. Most of the patients in the study had disease that no longer responded to 
fluoropyrimidines. To be eligible for the study, the patients had to undergo tumor testing 

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to determine whether their cancers harbored a mutant KRAS gene. Patients were also 
required to have received chemotherapy with each of the following agents: a 
fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and—for patients with non-
mutant KRAS tumors—cetuximab or panitumumab. The primary endpoint was overall 
survival. Secondary end points included progression-free survival, response rate (the 
proportion of patients whose best response was a complete or partial response), and 
safety. 
 
TAS-102 showed improved survival (median overall survival was 7.1 months in the 
TAS-102 group and 5.3 months in the placebo group), including those with both non-
mutated and mutated KRAS genes. The overall survival for KRAS-mutant patients was 
6.5 months if they received TAS-102, compared to 4.9 months if they did not. The 1-year 
overall survival rates were 27 percent and 18 percent, respectively. Additional analyses 
showed that the survival benefit of TAS-102 was seen in essentially all pre-specified 
subgroups, including KRAS status. 
 
The median progression-free survival was 2.0 months in the TAS-102 group and 1.7 
months in the placebo group. 221 patients (44 percent) in the TAS-102 group and 42 
patients (16 percent) in the placebo group had achieved disease control (complete 
response, partial response, or stable disease) measured at least 6 weeks after the patients 
were randomly assigned to treatment groups. In addition, the time to worsening of 
performance status was significantly longer in the TAS-102 group than in the placebo 
group (5.7 versus 4.0 months). Patients in the TAS-102 group experienced few serious 
adverse events. Overall, adverse events of grade 3 or higher occurred more frequently in 
the TAS-102 group than in the placebo group (69 percent versus 52 percent). The most 
common adverse events associated with TAS-102 included neutropenia, which occurred 
in 38 percent of those treated, and leukopenia, which occurred in 21 percent. Four percent 
of the patients in the TAS-102 group developed febrile neutropenia, and there was one 
death related to TAS-102 [43]. 
 
Based upon review of data submitted, the NCCN decided (in a Web Conference on July 
24, 2015) to add to the NCCN-Guidelines V.1.2016 the regimen of trifluridine + tipiracil 
as a subsequent therapy option for patients with disease progression after oxaliplatin‐ and 
irinotecan‐based chemotherapy. 
 
This protocol does not require prior TAS-102 for eligibility. This is based on the minimal 
efficacy of TAS 102 in the subject population. A reported phase II trial of TAS-102 
found an overall survival benefit in Japanese patients with metastatic colorectal cancer 
refractory to treatment. The RECOURSE study was a global phase III trial conducted in 
13 countries. Patients had metastatic colorectal cancer refractory to all standard therapies 
including with wild-type KRAS tumors. Patients were treated with TAS-102 (534 
patients) or placebo (266 patients) and directly compared. The researchers found that 
TAS-102 prolonged overall survival experiencing a median overall survival of 7.1 
months for TAS-102 and 5.3 months for placebo, a 1.8 month increase. 
 

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Subjects in this protocol that are progressing or not responding to experimental therapy 
can add TAS-102 after the Safety Evaluation Period as salvage therapy. 
6.3. CANCER VACCINES AND RATIONALE FOR CRYOVAXTM 
The current drugs used to treat colorectal cancer provide important treatment options for 
patients, their limitations including drug resistance, poor efficacy and severe side effects 
has focused efforts on developing safer and more effective therapies for these patients.  
The rationale for development of cancer vaccines is based on experimental work in 
animal models, in which it has been demonstrated that specific CD8+ cytotoxic T-cells 
(CTL) are able to eliminate tumors and develop memory which protects against 
recurrence. However, despite the promise of cancer vaccination shown in animal models, 
pooled results of published vaccine trials reveal a very weak clinical response rate of 
<1% for active specific immunization procedures with an objective response rate of 
2.6%, mainly among melanoma patients [44] even though about 50% of these vaccinated 
patients were shown to have developed specific CD8+ cytotoxic T-cells (CTL) able to 
specifically recognize and kill tumor cells in-vitro. 
 
The poor clinical results of immunotherapy vaccine approaches to cancer treatment have 
been attributed to tumor immunoavoidance mechanisms [45]. Tumors employ many 
escape strategies in order to evade immune attack. These strategies include 
downregulation of MHC molecules in order to hide from immune recognition [46], 
expression of inhibitory factors and immunosuppressive cytokines [47] [48] [49], 
including TGF-β [50, 51], IL-10 [52], and recruitment of regulatory immune cells 
CD4+CD25+FoxP3+ Tregs [53, 54], Tr1 cells [55], tolerogenic DCs, and myeloid 
suppressor cells, including immature macrophages, granulocytes, DCs and other myeloid 
cells at earlier stages of differentiation [56-58] [59] 
 
These immunoavoidance mechanisms employed by tumors render the immune system 
tolerant and permit tumors to grow unimpeded by immune surveillance. Establishment of 
this type of self-tolerance is a part of a natural immune regulatory mechanism which 
prevents autoimmune disease against organ-specific self-antigens. However, this 
normally beneficial effect may be responsible for tumor immune evasion, as many of the 
tolerance mechanisms that prevent autoimmunity are the same as employed by tumors to 
prevent immune destruction [60, 61].  
 
Therefore, the mechanisms of autoimmune disease serve as a model for developing 
strategies to break immune tolerance to tumors. A key mechanism for breaking self-
tolerance and induction of autoimmunity is related to inflammation. Autoimmune attack 
of self-tissues requires two conditions: activated T-cells and the "conditioning" of the 
target organ by irradiation or infection [62]. These two conditions are created in the 
CryoVaxTM protocol by first an ablation of a tumor lesion and then intratumoral injection 
of allogeneic activated immune cells. The combination creates an inflammatory 
microenvironment around the dead tumor cells.  
 

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In order to develop an effective immunotherapy strategy for metastatic cancer, new 
approaches are required that not only can create and enhance tumor-specific immunity, 
but also are able to counter-act the ability of the tumor to evade immune destruction. The 
experimental drug, AlloStim®, is designed to break tolerance to tumor tissues by taking 
advantage of the known mechanisms of breaking tolerance to self-tissue in autoimmune 
disease. AlloStim® provides a highly inflammatory environment. Inflammation in the 
presence of tumor tissue that has died pathologically is a formula that has potential to 
break tolerance. 
 
Type 1 cytokines including IL-1, TNF IFN-γ, IL-12, IL-18, and GM-CSF are generally 
believed to be required components of therapeutic cancer vaccines. AlloStim® cells are 
differentiated in culture to produce large amounts of these Type 1 cytokines. Because 
AlloStim® cells are allogeneic and recognized as foreign by the host immune system, 
they will be rejected by the host. Since these foreign cells produce large amounts of Type 
1 cytokines, they are expected to steer the immune response to the foreign antigens to 
Th1. In this manner, the rejection process is expected to increase the number of Th1 
memory immune cells in the circulation of patients injected with AlloStim®. This is 
significant because cancer patients are known to have an excess of Th2 immune cells and 
absence of Th1 cells. This imbalance is thought to be a mechanism of tumor immune 
evasion. 
 
The design of this in-situ anti-tumor vaccine is based upon an important paradigm shift in 
the field of immunology regarding the regulation of immunity. A new concept has 
emerged that proposes that the regulation of immunity and tolerance is not only 
determined by the specificity of immune T-cells as previously thought, but also by the 
context in which the antigens are presented to the immune system  [63] [64].  
 
The antigens are presented to the immune system by a network of specialized cells that 
are known as professional antigen-presenting cells (APCs) or dendritic cells (DCs). DCs 
are responsible for inducing immunity to pathogens or tumors by presenting antigens to 
naive T-cells, resulting in the differentiation of the T-cells into effector and memory T-
cells specific for the antigens. Effector T-cells, mainly CD8+ cytolytic T-cells (CTL), are 
capable of destroying cells which express the antigens. Memory T-cells provide immune 
protection against recurrence or reinfection. Differentiation of the DCs into potent APCs 
is triggered by molecular stimuli that are released as a result of the tissue disturbance and 
a local inflammatory response.  
 
The implications are that if a pathogenic infection occurs in the absence of appropriate 
inflammatory reactions, pathogen-specific T-cells will not be activated despite the 
presence of pathogen-specific foreign antigens, and, conversely, autoreactive T-cells, 
including those that are directed against tumor cells, can be readily activated provided the 
self (tumor) antigens are presented by DCs during an inflammatory response. Since 
tumors produce anti-inflammatory cytokines, they are capable of influencing the immune 
response by preventing an inflammatory response. 
 

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Therefore, successful anti-tumor immunity will develop in the situation where DCs are 
processing tumor antigens in the presence of an inflammatory reaction (“danger signals”) 
which is potent enough to also downregulate tumor-mediated immunosuppressive 
cytokine production. The magnitude and duration of the immune response will be 
dependent on the extent and quality of the local inflammatory response and will be 
contained by a variety of tolerogenic mechanisms.  
 
In summary, previous attempts at developing therapeutic cancer vaccines have 
demonstrated that it is possible to elicit specific immunity against self-tumor antigens. 
Recent insights on how immunity and tolerance are regulated indicate that the failure of 
these vaccines in the clinic may be related to the absence of sufficient danger signals at 
the time tumor antigens are processed by DCs. AlloStim® is designed to provide the 
necessary danger signals to elicit anti-tumor immunity in this CryoVaxTM protocol. 
6.4. ALLOSTIM® RATIONALE IN METASTATIC COLORECTAL CANCER 
Anti-cancer vaccines are believed to hold great promise as an anti-cancer treatment 
method. While the promise of this approach has been demonstrated in animal models, it 
has been difficult to translate these results to the clinic. Several leading cancer vaccine 
candidates that achieved promising results in Phase I and/or II studies later failed to 
obtain statistical significance for critical end points in randomized Phase II or III studies. 
Such disappointing outcomes have led to a critical evaluation of anti-cancer vaccine 
concepts. The failures of previous vaccines are thought to be due to differences in the 
mouse immune system compared to human immune system and the enhanced ability of 
human tumors to evade immune recognition and attack. These problems are addressed in 
the current vaccine design concept using the experimental AlloStim® drug. 
 
AlloStim® is based upon a novel approach [65]. Rather than being developed in animals 
as were previous vaccine concepts, AlloStim® was instead designed to elicit an immune 
mechanism already proven to be clinically effective in humans. This mechanism is 
known as the graft vs. tumor (GVT) effect that occurs after allogeneic stem cell/bone 
marrow transplant procedures.  
 
It is well accepted that solid tumors, including mCRC, can be effectively treated with the 
GVT effect that occurs after myeloablative allogeneic transplantation techniques [66] 
[67] [68]. Improved reduced-intensity allogeneic transplantation has also been shown to 
elicit an effective GVT effect in patients with breast cancer [69].  
 
The GVT effect has been described as the most powerful and most effective anti-tumor 
mechanism ever described in humans [70].  Unfortunately, these beneficial GVT effects 
are accompanied by graft-versus-host-disease (GVHD) toxicity. GVHD is associated 
with significant morbidity and is the leading cause for mortality after allogeneic 
hematopoietic stem cell transplantation. This toxicity significantly limits the clinical 
application of the GVT mechanism [71].  
 

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By analyzing the known immune-mediated mechanisms of the inter-related GVT and 
GVHD effects, it was hypothesized that instead of separating the GVT/GVHD effects, it 
might be possible to maintain the interrelationship of these immune mechanisms by 
reversing the direction of the effects. In the transplant setting, the immune effects flow 
from the graft to the host (GVT and GVHD). AlloStim® reverses these interrelated effects 
so that the effects flow from the host to the graft. Successful reversal of the direction of 
the effects is hypothesized to result in a beneficial host vs. tumor (HVT) effect coupled to 
a non-toxic host vs. graft (HVG) rejection effect  [64]. Pre-clinical studies validated this 
approach LaCasse, 2011 [65, 72-75]. 
 
Accordingly, this protocol also focuses on the replication of the proven GVT mechanism 
against metastatic colorectal cancer while eliminating the toxic effects of GVHD. The 
approach also eliminates the need for a tissue-matched donor. In addition, AlloStim® has 
demonstrated the unique ability to dysregulate the suppressor circuits which tumors use 
to evade immune attack [73].   
6.5. PRE-CLINICAL STUDIES 
In vitro activity studies demonstrated that AlloStim® is capable of eliciting anti-tumor 
effects in immunocompetent, non-conditioned tumor-bearing hosts, providing extended 
survival and curative immunity in both low and high tumor burden settings. For more 
detailed information and references on AlloStim®, please refer to the Investigator’s 
Brochure. 
6.6. PREVIOUS HUMAN EXPERIENCE 
A Phase I/II study under a US IND was conducted from September 2009 until May 2011.  
The study was placed on clinical hold by US FDA in May 2010 due to deficiencies found 
in the conduct of the trial during on-site inspections. Please refer to the Investigator’s 
Brochure and Appendix 5 for additional details.  Clinical Toxicity data submitted to the 
FDA is presented in Appendix 3. 
 
6.6.1. Clinical Toxicity data from the Phase I/II under the US IND  
Adverse events reported for the ITL-002-CRYO study are presented in the tables below. 
Please also refer to Appendix 3 for additional details regarding the Clinical Toxicity data 
which was submitted to the FDA. 
 

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The following table summarizes all AE regardless the causality: 

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6.7. EXPECTED BENEFITS FROM THE PROPOSED STUDY 
Subjects in this study have the potential to benefit from a new approach to cancer vaccination 
that is designed to provide the same tumor debulking effects of non-myeloablative allogeneic 
bone marrow transplantation (aBMT) without the graft-versus-host-disease (GVHD) toxicity 
or need for a matched donor. Patients with mCRC chemotherapy-refractory disease have only 
the option of Regorafenib. However, this drug has little, if any, efficacy in KRAS and BRAF 
mutant disease.  
 
The goal of this research is to develop new treatment options for mCRC KRAS mutant and 
BRAF mutant patients. This approach has the potential to benefit patients that would 
otherwise either not be treated or would be treated with minimally effective and highly toxic 
Regorafenib that provides a median of only 1.1 months of survival advantage. AlloStim®, 
combined with a percutaneous ablation technique of a selected metastatic lesion, creates an 
in-situ anti-tumor vaccine customized to the patient's own tumor. The ablation causes the 
release of the internal contents of the tumor cells and exposes tumor-specific antigens to the 
immune system. AlloStim® is then injected into the ablated lesion as an adjuvant to create the 
necessary inflammatory environment (“danger signals”) to steer the immune response to 
tumor-specific Th1 immunity. Accordingly, this study will provide patients suffering from a 
disease with an unmet medical need with access to a new class of treatment (immunotherapy) 
with a mechanism of action that has potential to debulk tumor and extend survival.   
6.8. RATIONALE FOR THE STUDY 
This study is evaluating a personalized in-situ anti-cancer vaccine combining AlloStim® and 
tumor ablation or AlloStim® alone. The protocol is designed to elicit a Th1 anti-tumor 
immune response in patients with mCRC KRAS mutant and BRAF mutant disease. Such 
immune response may be capable of debulking metastatic disease. Immune cell infiltration at 
the margins of primary colorectal disease has been correlated with longer survival in mCRC 
[76]. Specifically, increased infiltration of CD8+ CTL also correlated with survival [77]. In 
addition, colorectal cancer patients present with skewed Th1/Th2 ratios [78]and high Th1 
expression has correlated with survival [79].  
6.8.1. Rationale for the Doses and the Dosing Regimen 
In the Part 1 of the trial, the different dosing schedules will be evaluated. Assessment of 
different schedules should allow for better assessments of treatment safety, tolerability, and 
efficacy. 
 
There are 4 phases of dosing in this study: 
 
1. Priming phase:  
Since most metastatic patients will present with polarized Th2 immunity (or depleted 
Th1 immunity) [78, 80, 81], the objective of the "priming" phase of the protocol is to 
increase the amount of circulating Th1 cells in these patients. To accomplish this 
objective, patients will be injected with intradermal AlloStim® cells. The allogeneic 
CD4+ T-cells in AlloStim® are expected to be rejected by the patient and the Th1 type 
cytokines produced by AlloStim® are expected to steer the rejection response to Th1 
immunity, thus creating an increased pool of Th1 memory cells in the circulation 

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specific for the alloantigens contained within AlloStim®. In other words, the patients 
are expected to become immune to the investigational product with a Th1 bias. 
 
2. Vaccination phase:  
 
The objective of the "vaccination" phase of the protocol for cohorts with cryoablation 
is to create anti-tumor specific immunity through an in-situ vaccination method. 
Tumor vaccines generally contain a source of tumor antigen combined with an 
adjuvant which promotes immune recognition and primes for development of a 
specific immune response against the tumor antigen. In this protocol, a source of 
tumor antigen is created in-situ by ablating a selected tumor lesion using the 
minimally-invasive technique of image guided cryoablation.  
 
The ablation technique is designed to cause pathological death of tumor cells, 
releasing internal contents to the microenvironment. It is thought that necrotic cell 
death stimulates active cellular immunity, whereas apoptotic death stimulates immune 
tolerance. 
 
The ablation procedure results in release of large amounts of tumor debris into the 
tumor microenvironment that serves as a source of patient-specific tumor antigens. 
The ablation procedure causes a pathological type of tumor killing (necrosis) that 
alerts the immune system and mobilizes the cells that will respond to clean up and 
repair the debris, including immature dendritic cells (DC) which are responsible for 
directing an immune response to the engulfed antigens to either Th1 or Th2.  
 
In order to provide an adjuvant to drive correct DC maturation, AlloStim® will be 
injected into the necrotic center of the ablated tumor lesion within approximately ten 
minutes to one hour following the ablation procedure. AlloStim® cells produce large 
amounts of inflammatory cytokines and express surface molecules (e.g. CD40L) 
which are known to cause the maturation of dendritic cells and promote development 
of Th1 anti-tumor immunity. Further, since the patients will be immune to the 
alloantigens in AlloStim®, intratumoral injection (IT) is expected to elicit a potent 
memory response of Th1 cells to reject these allogeneic cells. All these factors are 
expected to serve as an adjuvant by promoting maturation of DC to prime for anti-
tumor specific Th1 immunity.  
 
In the cohort without cryoablation, the IV AlloStim® infusion and subsequent 
rejection is expected to cause release of inflammatory cytokines that will activate NK 
cells and memory T-cells and cause them to traffic to metastatic tumor lesions, 
creating an in-situ vaccination step intended to create anti-tumor specific immunity. 
Tumor vaccines generally contain a source of tumor antigen combined with an 
adjuvant which promotes immune recognition and primes for development of a 
specific immune response against the tumor antigen. In these schedules, a source of 
tumor antigen is created in-vivo by AlloStim® leading to the release of internal 
antigens. These factors are expected to serve as an adjuvant by promoting maturation 
of DC to prime for anti-tumor specific Th1 immunity.  
 
3. Activation phase:  
Intravenous infusions of AlloStim® are designed to create a "cytokine storm" of 
inflammatory cytokines capable of suppressing the ability of tumors to evade immune 
responsiveness. In addition, intravenous AlloStim® has been shown to activate host T-

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cells and macrophages through CD40L-CD40 interaction and cause these activated 
cells to extravasate to the tissues. Since priming and vaccination are expected to 
increase the titer of circulating Type 1 memory cells, extravasation causes an increase 
in immune cell infiltration at sites of inflammation, including metastatic tumor sites. 
This provides a mean to maintain and support an active cellular immune response 
against widely disseminated tumors. However, the inflammation is non-specific such 
that any inflammatory lesion such as arthritic lesions, inflammatory bowel or sites of 
previous injury can also become inflamed or the existing inflammation becomes 
exacerbated.  
 
Since tumors are known to be capable of evading Th1 immune responses, the 
"activation" phase of the protocol is designed to both activate the previously created 
immunity and to try to disable these tumor immunoavoidance mechanisms. It is 
known that a highly inflammatory environment can have the effect of suppressing 
tumor immune avoidance and breaking tolerance to the tumor antigens in much the 
same manner as inflammation can break tolerance to self-tissue antigens and promote 
autoimmunity. In order to create this inflammatory environment, AlloStim® is infused 
intravenously. The infusion of the foreign cells in AlloStim® is expected to cause a 
highly inflammatory environment as the primed immune system of the patient 
activates to reject these cells. In addition, the rejection of AlloStim® is expected to 
have the secondary effect of activating components of the host innate immune system 
(such as NK cells and macrophages) and activation of both allo-specific and tumor-
specific Th1 cells which should initiate the cascade of immunological events 
necessary for systemic tumor elimination and suppressing the ability of the tumor to 
avoid this immune attack. 
 
4. Booster phase:  
Intravenous infusions of AlloStim® are designed to maintain the highly inflammatory 
environment believed to be necessary in order to maintain an active cellular immune 
response against the tumor and to suppress the tumor's ability to evade immune 
attack.  
 
The final "booster" phase of the protocol is designed to maintain the chronic 
inflammatory environment to suppress tumor immunoavoidance and to maintain the 
activation of both innate and adaptive immunity. To meet this objective two-three 
intravenous infusions of AlloStim®  
 
7. STUDY OBJECTIVES 
7.1. PRIMARY OBJECTIVES 
1. To determine the safety of AlloStim® combined with cryoablation vs AlloStim® 
alone. 
2. Determine the schedule that provides the greatest efficacy and least adverse events 
7.2. EXPLORATORY OBJECTIVES 
1. To assess the longitudinal changes in tumor burden by RECIST and compare these 
changes with the histopathological analysis of corresponding biopsies (Parts 1 and 2).  

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2. To assess whether immune response correlates with RECIST, histopathology, plasma 
biomarkers and Overall Survival (OS). 
 
 
8. STUDY DESIGN 
This is a single center, open label study of CryoVaxTM personalized anti-tumor vaccine 
protocol combining the cryoablation of a selected metastatic lesion with intra-lesional 
immunotherapy compared to AlloStim® alone. 
 
Part 1 
 
3 subjects will be accrued sequentially into schedule A-1 and A-2 (Part 1). After accrual of 6 
subjects, up to 25 additional subjects will be accrued into the most favorable schedule (Part 2) 
 
Dosing Schedule A-1: Intradermal and Intravenous Dosing Combined With 
Cryoablation 
 
The priming step: Subjects will receive an ID injection of AlloStim® (0.5ml) on Days 0, 7, 
and 14 all in different locations. 
The vaccination step: Subjects will receive cryoablation and intratumor (IT) injection of 
AlloStim® (3 ml) on Day 21.  
The activation step: Subjects will receive an IV infusion of AlloStim® (3ml) on Day 28. 
The booster step: Subjects will receive two (optional) IV booster infusions of AlloStim® 
(5ml), one on Day 56 and Day 84. 
 
Dosing Schedule A-2: Intradermal and Intravenous Dosing With AlloStim® alone 
 
The priming step: Subjects will receive an ID injection of AlloStim® (0.5 ml) on Days 0, 3, 7, 
10 and 14.  
The vaccination step: Subjects will receive IV AlloStim® (3 ml) on Day 21.  
The activation step: Subjects will receive an IV infusion of AlloStim® (3ml) on Day 28.  
The booster step: Subjects will receive two IV booster infusions of AlloStim® (3ml), one on 
Day 49 and another on Day 77. 
 
Toxicity Monitoring 
Two types of toxicity are assessed for determination of whether a Dose Limiting Toxicity 
(DLT) has occurred. An acute dose limiting toxicity (ADLT) is assessed within 48h of a dose 
administration during the priming, vaccination and activation steps of each protocol. 
Cumulative dose limiting toxicity (CDLT) is assessed during the complete Safety Evaluation 
Period including any ADLT that occurs in the booster dosing.  
An ADLT is defined as the occurrence of any of the following within 48h of dosing: 
• Any ≥ Grade 3 local injection site reaction;  
• Any ≥ Grade 3 graft vs host disease; 
• Any ≥ Grade 3 infusion related symptoms of duration > 2 days; 
• Any ≥ Grade 4 infusion reaction of any duration 
For any Grade 1-2 acute toxicity, the study drug administration schedule can continue to the 
next scheduled dose. If an ADLT is observed, the subject will be followed until the toxicity is 

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resolved or the subject is stable.  No further dosing for that subject will occur after an ADLT 
event. 
A CDLT event is defined as the occurrence of any of the following within the Safety 
Evaluation Period: 
• Any ≥ Grade 3 graft vs. host disease 
• Any toxicity ≥ Grade 3 that is probably or definitely related to the study drug; 
• Any toxicity not present at baseline that occurs at ≥ Grade 4 
• Any autoimmune toxicity ≥ Grade 3 not present at baseline 
All adverse events (AEs) and serious adverse events (SAEs), regardless of attribution to the 
study drug, will be coded, graded and become part of the final safety report for each cohort.  
The DSMB will review the safety data on each cohort and recommend whether to advance 
enrollment to the next cohort. 
The development of any Grade 4 or greater toxicity in any subject at any time will prompt a 
review of safety data by the Sponsor, PI and the DSMB prior to accrual of any additional 
subjects. It is recognized that Grade 4 events and death can occur in this population due to 
disease progression. Therefore, dosing will continue for currently enrolled subjects at the 
occurrence of a grade 4 event according to protocol unless the PI determines the event is 
definitely or probably related to the study drug. If attribution is assigned to the study drug 
dosing will be suspended pending review by DSMB.  
In accordance with the 3+3 design, three subjects will be accrued into the first dosing 
schedule. If during the priming, vaccination and activation steps no ADLT are observed in 
any of the three subjects, accrual into the next cohort is allowed. If an ADLT occurs in two of 
the three subjects, no further dosing is allowed. If ADLT occurs in one of the three subjects, 
three additional subjects will be accrued into the same cohort. If no ADLT occurs within the 
additional three subjects, accrual into the next cohort can begin. If an ADLT is observed in 
any of the additional three subjects, no further dose escalation is permitted.  
The development of any DLT toxicity in ≥ 33% of the accumulated number of subjects in any 
and all dosing schedules during the Safety Evaluation Period will result in protocol 
discontinuation.  
At the completion of the Safety Evaluation Period for all cohorts, the safety evaluation of Part 
1 will be considered completed and all enrollment will be closed.  Efficacy evaluation will 
continue monthly for each subject until death or loss to follow-up. 
 
Part 2 
The safety and efficacy data from Part 1 will be evaluated and the favored schedule advanced 
to Part 2. In Part 2 of the trial, up to 25 additional subjects may be accrued. 
 
9. STUDY ENDPOINTS 
9.1. PRIMARY ENDPOINT 
Safety will be the primary endpoint of this study and will be evaluated on the basis of the 
following parameters: 

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• Physical examination and vital signs (temperature, blood pressure, pulse rate, 
respiratory rate, and blood oxygen saturation). 
• Clinical laboratory profile (complete blood count (CBC), comprehensive metabolic 
panel (CMP), C-reactive protein (CRP), coagulation factors and autoimmune 
parameters. 
• Adverse events according to the National Cancer Institute (NCI) Terminology Criteria 
for Adverse Events (CTCAE) version 4.03  (refer to section 15 for AE/SAE 
management and reporting): 
9.2. EXPLORATORY ENDPOINT 
• Correlation of tumor burden by RECIST, pathological response and immune response 
to Overall Survival (OS). 
- 
Overall Survival (OS) is evaluated from time of enrollment until death from any 
cause. Subjects are followed for survival during the trial, as long as they are alive, 
for 12 months after the last study treatment through follow-up phone calls. 
- 
Traditionally, oncology investigators have relied upon Response Evaluation 
Criteria in Solid Tumors (RECIST) to serve as a surrogate to predict clinical 
benefit. RECIST criteria for clinical outcomes rely upon the assumption that agent 
activity results in shrinkage of tumor and that enlargement of disease is a result of 
tumor growth. RECIST is a composite evaluation of response based upon 
measurements of the changes in tumor size [82]. RECIST criteria have been 
criticized for not being a reliable method to predict OS benefit for cytotoxic 
agents [83].  
In order to determine the utility of RECIST in evaluating response of patients to 
immunotherapy, RECIST 1.1 [82] guidelines will be used to determine objective 
tumor response. This endpoint will be determined and analyzed for correlation 
with OS. Malignant tumor masses (target lesions) will be selected on the basis of 
their size and their suitability for accurate repetitive measurements. All patients 
must have at least one target lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded) greater than or equal to 1.0 cm with 
spiral CT scan. To assess objective response, it is necessary to estimate the overall 
tumor burden at baseline and use this as a comparator for subsequent 
measurements. Whenever possible, several measurable lesions, up to a maximum 
of 2 lesions per organ and 5 total target lesions representative of involved organs, 
should be identified, measured and recorded at baseline. To allow later retrieval, 
lesions should be clearly marked on the films or otherwise identified. If the lesion 
is detected by more than one method at baseline, the investigator should select at 
baseline the method to be used at subsequent evaluations. All measurements 
should be performed using a caliper or ruler and should be recorded in metric 
notation in centimeters. A sum of the longest diameter for all target lesions will be 
calculated and reported as the baseline sum longest diameter. The baseline sum 
longest diameters will be used as reference to further characterize the objective 
tumor response of the measurable dimension of the disease by repeated 
assessment of the sum of the longest diameters during treatment. 

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All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as "present" or "absent". All baseline evaluations 
should be performed as closely as possible to the treatment start and never more 
than 14 days before the beginning of the treatment.  
- 
RECIST evaluations are particularly problematic for evaluating responses to 
immunotherapy, as the mechanism of action of immunotherapy drugs may cause 
swelling or flare of tumors, resulting in the appearance of increased size on CT 
scans, but may actually represent decreased burden of viable tumor. In addition, 
immune-mediate responses may manifest after an initial increase in tumor burden 
or may delay or stop tumor growth, resulting in disease stabilization and increased 
survival, but will be scored as progressive disease by RECIST criteria. Therefore, 
RECIST may erroneously predict progression in a subject treated with 
immunotherapy. 
For this reason, this study proposes: 
1. Longitudinal serial biopsies for comparison and correlation with RECIST data 
in order assess whether RECIST can be used to predict survival when using 
this immunotherapy. 
2. Evaluation of subjects according to newly proposed immune-related response 
criteria (irRC) [85].  The irRC is thought to better address patients' treatment, 
investigators' patient management and sponsors' analysis needs for targeted 
immunotherapy developments in oncology. 
- 
Subjects treated on this study will undergo evaluation of immune response to 
treatment. The results will be used to correlate response to vaccination with 
subsequent clinical outcome and OS. 
10. SELECTION OF SUBJECTS 
10.1. NUMBER OF SUBJECTS 
Approximately 6 subjects will be enrolled in the dose schedule evaluation Part 1 of the trial. 
In Part 2 of the trial, up to 25 additional subjects may be accrued in the one of the dose 
schedules. Recruitment Methods 
Efforts will be made to include all eligible subjects in this study. Subjects will be recruited 
from a population of patients who have been previously evaluated at the participating 
institution or have been referred from other institutions. The subject’s medical record will be 
reviewed by the investigator to determine his/her eligibility for the study.  
 
Each subject or subject’s legally acceptable representative must sign a current Institutional 
Review Board (IRB) approved Informed Consent Form (ICF) before any study-related 
procedures are performed.  
10.2. INCLUSION CRITERIA 
1. Adult males and female subjects aged 18-80 years at screening visit 
2. Pathologically confirmed diagnosis of colorectal adenocarcinoma  

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3. Presenting with metastatic disease:  
o Primary can be intact or previously resected 
o Metastatic lesion(s) in liver must be non-resectable 
o Extrahepatic disease acceptable 
4. At least one liver lesion able to be visualized by ultrasound and determined to be 
safely assessable for percutaneous cryoablation (if schedule includes cryoablation) 
5. Previous treatment failure of two previous lines of active systemic chemotherapy:  
o Previous chemotherapy must have included an oxaliplatin-containing (e.g. 
FOLFOX) and an irinotecan-containing (e.g. FOLFIRI) regimen  
o With or without bevacizumab 
o Administered in adjuvant setting or for treatment of metastatic disease    
o If KRAS wild type, must have at least one prior anti-EGFR therapy 
o Treatment failure can be due to disease progression or toxicity 
o Disease progression on second line therapy must be documented 
radiologically and must have occurred during or within 30 days 
following the last administration of treatment for metastatic disease  
6. ECOG performance score: 0-1 
7. Adequate hematological function: 
o Absolute granulocyte count ≥ 1,200/mm3  
o Platelet count ≥ 100,000/mm3  
o PT/INR ≤ 1.5 or correctable to <1.5 at time of interventional procedures 
o Hemoglobin ≥ 9 g/dL (may be corrected by transfusion) 
8. Adequate Organ Function: 
o Creatinine ≤ 1.5 mg/dL  
o Total bilirubin ≤ 1.5 times upper limit of normal (ULN) 
o Alkaline phosphatase ≤ 2.5 times ULN * 
o Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN *  
o Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN * 
*or ≤5x ULN if liver involvement 
9. EKG without clinically relevant abnormalities 
10. Female subjects: Not pregnant or lactating  
11. Patients with child bearing potential must agree to use adequate contraception  
12. Study specific informed consent in the native language of the subject.  
 
10.3. EXCLUSION CRITERIA 
1. Bowel obstruction or high risk for obstruction 
2. Moderate or severe ascites requiring medical intervention   
3. Clinical evidence or radiological evidence of brain metastasis or leptomeningeal 
involvement  
4. Symptomatic asthma or COPD  
5. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in 
pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room 
air  

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6. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation 
procedure (if schedule includes cryoablation) 
7. Regorafenib prior to the Study Period 
8. Previous treatment with TAS102  
9. Any of the following mood disorders: active major depressive episode, history of 
suicidal attempt or ideation  
10. Taking anticoagulant medication for concomitant medical condition (unless can be 
safely discontinued for invasive cryoablation, biopsy and intratumoral injection 
procedures) 
11. Prior allogeneic bone marrow/stem cell or solid organ transplant 
12. Chronic use (> 2 weeks) of greater than physiologic doses of a corticosteroid agent 
(dose equivalent to > 5 mg/day of prednisone) within 30 days of the first day of study 
drug treatment  
o Topical corticosteroids are permitted 
13. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple 
sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes 
allowed 
14. Prior experimental therapy  
15. History of blood transfusion reactions 
16. Known allergy to bovine products   
17. Progressive viral or bacterial infection  
o All infections must be resolved and the subject must remain afebrile for seven 
days without antibiotics prior to being placed on study 
18. Cardiac disease of symptomatic nature  
19. History of HIV positivity or AIDS 
20. Concurrent medication known to interfere with platelet function or coagulation (e.g., 
aspirin, ibuprofen, clopidogrel, or warfarin) unless such medications can be 
discontinued for an appropriate time period based on the drug half-life and known 
activity (e.g., aspirin for 7 days)  prior to cryoablation and biopsy procedures  
21. History of severe hypersensitivity to monoclonal antibody drugs or any 
contraindication to any of the study drugs 
22. Psychiatric or addictive disorders or other condition that, in the opinion of the 
investigator, would preclude study participation. 
23. Subjects that lack ability to provide consent for themselves 
 
11. STUDY PLAN AND PROCEDURES 
11.1. OVERALL STUDY PLAN 
Subjects will be screened for eligibility for the study. The screening process involves 
examining medical records to determine eligibility based on the IC/EC criteria. After 
obtaining informed consent, subjects will undergo physical exam, provide blood for lab 
analysis (CBC, CMP, total IgG and IgM, lipase, erythrocyte sedimentation rate, and CRP), an 
ultrasound of the liver, and a CT scan. The results of these baseline tests will be reviewed by 
the Principal Investigator (PI) and the Sponsor's medical monitoring team to determine if the 
subject still meets IC/EC. In schedule A-1, the study interventional radiologist will determine 

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if the subject has a lesion assessable for cryoablation. If the subject meets IC/EC criteria, a 
biopsy and tumor harvest procedure will be conducted. 
When the PI and the Sponsor agree that all IC/EC criteria are met, the subject is accrued/ 
enrolled in the study and assigned a protocol number. The enrollment date will be 
documented in CRF/eCRF. Upon accrual, the study site develops an appointment schedule 
for the subject and sends to the Sponsor for approval. Upon approval, the subject is notified 
of the schedule. The Sponsor will produce and ship AlloStim® in accordance with the 
approved schedule. 
AlloStim® will be formulated in Israel by the Sponsor, packaged in validated temperature-
controlled container and delivered by specialized courier service to the study site at least one 
day before the established treatment schedule day. AlloStim® is stable in formulation for at 
least 72 hours. All protocol required CT scans will be conducted at a radiology center. 
Cryoablation, intratumoral AlloStim® and voluntary tumor biopsies will be conducted at a 
radiology center.  
11.2. STUDY PROCEDURES 
11.2.1. Physical Examination 
A Comprehensive Physical Examination will be conducted at baseline. The exam will include 
the following organ systems: Constitutional; Eyes; Ears, Nose, Mouth and Throat; Neck; 
Respiratory; Cardiovascular; Gastrointestinal (abdomen); Lymphatic; Musculoskeletal; Skin; 
Neurologic; and Psychiatric. Subjects should be carefully screened at baseline for depression 
and suicide attempts or ideations. If there are indications or a history of depression is strongly 
recommended that these patients be closely followed together with behavioral health or 
psychiatric medical support. Subjects with an established diagnosis of depression or reported 
previous suicide attempts or suicidal ideations should not be enrolled on this protocol; the 
risks and benefits of being treated with the study drug should be weighed very carefully in 
consultation with behavioral health or psychiatry. 
 
A Basic Physical Examination will be performed at each subject visit, the presence of 
lymphadenopathy, edema, rash or pain will be recorded. The subject’s psychological status will 
be evaluated as part of the physical examination in each study visit. Information on exam will be 
documented in the medical record and on CRF/eCRF.  
 
Subjects will be evaluated for response by laboratory blood tests, radiological, pathological 
and immunological tests, as well as by performance status in order to determine if there is 
evidence of disease progression. Subjects that have clinically deteriorated and do not show 
evidence of response, in the judgment of the PI, will be discontinued on further experimental 
treatment and advised of alternative treatment options. 
11.2.2. Monitoring Vital Signs  
After each ID injection of study drug, the vital signs will be monitored with real-time monitoring 
equipment for heart rate, respiration rate, blood pressure, temperature, and pulse 
oximetry. Values will be recorded every 15 minutes for one hour on a provided form. If vital 
signs are stable, the subject can be discharged after 1 hour. Otherwise, the subject should 
continue to be observed until stable.   

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After each IV infusion and IT injection of study drug the vital signs will be monitored with real-
time monitoring equipment for heart rate, respiration rate, blood pressure, temperature, and pulse 
oximetry. Values will be recorded every 15 minutes prior, during and for 2 hours following the 
infusion. All changes in vital signs from baseline during and after the infusion will be recorded 
in the treatment notes. If vital signs are stable, the subject can be discharged after 2 hours. 
Otherwise, the subject should continue to be observed until stable. 
11.2.3. Laboratory tests 
All scheduled and unscheduled laboratory assessments will be analyzed by the local 
laboratory. 
Hematology Profile – includes a complete blood count (CBC) with differential. 
Chemistry Profile – includes sodium, potassium, chloride, calcium, BUN, creatinine, 
calcium, total protein, albumin, Aspartate transaminase (AST), Alanine transaminase (ALT), 
alkaline phosphatase, total bilirubin and direct bilirubin. 
Inflammation Marker – C-reactive protein (CRP), erythrocyte sedimentation rate, total IgG 
and IgM, and lipase 
Coagulation Profile – includes INR or prothrombin time (PT) if available (whichever is 
selected should be followed throughout) and partial thromboplastin time (PTT). 
Autoimmune Profile – includes complement C3, anti-DNA Ab, anti-nuclear Ab (ANA), anti-
mitrochondrial Ab(AMA), anti-smooth muscle Ab (SMA), liver/kidney/microsomal Ab 
(LKM). 
Pregnancy Test – for women of childbearing potential, a pregnancy test (serum or urine) is 
required pretreatment. Minimum sensitivity 25 IU/L or equivalent units of β-human chorionic 
gonadotropin (β-HCG). 
11.2.4. Tumor Assessment 
CT scan of the Head/Chest/Abdomen/Pelvis with and without contrast (if tolerated) will be 
conducted at baseline and Day 91.  All subjects accrued in schedule A-1 will also be 
evaluated at baseline to confirm they have a liver lesion that can be readily visualized and 
safely approached percutaneously for cryoablation.  
 
Subjects will undergo mandatory tumor biopsies of at least one selected target lesion (not 
lesion targeted for ablation) at baseline, during intratumoral injections (day 21 Schedule A1 
and on Day 91.  
 
The intratumoral procedures use a trocar that will have already been inserted into the tumor 
to conduct the intratumoral injection and thus these biopsies will not add an additional 
invasional procedure. 
 
In order to obtain information on the longitudinal changes in the immune cell patterns of 
tumors as well changes in tumor size, biopsies will be collected for subjects who consented 
under a separate inform consent. These additional biopsies will be conducted only if subjects 
separately consent.  Failure to consent for the intermediary biopsy procedures will not 
disqualify subjects. 
 
The biopsies material should be placed in containers supplied by the Sponsor. The samples 
should be labeled with protocol number, subject study ID, date of birth, date of sample 

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collection and sample time point (protocol day). The containers should be kept at room 
temperature (RT) and delivered to Sponsor's histology lab within 24h of collection to: 
Dr. Miriam Bloch, MD (Pathologist): 
Immunovative Clinical Research, Inc., 
4824 East Baseline Road 
Suite #113, Mesa, AZ 85206, USA 
 
A biopsy is useful because subjects on immunotherapy can present with "flared" lesions that 
appear to be larger on CT scan, but may not necessarily represent disease progression. 
Increase in size can be due to immune cell infiltration, edema, coagulative necrosis and/or 
fibrotic changes rather than tumor growth. In addition, subjects may present with new lesions 
which may not necessarily represent progressive disease, but may instead represent immune 
reactivity to microscopic disease previously not visible. The initial appearance of progressive 
disease may occur during immunologic therapy for at least two reasons. First, 
immunotherapy may induce lymphocytic tumor infiltration and inflammation of the tumor, 
and the associated increase in tumor diameter is then scored as progression on radiographic 
imaging (i.e. ‘tumor flare’). Second, the appearance of new lesions or growth of primary 
lesions may occur after immunotherapy has been administered, since the process of immune 
activation is complex and delayed. During this period of activation, the tumor may be able to 
transiently grow even when effective therapy is priming the immune system to eventually 
respond.  
 
Immunotherapy may induce responses with a variety of kinetic patterns. Some tumors may 
respond rapidly, meeting criteria for a RECIST response. Other tumors may respond late in 
the course of treatment, wherein standard 2- and 3-month evaluations of these patients would 
classify them as non-responders. Some tumors may actually increase in diameter before 
eventually regressing. Using RECIST criteria, such patients would be classified as having 
disease progression and generally would be removed from a trial before late response might 
be documented [84]. Because of the unique patterns of clinical response that arise with 
immune-modulating therapies, alternative clinical trial design and end points are necessary to 
properly evaluate these agents. 
 
For these reasons, irRC and longitudinal tumor biopsies are used in this study in order to 
distinguish whether changes in the radiographic appearance of tumors correlates with 
progression or tumor flare, while overall survival is used as the primary endpoint due to the 
unreliability of RECIST as a method to evaluate response to immunotherapy. The 
experimental endpoint of seroconversion to IL-12 positivity was found in an earlier Phase I/II 
clinical trial to correlate with survival. Therefore, radiological, pathological and 
immunological endpoints will be used for assessment of tumor response. 
11.2.5.   Immunological Research Assays 
11.2.6. Cytokines 
Subject sera will be collected for cytokines (such as IL-12p70, IFN-γ and TNF-α) detection 
and analyses. AlloStim® is designed to activate a Th1 immune response. Measuring IL-12, 
TNF-α and IFN-γ in a subject’s sera can provide evidence to support activation and 
sustainability of a Th1 immune response activated by AlloStim®. In addition, chronic 
inflammatory adverse events could be attributed to AlloStim® by following these cytokines, 
especially TNF-α.  

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When cytokines testing is required, ~5 ml of whole blood is collected in blood tubes provided 
by the sponsor and incubated for 30 to 60 minutes at room temperature. Tubes will be 
centrifuged for 15 minutes at ~1000 rcf and the serum will be separated and aliquoted into 
new pre-labeled tubes. All samples should be labeled with subject study ID, protocol number, 
protocol day, date and time of collection. Serum samples should be kept at minus 20°C (-20°C) 
or below until shipped. Samples will be shipped on a dry ice or in a liquid nitrogen dry shipper 
via overnight courier to:    
     
                         Immunovative Therapies, Ltd. 
Malcha Technology Park  
Building 1, First Floor  
Jerusalem, Israel 96951  
Phone: +972-2-6506288  
 
11.2.7. Th1/Th2 Intracellular Staining 
AlloStim® priming is designed to increase the number of Th1 cells in circulation. Since IFN-γ 
is a prototypic marker of Th1 cells and IL-4 is a prototypic marker of Th2 cells, the Th1/Th2 
balance can be detected by activating T-cells and measuring the expression of IFN-γ and IL-
4. Th1/Th2 analysis requires ~50 ml of whole blood in blood tubes provided by the sponsor. 
The PBMC will be isolated from whole blood following the instructions provided by the 
Sponsor. Briefly, the whole blood tubes should be centrifuged at 1500 rcf for 15 minutes and 
whitish layer to be collected into new pre-labeled tube. After the cell counting, the separated 
PBMC will be washed by centrifugation 8 minutes at 402 rcf, and re-suspended in freezing 
medium to final concentration of 10×106/ml. The suspended cells will be aliquoted to 107 
PBMC/vial. All PBMC samples should be labeled with subject study ID, protocol number, 
protocol day, date and time of collection. PBMC samples should be frozen and stored at -
80°C or below until shipping. All PBMC samples will be shipped on a dry ice or in a liquid 
nitrogen dry shipper via overnight courier to:  
 
Immunovative Therapies 
Malcha Technology Park  
Building 1, First Floor  
Jerusalem, Israel 96951  
Phone: +972-2-6506288 
 
12.    DESCRIPTION OF STUDY VISITS 
The following tables summarize all planned assessments, tests, and treatments scheduled to 
occur as part of this study, including pretreatment evaluations, end of therapy assessments, 
and follow-up. These assessments will be conducted at the PI clinic and a Sponsor-designated 
radiology center (imaging, cryoablation and biopsy). Some deviations in the schedule of 
assessments are allowed as indicated in protocol deviation section 12.1. 

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Table 1 Table of Assessments Schedule A-1 
Protocol activity 
Baseline 
 
ID# 1 
ID# 2 
ID# 3 
Cryoablation 
IV #1 
IV booster #1 
IV booster #2 
CT+biopsy 
Protocol day 
-14 to-1 
0 
7 
14 
21 
28 
56 
84 
91 
Informed Consent 
x 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
Medical History  
x 
 
 
 
 
 
 
 
 
Physical Examination (complete) 
x 
 
 
 
 
 
 
 
 
Physical Examination (brief) 
 
x 
x 
x 
 
 
x 
 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG 
x
 
 
 
 
 
 
 
 
 
EKG 
x
 
 
 
 
 
 
 
 
 
CT Scan (head, chest, abdomen, pelvis) 
x
 
 
 
 
 
 
 
 
 
CT Scan (chest, abdomen, pelvis) 
 
 
 
 
 
 
 
 
x 
Cryoablation under US or CT guidance  
 
 
 
 
x 
 
 
 
 
Biopsy  
x 
 
 
 
 
 
 
 
x 
Hematological Profile (CBC)  
x 
 
x 
x 
x 
x 
x 
x 
x 
Chemistry Profile (CMP) 
x 
 
x 
x 
x 
x 
x 
x 
x 
Inflammation Biomarkers* 
x 
 
x 
x 
x 
x 
x 
x 
x 
Pregnancy Test (β-HCG) 
x 
 
 
 
 
 
 
 
 
Coagulation profile (PT, PTT, INR) 
x 
 
 
x 
 
 
 
 
 
Autoimmune Panel** 
 
x 
 
 
 
 
 
 
x 
HLA engraftment test 
x 
 
 
 
 
 
 
 
x 
Research blood draw*** 
 
x 
 
 
x 
 
x 
x 
 
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 

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Table 2 Table of Assessments Schedule A-2 
 
 
Protocol activity 
Baseline 
 
 
ID# 1 
ID# 2 
ID# 3 
ID #4 
ID #5 
IV #1 
IV #2 
IV#3 
IV #4 
CT+biopsy 
Protocol day 
-14 to-1 
0 
3 
7 
10 
14 
21 
28 
49 
77 
91 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
Medical History  
x 
 
 
 
 
 
 
 
 
 
 
Physical Examination (complete) 
x 
 
 
 
 
 
 
 
 
 
 
Physical Examination (brief) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Vital signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECOG 
x
 
 
 
 
 
 
 
 
 
 
 
EKG 
x
 
 
 
 
 
 
 
 
 
 
 
CT Scan (4 phase) head, chest, abdomen, pelvis) 
x
 
 
 
 
 
 
 
 
 
 
 
CT Scan (3 phase) chest, abdomen, pelvis) 
 
 
 
 
 
 
 
 
 
 
 
Biopsy  
x 
 
 
 
 
x 
 
 
 
 
x 
Hematological Profile (CBC)  
x 
 
x 
x 
 
x 
 
x 
 
x  
x  
Chemistry Profile (CMP) 
x 
 
x 
x 
 
x 
 
x 
 
x  
x  
Inflammation Biomarkers* 
x 
 
x 
x 
 
x 
 
x 
 
x  
x  
Pregnancy Test (β-HCG) 
x 
 
 
 
 
 
 
 
 
 
 
Coagulation profile (PT, PTT, INR) 
x 
 
 
 
 
x 
 
 
 
x 
 
Autoimmune Panel** 
 
x 
 
 
 
 
 
 
 
 
 
HLA test 
x 
 
 
 
 
 
 
 
 
 
x 
Research blood draw 
 
x 
 
x 
 
x 
 
x  
x 
x  
x  
Concomitant Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 

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12.1. SCHEDULE DEVIATIONS 
Scheduled protocol activities should be conducted on the specified protocol days. In some 
cases the scheduling may not be able to be followed precisely. For example, subjects may 
miss appointments causing deviations due to illness, weather, transportation problems or 
miscommunication. The clinic may experience deviations in scheduling due to lack of 
available site personnel, lack of available supplies, mechanical or equipment failures. 
Deviations may also occur due to unavailability of the study drug, due to QC failures or study 
drug transport problems. In addition, holidays and weekend scheduling may cause conflicts.  
 
If a scheduled protocol appointment is missed for any reason and the study drug has already 
been shipped, the protocol procedure can be delayed by one or two days, as long as the study 
drug is delivered within its 72 hours shelf life time. If the study drug cannot be delivered 
within the 72 hours shelf-life window, then the protocol procedure should be rescheduled for 
the next available protocol activity day. When rescheduling protocol treatments, the study 
drug should not be administered within 3 days of a previous study drug administration. Thus, 
up to a 7 day delay in protocol procedures is allowed for a missed appoint. 
 
For schedule C, the second intratumoral injection after cryoablation (day 17) must occur 3 
days +/- 1 day after the ablation procedure.  
 
Schedules for laboratory and research blood tests and follow-up assessments can deviate +/- 3 
days from the scheduled protocol days. Schedules for CT scans can deviate +/- 1 week from 
the protocol days. All protocol deviations should be documented with the reason and the 
rescheduling clearly stated on a form provided by the Sponsor for this purpose.  
 
If protocol deviations in treatment days occur more than once or occur outside of the allowed 
deviation windows, the subject will be censored as of the date of the violating deviation for 
survival analysis.  
12.2. SCREENING ASSESSMENTS FOR ALL SCHEDULES 
Any subjects deemed possibly eligible for participation will be recruited and assigned a screening 
number. Before screening assessments are conducted, the PI or designated representative will 
explain the protocol procedures, including timing; the expected and unknown risks and 
possible benefits; and answer all subject’s questions and concerns. The informed consent 
procedure should be documented in the source record and include at least the following: (1) 
subject screening number; (2) date and time; (3) person performing the consent procedure; 
(4) persons present during the consent procedure and their relationship to the subject or the 
study; (5) document any questions asked or concerns expressed by subject or subject’s 
representative(s); (6) confirmation that subject understands that participation is voluntary and 
can withdraw at any time without penalty, that the protocol is experimental, that no particular 
outcome can be assured or is known, that there is the possibility of side-effects some of 
which may be serious, and that the protocol requires commitment of significant time to visit 
clinic and participate in telephone interviews.  Subsequently, the subject must sign and date and 
receive a copy of an informed consent document that was approved by the Institution Review 
Board (IRB) or Independent Ethics Committee (IEC) before any study specific procedure is 
performed. An additional signed copy should be retained and placed in the Study File. 

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Baseline assessments can be initiated up to two weeks prior to the first scheduled 
investigational product administration (Day -14) and must be completed at least 4 day prior to 
the scheduled investigational product administration (Day -4) due to formulation logistics and 
transits times. Results of tests or examinations performed as standard of care prior to 
obtaining informed consent and within 14 days prior to protocol Day 0 may be used, rather 
than repeating required tests. The following evaluations and procedures will be performed 
during screening: 
• Written informed consent(s) 
- 
Study informed consent 
• Complete medical history, including disease history (date of diagnosis, prior cancer 
therapy and surgery, tumor/node/metastasis staging at the time of diagnosis and study 
entry and pre-existing toxicities from previous therapies) 
• Prior (within 30 days) and current concomitant medications 
• Complete comprehensive physical examination, including the evaluation of any 
evidence of major depression and suicidal behavior (subject’s previous suicide 
attempts and any suicidal ideations) 
• Demographics 
• Vital signs, including heart rate, respiration rate, blood pressure, temperature, pulse 
oximetry, and weight. 
• EKG 
• Blood draws for CBC, CMP, Total IgG and IgM, erythrocyte sedimentation rate, 
lipase, and CRP  
• Pregnancy test (if applicable) 
• Coagulation test (PTT, PT, INR) 
• HLA baseline test 
• ECOG performance score 
• Baseline CT scan of head, chest, abdomen, and pelvis (w/ and w/o contrast). If brain 
involvement at baseline, subjects will be excluded. Future scans only require chest, 
abdomen and pelvis (unless symptoms are present which suggest possible brain 
metastasis). Subjects with medical conditions which contraindicate the use of contrast 
will be scanned without contrast. The baseline scan will be reviewed by an 
interventional radiologist for determination of a target lesion for cryoablation. An 
ultrasound study will be conducted on the target lesion(s) to determine feasibility of 
using ultrasound guidance for the procedure. The interventional radiologist must 
certify that a metastatic lesion exists in a location that can be safely approached 
percutaneously for image-guided cryoablation. This certification along with a 
summary report describing the target lesion will be sent to the referring PI and 
Sponsor. 
• Tumor biopsy (mandatory). Place biopsy in the container provided by the Sponsor 
and send for pathology analysis 
12.3. ELIGIBILITY DETERMINATION (SCREENING) FOR ALL SCHEDULES 
(STUDY SITE) 
After all the baseline data are obtained (baseline H&P, laboratory and imaging data), the PI 
or designee will conduct a final assessment including opinion of the interventional radiologist 
regarding tumor accessibility for cryoablation and biopsy (subject need not be present) in 

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order to assure that the subject meets all inclusion/exclusion (IC/EC) criteria prior to the first 
investigational product administration (on or before Day -1). Subjects failing to meet IC/EC 
criteria after baseline assessment will be dropped from the study.  A baseline assessment 
form will be filed by the PI with the Sponsor certifying either enrollment or drop status of the 
subject after baseline assessment.  
Accepted subjects will be assigned a subject number by the Sponsor that will be used for all 
future reference to the subject. 
13. DISCONTINUATION CRITERIA  
13.1. 
  EARLY DISCONTINUATION OF THE STUDY 
The study may be discontinued due to clinical hold or other regulatory action. The Sponsor 
can discontinue the study at any time for any reason with appropriate notice to the study site 
and the IRB with oversight responsibility. The Sponsor can terminate the participation of the 
study site if the site is not conducting the protocol in accordance with the procedures defined 
in the approved protocol (i.e. protocol deviations, failure to ensure the quality of the data 
collected, etc.) or due to low rate of recruiting.  
 
The DSMB can recommend termination of the study if they are of the opinion that the 
benefit/risk ratio has become adverse to the subject. The PI can terminate participation in the 
study if in the opinion of the investigator, information on the investigational product causes 
doubt as to the benefit/risk ratio for participation.   
13.2. 
  EARLY DISCONTINUATION OF INDIVIDUAL SUBJECTS 
Subjects may discontinue participation in the study for the following reasons: 
• Protocol violation 
• Withdrawal of consent 
• DLT event 
• Non-compliance 
• Changes in the subject's condition render the subject unacceptable for further 
treatment in the judgment of the Principal Investigator (the reason(s) must be 
documented) 
• Subject becomes pregnant (withdrawal is required) 
• Subject is lost to follow-up 
After termination of study therapy, the subject will be treated as clinically indicated by the 
investigator. All subjects will be followed until resolution or stabilization of any study-related 
toxicity. If a subject is discontinued from all study therapy, the reason(s) for discontinuation 
should be documented in the subject’s medical record and CRF/eCRF. A follow-up 
evaluation should be performed approximately 28 days after the last dose of study drug. 
 

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14. STUDY TREATMENT 
14.1. STUDY DRUG FORMULATIONS 
AlloStim® is formulated T-StimTM cells that have been activated by adding CD3/CD28-
conjugated microbeads and packaged in a syringe. AlloStim® is prepared by thawing frozen, 
QC released T-StimTM cells and incubating the cells for 4 hours with Dynabeads® 
ClinExVivo™ CD3/CD28. The beads are mixed with the cells at a 2:1 bead to cell ratio. After 
4 hours, the cells with the beads attached are harvested, washed and suspended in formulation 
buffer containing PlasmaLyteA® supplemented with 1% human serum albumin. The 
formulated cells with the beads still attached are then loaded in a syringe for infusion or 
injection. A sample from the syringe lot is tested for bacterial contamination with a Rapid 
Microbiological Method (RMM) with results available in 48 hours. The investigational 
product AlloStim® is formulated in syringes as follows:  
• Intradermal (ID) dose: 1 x 107 cells with 2 x 107 beads in 1 ml in a 3 ml syringe 
• Intravenous (IV) dose: 3 x 107 cells with 6 x 107 beads in 3 ml in a 10 ml syringe  
14.2. DRUG STORAGE AND RELEASE  
The AlloStim® syringes are packaged in validated temperature-controlled containers and 
shipped by specialized courier service to the study site at least 48 hours prior to the protocol 
required treatment day.  
 
Each shipment is accompanied by a Shipment Receipt Form and a Certificate of Analysis for 
product safety testing. Upon receipt, at the clinical site, the product is unpacked by a 
designated person(s) and immediately transferred to 2˚C to 8˚C (36˚F to 46˚F) storage. The 
syringe lot is quarantined at the study site until notification of Rapid Microbiological Method 
(RMM) release. The lot must pass RMM test, prior to release of each syringe to the clinic. 
The release must be documented on provided forms. 
 
The AlloStim® is stable for 72 hours under refrigeration at 2˚C to 8˚C (36˚F to 46˚F). DO 
NOT FREEZE. Do not use AlloStim® after the expiry time and date that are printed on the 
label. If the AlloStim® is not administered and the expiry time and date have passed, the 
syringes should be discarded and another dose should be requested for use. 
14.3. DRUG PREPARATION PRIOR TO ADMINISTRATION  
Prior to use, the AlloStim® is removed from storage and kept at room temperature for 15-45 
minutes. The AlloStim® is stable for 90 minutes at room temperature. If the AlloStim® is not 
administered within 90 minutes window, the syringes should be discarded and another dose 
should be requested for use. 
 
For each AlloStim® use, the study drug lot number, time and date the cells released to the 
clinic, incubation time at room temperature, administration date, time, and dose, injection site 
location (as applicable) should be documented in subject’s medical records and provided 
forms. 

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14.4. TREATMENT ADMINISTRATION  
14.4.1. Intradermal Injection 
Each ID injection contains 1 x 107 AlloStim® cells formulated in 0.5ml of 1% human serum 
albumin in PlasmaLyteA. One pre-formulated 3 ml syringe of AlloStim® will be delivered to 
the study site per subject for the ID injection days.  
For schedules A-1 and A-2, 0.5 ml of AlloStim® will be administered, and the remaining 0.5 
ml will be discarded. 
ID Injections shall be administered into the forearm (abdomen and deltoid areas can also be 
used) for schedule A-1 and A-3 on days 0, 7, 14, and 21, schedules A-2 and A-4 on days 0, 7, 
14 and for schedule B, C, D, E and F on days 0, 3, 7, and 10. The injection on Day 3 must be 
in the same location as on days 0. The day 7 injection should be in different place than the 
day 0 and 3 injections and the day 10 injection in the same location as the day 7 injection. If 
the skin in the selected site is hardened, inflamed or otherwise not suitable for ID injection, 
select a different site. The site selected for each injection and the barcode sticker indicating 
the batch of the dose will be recorded on a provided form.  
For the ID injection, the needle should be at a shallow angle, approximately 15 degrees (just 
under the skin). Some resistance should be felt, if not, the needle is likely too deep and should 
be pulled back until the bevel is barely under the skin. The plunger should be pressed slowly 
and a wheal or bubble should appear at the injection site. The longest diameter of the wheal 
will be recorded immediately following injection in the source document. 
14.4.2. Intravenous Infusions (IV) 
Schedules A-1 and A-2: Each IV push contains 3 x 107 AlloStim® cells formulated in 3 ml of 
1% human serum albumin in PlasmaLyteA. Pre-formulated 10 ml syringes of AlloStim® will 
be delivered to the study site on or prior to the IV administration day. AlloStim® is 
administered as an IV push over approximately 5 minutes.  
Subjects may be hydrated with 500 - 2000 ml of NS (or similar) prior to infusion and may be 
medicated with 25-50 mg diphenhydramine PO/IV, 150 mg ranitidine (Zantac) PO or other 
H-2 blocker, 25-50 mg PO indomethacin (or equivalent NSAID) during or after the infusion 
if medically indicated. 
 
After each IV administration of study drug, the vital signs will be monitored manually every 
15 minutes or with real-time monitoring equipment for heart rate, respiration rate, blood 
pressure, temperature, and pulse oximetry. Values will be recorded prior, during and for 2 
hours following the infusion. All changes in vital signs from baseline during and after the 
infusion will be recorded in the treatment notes.  
 
The physician on duty has the authority to stop, delay, or cancel the infusion at any time if 
medically indicated. Any such actions that deviate from the infusion protocol will be 
recorded in the treatment notes and appropriate CRF or eCRF.  

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14.4.3. Intratumoral Injections (IT) 
 Subjects in schedule A-1 will receive an IT injection of AlloStim® (3 ml) on Day 21 into the 
same ablated lesion on Day 17. 
Each IT injection contains either 1 x 107 AlloStim® cells formulated in 1 ml or 3 x 107 
AlloStim® cells formulated in 3 ml of 1% human serum albumin in PlasmaLyteA. Pre-
formulated 3 or 10 ml syringes of AlloStim® will be delivered to the study site on or prior to 
the IT administration day.  
After each IT administration of study drug the vital signs will be monitored with real-time 
monitoring equipment for heart rate, respiration rate, blood pressure, temperature, and pulse 
oximetry. Values will be recorded every 15 minutes prior, during and for 2 hours following 
the administration. All changes in vital signs from baseline during and after the 
administration will be recorded in the treatment notes.  
 
14.5. 
 DRUG ACCOUNTABILITY 
As required by FDA regulations, all drug storage, procurement and usage will be carefully 
monitored and documented. The Principal Investigator will oversee this process and may 
delegate duties to others as needed to conduct the trial under Good Clinical Practices. The 
study site will be responsible for tracking receipt of the study drug and storage conditions of 
the study drug up until the time of administration. In addition, the study site must track which 
study drug syringe was administered to each subject, including date and time, location and 
route with forms and labels provided by the Sponsor. 
14.6. CONCOMITANT TREATMENTS PROHIBITED AND RESTRICTED THERAPIES   
DURING THE STUDY 
No chemotherapy or other anti-cancer treatment is allowed within the first 140 days for 
Schedules A1-4 subjects and 105 days for Schedule B, C, D, E and F subjects (“Study 
Period”). If the PI determines that a subject requires anti-cancer treatment during the Study 
Period, the subject data will be dropped from the protocol. The safety data will be reported 
but will be censored as of the treatment date. An additional subject will be accrued for each 
censored subject.  
 
Subjects with bone metastases may receive palliative radiation therapy to treat pain or 
prevent pathological fractures during the Study Period. 
 
Subjects experiencing anemia can be transfused as medically required (e.g., if Hgb < 9.0) at 
discretion of the PI. Erythropoietin may be used in continuation therapy, if indicated.   
 
Subjects will receive medically appropriate supportive care, including treatment of pain and 
infection during the Study Period.  
 
Additional  IV booster infusions are allowed at the discretion of the investigator on a monthly 
basis after the completion of the Study Period.  
 
Use of steroids is not allowed unless medically indicated. NSAIDs should be used as first 
choice and methylprednisone or SoluMedrol as next choice if anti-inflammatory medication 

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is deemed necessary. Inhaled steroids are allowed on study. If a subject is administered 
systemic steroids during the Study Period for any reason, the subject will be dropped from the 
study and the data will be censored from the first day of steroid administration.  
 
Dexamethasone therapy is contraindicated in immunotherapy protocols, as it has been 
shown to selectively cause apoptosis of activated effector immune cells.  
 
Administration of dexamethasone will necessitate dropping the subject from the protocol and 
censoring data from the first day of administration. 
 
If evidence of severe immune-related adverse events (e.g., GVHD, VOD, autoimmune 
disease) at any time during the protocol, the investigator should first attempt to suppress the 
inflammation using high dose IV SoluMedrol. 
 
If the condition is refractory to steroids, additional immunosuppressive agents should be 
considered (e.g., Imuran, cyclosporine). Specific agents for cytokine storm related events, 
such as Remicade can be considered. T-cell inflammation can be treated with Orthoclone 
OKT3, monocyte inflammation with Etoposide and B-Cell inflammation with Rituximab. If 
immunosuppressive treatment does not reverse a suspected immune-mediated adverse event, 
dexamethasone should be administered to eliminate any activated immune cells. 
Dexamethasone can be administered alone or in combination with Cytoxan as a reversal 
strategy. 
 
All concurrent medical care must be documented. Any use of immunosuppressive agents will 
result in censor of the subject for analysis, but the AE/SAE must be reported even after 
administration and documented. 
 
15. ADVERSE EVENTS 
An adverse event (AE) is any untoward medical occurrence in a trial subject that has been 
administered the study drug; the event does not necessarily have to have a causal relationship 
with AlloStim® treatment or usage. 
 
All observed or volunteered AEs, regardless of causal relationship to the investigational 
product, will be recorded as an adverse event on a supplied case report form (CRF) or 
electronic CRF (eCRF). Events involving adverse drug reactions, illnesses with onset during 
the study, or exacerbations of preexisting illnesses should also be recorded as AEs. 
  
Exacerbation of pre-existing illness, including the disease under study, is defined as 
manifestation (sign or symptom) of the illness that indicates a significant increase in the 
severity of the illness as compared to the severity noted at the start of the trial and the known 
normal course of disease progression for stage IV colorectal cancer. This may include 
worsening or increase in severity of signs or symptoms of the illness, increase in frequency of 
signs 
and 
symptoms 
of 
an 
intermittent 
illness, 
or 
the 
appearance 
of 
new 
manifestations/complications. Exacerbation of a pre-existing illness should be considered 
when a subject requires new or additional concomitant drug or non-drug therapy for the 
treatment of that illness during the trial. 
 
Lack of, or insufficient clinical response, benefit, efficacy or therapeutic effect, should not be 
recorded as an AE. The investigator must make the distinction between exacerbation of pre-
existing illness and lack of therapeutic efficacy. The investigator can take into consideration 

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the results of radiology and pathology exams and immunological monitoring data when 
making this assessment. 
In addition, abnormal objective diagnostic procedures findings (e.g., abnormal laboratory test 
results) should be recorded as an AE if it is fulfills one or more of the following: 
• Results in subject’s withdrawal by the Investigator; 
• Is associated with an SAE; 
• Is associated with clinical signs or symptoms; 
• Is considered by the physician to be of clinical significance; 
• Requires the subject to have study therapy discontinued, modified, or interrupted;  
• Requires the subject to receive specific corrective therapy; and 
• Requires diagnostic evaluation to assess the risk to the subject. 
 
Laboratory adverse events should be captured on the AE /SAE CRF/eCRF as appropriate. It 
is expected that wherever possible, the clinical, rather than the laboratory term, will be used 
by the reporting investigator.  
Clinically significant changes in physical examination findings should also be recorded as 
AEs.  
15.1.1. Clinical Laboratory Adverse Events 
All laboratory test values captured as part of the study should be recorded on the appropriate 
laboratory test results pages of the CRF/eCRF. In addition, to collecting additional 
information about clinically important laboratory abnormalities, at a minimum, the following 
laboratory abnormalities should be captured on the AE /SAE CRF/eCRF as appropriate: 
• Any laboratory test result that meets the criteria for an AE or SAE; 
• Any laboratory abnormality that requires the subject to have study therapy 
discontinued, modified, or interrupted; and 
• Any laboratory abnormality that requires the subject to receive specific corrective 
therapy. 
It is expected that wherever possible, the clinical, rather than the laboratory term, will be used 
by the reporting investigator.  
15.1.2.   Immune-Related Adverse Events  
The FDA approved the drug Yervoy (Ipilimumab), a checkpoint blockade immunotherapy for 
the treatment of Melanoma. The immune mechanism of this drug is novel and resulted also in 
novel immune-related adverse events. Since the immune mechanism of Yervoy and other 
drugs of this class may be similar to the mechanism of the Study Drug, the Investigators 
should be particularly vigilant in diagnosing and reporting Immune-Related Adverse Events.  
 
The manufacturer of Yervoy has provided literature to assist physicians in identifying 
immune-related adverse events. This literature might serve as a guide to investigators as to 
the types of adverse events that might occur with drugs that have an immune mechanism of 
action. 

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15.1.3.   Expected Adverse Events  
Expected AEs are any AEs whose nature and severity have been previously observed and 
documented (in the Investigator Brochure) for the study drug. Expected AEs should not be 
reported to the IRB/EC. 
 
The following adverse events are known to be associated with the administration of 
AlloStim®: 
- 
Allergy, Immunology Reaction 
- 
Flu-like Symptoms 
- 
Pain-NOS 
The following adverse events have been observed but have not been attributed to the study 
drug as they may be related to the underlying disease: 
- 
Hemoglobin (Low) 
- 
Lymphopenia (Low Abs. Lymphs) 
- 
Alkaline phosphatase (High) 
- 
AST (High) 
- 
Calcium (Hypocalcemia) 
- 
Hypoalbunemia (Low Albumin) 
- 
DVT (deep vein thrombosis) or other thrombolic events 
In addition, subjects in trials enrolling patients who failed two treatment lines with no available 
treatment options (such as the subjects in the current study) are expected to die from their disease. 
 
AEs do not include the following: 
• Medical surgical procedures are not AEs (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if the procedure was 
not planned at screening visit. 
• Overdose of concomitant medication without any signs or symptoms unless the 
subject is hospitalized for observation. 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred). 
 
AEs will be solicited from physical exam, subject and caregiver/family interview in person or 
by telephone and laboratory test results. The investigator is to report all directly observed 
adverse events and all adverse events spontaneously reported by the trial subject or 
caregiver/family member. Each trial subject will be questioned about adverse events at each 
clinic visit following initiation of treatment and by telephone at least once a month during the 
follow-up phase. The question asked should be, "Since your last clinic visit have you had any 
health problems?", or a similar type of open-ended query. 
 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE, and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE). For all AEs, sufficient information should be obtained by the 
investigator to determine the causality of the AE (i.e., investigational product or other 
illness). The investigator is required to assess causality and indicate that assessment on the 
CRF/eCRF. Follow-up of the AE is required if the AE persists. Follow-up is required until 

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the event is resolved or stabilized at a level acceptable to the investigator and the Sponsor's 
medical monitor or his/her designated representative. 
 
AE severity will be recorded and graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (June 14, 2010) 
and coded into the database according to the latest version of MedDRA. 
 
 
 
Table 7 
Severity of Adverse Events According to CTCAE (Version 4.03)  
Grade Description 
0 
No AE or within normal limits 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate 
instrumental Activities of Daily Living (ADL) 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
A semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available 
 
 
The following definitions should be used for toxicities/AEs that are not specified in the 
CTCAE: 
 
• Mild (Grade 1): The AE is noticeable to the subject, it does not require 
discontinuation or reduction of the dose of the investigational product, but may 
require additional therapy. 
• Moderate (Grade 2): The AE interferes with the subject’s daily activities; it does not 
require discontinuation of the investigational product, but may require additional 
therapy. 
• Severe (Grade 3): The AE is intolerable and necessitates discontinuing or reducing the 
dose of the investigational product or additional therapy. 
• Life-threatening (Grade 4): The patient is at immediate risk of death from the AE. 
• Death (Grade 5). 
 
The PI will assess the relationship between the investigational product and the occurrence of 
each AE or SAE by using his or her best clinical judgment. The PI must document the 
reasoning for any decision on attribution. Other potential causes of an AE other than the 
Study Drug, such as the history of the underlying disease, concomitant therapy, other risk 
factors, and the temporal relationship of the event to the investigational product will be 
considered and investigated. All alternative causation that was considered, investigated and 
ruled out will be documented. The causality of all AEs will be based on the Principal 

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Investigator’s assessment of the AE using the causality terms and assessment criteria as 
presented in Table 8 below. The investigator must provide written justification to 
demonstrate that a particular event met the chosen criteria and did not meet the criteria that 
was not selected. 
 
 
 
Table 8 
Causality of Adverse Event 
Relationship 
Assessment Criteria 
Definitely 
Related 
There is evidence of exposure to the study drug. 
The time sequence of drug intake and event is reasonable 
The AE is more likely explained by the study drug than by another cause 
The event corresponds to what is known about the drug  
A direct cause and effect relationship between the suspected drug and the 
AE has been demonstrated 
The event ceases or diminishes upon stopping drug intake or diminishes 
during the interval before rechallenge (dechallenge)  
The event resumes upon restarting drug intake (rechallenge) 
Probably 
Related 
There is evidence of exposure to the study drug. 
The time sequence of drug intake and event is reasonable  
The event corresponds to what is known about the drug  
The AE is more likely explained by the study drug than by another cause 
The event ceases or diminishes upon stopping drug intake or diminishes 
during the interval before rechallenge (dechallenge)  
The effect of rechallenge is unknown or does not elicit or exacerbate the 
event 
Possibly 
Related 
There is evidence of exposure to the study drug. 
The time sequence of the drug intake and event is reasonable  
The event corresponds to what is known about the drug  
The effect either remains or continues to exacerbate after dechallenge  
No change occurs after rechallenge 
The AE could have been due to another equally likely caus 
Unlikely 
There is evidence of exposure to the study drug. However, it does not 
follow a reasonable temporal sequence from administration of drug; or 
The event does not correspond to what is known about the drug; or 
The effect either remains or continues to exacerbate after dechallenge and 
no change occurs after rechallenge; or 
There is another more likely cause of the AE 
Not Related 
The subject did not receive the study drug; or 
The temporal sequence of the AE onset relative to administration of the 
study drug is not reasonable; or  
There is another obvious cause of the AE 
 
Outcome to Date are classified as follows: 
• Recovered/Resolved: The subject has fully recovered from the AE with no residual 
effects observable 
• Recovered/Resolved with sequelae: The subject has recovered from the AE with 
residual effects observable 

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• Improved: The subject status improved but has not been fully recovered 
• Ongoing: AE is not recovered/not Resolved  
• Fatal 
• Unknown 
AEs will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) AE dictionary. 
All AEs, serious and not serious, will be recorded on the AE CRF page, and if relevant, the 
Concomitant Medications Record in the CRF will be updated.  Particular attention should be 
made to ensure no discrepancies between the AE and the SAE form (i.e. outcome, severity, 
relationship must be consistent).   
15.2. 
  SERIOUS ADVERSE EVENTS  
A Serious Adverse Event (SAE) is an untoward medical occurrence, regardless of whether or 
not it is considered related to the study medication. Seriousness (not severity) serves as a 
guide for determining if an AE qualifies as a SAE.  
The following must be reported as SAE: 
• Death (regardless of the cause) while on treatment that occurs during the safety 
evaluation period, including deaths due to disease progression.  
o Deaths occurring after the Safety Evaluation Period need not be reported as 
SAE unless they are a result of an event that started while on treatment during 
the Safety Evaluation Period.  
• A life-threatening AE (e.g., the patient was at immediate risk of death from the event 
as it occurred) should be reported as SAE. This does not include an event that, had it 
occurred in a more serious form, might have caused death.  
• In-patient hospitalization or prolongation of existing hospitalization  
o Excluding hospitalizations for: 
▪ administration of the investigational product or procedures required by 
the study protocol or tumor-related diagnostic procedures  
▪ other planned hospitalization  
▪ social reasons and respite care in the absence of any deterioration in 
the subject’s general condition  
o Emergency room visits do not automatically qualify as SAE. Treatments in the 
emergency room for procedures such as hydration that did not require 
admitting the patient to the hospital are not considered a SAE, but should be 
reported as AE. 
• A Persistent or significant disability/incapacity. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAE drug experiences when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
An event need not be reported as SAE if it exclusively represents a relapse or an expected 
change or progression of the baseline malignant disease. This type of event needs only to be 
reported as AE.  

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Pre-planned hospitalizations or procedures for pre-existing conditions that are already 
recorded in the subject’s medical history at the time of study enrollment will not be 
considered SAEs. 
Any newly emergent SAEs, after treatment is discontinued or the subject has completed the 
study, and is considered to be related to the study drug or study participation, should be 
recorded and reported immediately to the Sponsor. The post-study period for the purpose of 
SAE reporting is up to 30 days following last IV booster administration.   
15.2.1. Definition of an Unexpected Adverse Event 
An unexpected adverse drug event is any AE, the specificity or severity of which is not 
consistent with information in the current Investigator’s Brochure (IB) for an unapproved 
investigational product. 
Serious Unexpected Suspected Adverse Reaction (SUSAR) is a SAE assessed as 
unexpected by the Sponsor and that is judged by either the reporting investigator or the 
Sponsor to have a reasonable causal relationship to a medical product. 
15.2.2. Handling of Serious Adverse Events 
For all SAEs, the investigator is obligated to pursue and provide information as requested by 
the Sponsor's clinical monitor or designated representative in addition to that on the 
CRF/eCRF.  In general, this will include a description of the SAE in sufficient details to 
allow for a complete medical assessment of the case and independent determination of 
possible causation. Information on other possible causes of the event, including concomitant 
medications and illnesses must be provided. The investigator's assessment of causality must 
also be provided. If causality is unknown, it should be indicated. In the case of a subject 
death, a summary of available autopsy findings must be submitted as soon as possible to the 
Sponsor or its designated representative. The investigator should ensure that information 
reported immediately by telephone or other means and information entered in the CRF/eCRF 
are accurate and consistent. 
Any SAE or death must be reported immediately to the Sponsor, independent of the 
circumstance or suspected cause, if it occurs or comes to the attention of the investigator at 
any time during the study through the last follow-up visit required by the protocol. Any SAE 
occurring at any other time after completion of the study must also be promptly reported if a 
causal relationship to the investigational product is suspected.  
 
Any AEs classified as “serious” must be recorded on the AE/SAE CRF/eCRF and require 
expeditious handling and reporting to Sponsor to comply with regulatory requirements, 
independent whether considered related or unrelated to the study therapy. These SAEs will 
include the immediate cause of deaths, regardless of their causal relationship to the 
investigational product. All SAEs must be reported using the AE/SAE Form. To the extent 
possible, the descriptive terminology and other SAE attributes entered on the form should 
approximate similar information in the CRF/eCRF. The completed form must be 
faxed/emailed to the sponsor within 24 hours of the study site personnel’s initial 
notification/awareness of the event, even if only limited information is available. Preliminary 
or supplemental SAE information captured on the clinic note, concomitant report, and 
laboratory report, may alternatively be scanned and transmitted to the Sponsor or designee. 
The authorized study site personnel may sign completed AE/SAE forms. The investigator 
signs each final SAE report. The original AE/SAE form must be kept on file at the study site.  

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Collection of complete information concerning SAEs is extremely important. Thus, follow-up 
information that becomes available as the SAE evolves, as well as supporting documentation 
(e.g. hospital discharge summaries, additional laboratory and test results, autopsy reports, 
etc.), should be collected subsequently, if not available at the time of the initial report, and 
immediately sent to the Sponsor or designee using the same procedure as the initial SAE 
report. 
 
Follow-up of all SAEs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without 
further follow-up” by the Investigator's and Sponsor’s joint decision. 
 
A follow-up SAE Report Form must be completed by the site (marked as “follow-up report”) 
and emailed within 24 hours to the sponsor (safety@immunovative.com).  A SAE follow-up 
report is required whether or not there is any additional information to the initial report.   
 
As for the initial SAE report, once faxed/emailed, the follow-up SAE report and 
accompanying documentation should be placed in the SAE section of the Investigator’s site 
file.  
 
For ease of analysis, worldwide standardization, and regulatory reporting, Sponsor or 
designee will code each reported SAE or symptom to its corresponding preferred term and 
system organ class in the Medical Dictionary for Regulatory Activities (MedDRA®). The 
NCI-CTCAE Version 4.03 will serve as the reference document for determining/grading the 
severity or toxicity grade of all SAEs and other symptoms.  
 
For SAEs whose toxicity grading is not contained within the NCI-CTCAE Version 4.03 
toxicity criteria, the Principal Investigator will be responsible for assessing severity based on 
the intensity of the event as it presented. Investigators and study site personnel enter the SAE 
term on the CRF/eCRF and AE/SAE form as accurately as possible, regardless of the NCI-
CTCAE Version 4.03 terminology for the event. 
 
15.2.1. Exceptions in the 
Reporting 
of 
Serious 
Adverse 
Events 
According to EU Detailed guidance on the collection, verification and presentation of adverse 
reaction reports arising from clinical trials on medicinal products for human use, ENTR/CT3, 
5.1.9, regarding clinical trials in high morbidity or mortality diseases, it is acceptable to 
define some exceptions in the  immediate reporting of specific SAEs. 
Metastatic colorectal cancer is a recognized condition with high morbidity and/or high 
mortality.  
 
Under these circumstances, it seems appropriate that the SAEs, clearly related to the MCRC 
(i.e. disease-related) could be an exception for an immediate systematic reporting. 
These AEs will be thoroughly handled and followed up through the CRF (AE form) and will 
be reviewed monthly by the sponsor’s medical monitor and could be re-qualified for 
reporting if necessary. 

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Each event must be carefully analyzed by the Investigator to decide whether the SAE could 
be considered as an exception or must be immediately reported.  
15.3. ADVERSE EVENTS REPORTING 
15.3.1. Reporting Requirements 
• The adverse events reporting period for this trial begins upon receiving the first dose 
of investigational product and ends on the last day of the Safety Evaluation Period.  
• All adverse events that occur in trial subjects during the adverse events reporting 
period specified in the protocol must be reported to the Sponsor, whether or not the 
event is considered study medication related. 
• In addition, any known untoward event that occurs subsequent to the adverse events 
reporting period that the investigator assesses as possibly related to the study 
medication should also be reported as an AE. 
• The investigator also should comply with the IRB/IEC procedures for reporting any 
other safety information. 
• All AEs should be reported to the Sponsor within 10 calendar days. 
• All SAEs must be reported to Sponsor immediately (within 24 hours) upon 
knowledge. 
• The Sponsor shall forward these AE reports to the Data Safety Monitoring Board. 
• The Sponsor shall forward all SAE reports to the Data Safety Monitoring Board 
immediately upon receipt.  
 
15.3.2. IND Safety Reports  
The sponsor will notify FDA and all participating study investigators of an IND safety report 
that are Serious and Unexpected Suspected Adverse Reaction (21 CFR 312.32(c)(1)(i))  
within 7 or 15 day report,  but no later than 15 calendar days as follows: 
• For any Unexpected Fatal or Life-threatening event associated with the use of the 
study drug, the Sponsor notifies the FDA of the SAE by telephone or fax as soon as 
possible, but no later than seven (7) calendar days after initial receipt of the SAE. 
Then Sponsor will follow with the written report (via MedWatch Form 3500A) no 
later than 15 days since the occurrence.  
• For any Serious and Unexpected, Non-fatal event associated with the use of the study 
drug, the Sponsor notifies the FDA as soon as possible, but no later than 15 days after 
initial receipt of the event. 
All other safety information will be submitted to FDA at the end of Part 1 and in the annual 
report. 
15.3.3. Reporting Adverse Events in the (e)CRFs 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject. In addition, each trial subject will be questioned 

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about adverse events at each clinic visit following initiation of treatment (toxicity 
assessment).  
 
Data on all adverse events (serious and non-serious, related or not related) will be collected in 
the CRFs/eCRF. Minimum requirements of adverse event data to be recorded are type of 
event, start and stop dates, highest severity grade, seriousness, action taken, outcome, and 
relatedness to either study medication or tumor. 
15.3.4. SAE Contact Information 
All AEs should be reported to the Sponsor every 10 days by email to 
safety@immunovative.com. The Sponsor shall forward these AE reports to the Data Safety 
Monitoring Board. 
 
All SAEs must be reported to Sponsor immediately (within 24 hours) upon knowledge and 
sent by email to safety@immunovative.com.  
15.4. ALLOSTIM® INFUSION-RELATED ALLERGIC OR AUTOIMMUNE TOXICITY 
In this study, subjects will continue to be closely monitored for infusion reactions, any 
allergic or autoimmune toxicity Grade 3 and higher and other study drug related Grade 3 and 
higher toxicities. Physicians should always remain vigilant for signs and symptoms of severe 
hypersensitivity reactions. 
Symptoms occurring during or following infusion of the investigational treatment may also 
be defined according to adverse event categories, such as allergic reaction, anaphylaxis, 
autoimmune disorder or cytokine release syndrome (Immune system disorders). The NCI-
CTCAE version 4.03 definition of Immune system disorders is provided in Table 9. 
In the setting of symptoms occurring during or following infusion of the investigational 
treatment, investigators are encouraged to use the adverse event term listed below and any 
additional terms (including those not listed here) that best describe the event. Those events 
described above should be graded as follows:  
 
Table 9 NCI-CTCAE v 4.03 Infusion-related Allergic or Autoimmune Toxicity 
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Allergic 
reaction 
Transient 
flushing or 
rash, 
drug fever <38 
degrees C 
(<100.4 
degrees F); 
intervention 
not indicated 
Intervention or 
infusion 
interruption indicated; 
responds promptly to 
symptomatic 
treatment 
(e.g., antihistamines, 
NSAIDS, narcotics); 
prophylactic 
medications 
indicated for ≤ 24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Autoim
Asymptomatic; Evidence of 
Autoimmune reactions 
Life-
Death 

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Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
mune 
disorder 
serologic or 
other evidence 
of autoimmune 
reaction, with 
normal organ 
function; 
intervention not 
indicated 
autoimmune 
reaction involving a 
nonessential 
organ or function 
(e.g., hypothyroidism) 
involving major organ 
(e.g., colitis, anemia, 
myocarditis, kidney) 
threatening 
consequences; 
urgent 
intervention 
indicated 
Cytokine 
release 
syndrome 
Mild reaction; 
infusion 
interruption 
not 
indicated; 
intervention 
not 
indicated 
Therapy or infusion 
interruption indicated 
but 
responds promptly to 
symptomatic 
treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, 
I.V. 
fluids); prophylactic 
medications indicated 
for ≤ 24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication 
and/or brief 
interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated 
for clinical sequelae 
(e.g., 
renal impairment, 
pulmonary infiltrates) 
Life-
threatening 
consequences; 
pressor or 
ventilator 
support 
indicated 
Death 
 
The following are treatment guidelines for AlloStim® infusion reactions: 
 
Grade 1 
• Monitor the subject for worsening of condition. 
• For subsequent infusions or IV push, premedicate with 25-50mg diphenhydramine 
PO/IV, 150mg ranitidine (Zantac) PO or other H-2 blocker, 25-50mg PO 
indomethacin (or equivalent NSAID). During or after the infusion if showed signs of 
infusion reactions in prior intravenous dosing (rash, itching, shortness of breath) at the 
investigator’s discretion. 
 
Grade 2 
• Monitor for worsening of condition. 
• Administer diphenhydramine hydrochloride 50 mg IV (or equivalent), acetaminophen 
650 mg orally for fever, and oxygen. 
• For subsequent infusions or IV push, premedicate with 25-50mg diphenhydramine 
PO/IV, 150mg ranitidine (Zantac) PO or other H-2 blocker, 25-50mg PO 
indomethacin (or equivalent NSAID). During or after the infusion if showed signs of 
infusion reactions in prior intravenous dosing (rash, itching, shortness of breath) at the 
investigator’s discretion. 
• If steroid therapy is medically indicated, methylprednisone or SoluMedrol should be 
considered as first choice. Administration of dexamethasone will necessitate dropping 
the subject from the protocol and censoring data from the first day of administration. 
Dexamethasone therapy is contraindicated in immunotherapy protocols, as it has 
been shown to selectively cause apoptosis of activated effector immune cells.  
• If a subject should have an infusion reaction to AlloStim®, all attempts should be 
made to obtain a cytokine blood sample as close to the onset of the event as possible, 

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at the resolution of the event, and 30 days following the event. The procedure for 
sample collection and handling is described in a separate procedural manual. 
 
Grade 3 
• Stop the infusion or IV Push if not completed. 
• Administer methylprednisone or SoluMedrol (or equivalent) medications/treatment as 
medically indicated. 
• Subjects who have a Grade 3 infusion reaction will not receive further AlloStim® 
treatment, but will continue to be followed on the protocol. 
• If a subject should have an infusion reaction to AlloStim®, all attempts should be 
made to obtain a cytokine blood sample as close to the onset of the event as possible, 
at the resolution of the event, and 30 days following the event. The procedure for 
sample collection and handling is described in a separate procedural manual. 
 
Grade 4 
• Stop the infusion or IV push if not completed. 
• Administer methylprednisone or SoluMedrol (or equivalent) medications/treatment as 
medically indicated. 
• Hospital admission for observation may be indicated. 
• Subjects who have a Grade 4 infusion reaction will not receive further AlloStim® 
treatment, but will continue to be followed on the protocol. 
• If a subject should have an infusion reaction to AlloStim®, all attempts should be 
made to obtain a cytokine blood sample as close to the onset of the event as possible, 
at the resolution of the event, and 30 days following the event. The procedure for 
sample collection and handling is described in a separate procedural manual. 
15.5. PRINCIPAL INVESTIGATOR/SPONSOR SAFETY REVIEW 
The investigator will ensure that the protocol and consent form are reviewed and approved by 
the appropriate Institutional Review Board/Independent Ethics Committee (IRB/IEC) prior to 
the start of any study procedures. The IRB/IEC will be appropriately constituted and will 
perform its functions in accordance with US Food and Drug Administration (FDA) 
regulations, International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 
guidelines, and local requirements as applicable. 
 
The investigator(s) undertake(s) to perform the study in accordance with this protocol, Good 
Clinical Practice (GCP), and the applicable regulatory requirements. The Investigator is 
required to ensure compliance with the investigational product administration schedule, visits 
schedule and procedures required by the protocol. The investigator agrees to provide all 
information requested in the CRF in an accurate and legible manner according to the 
instructions and to provide the Sponsor representatives direct access to source documents. 
 
The Principal Investigator will be responsible for monitoring the safety and efficacy of the 
trial, executing the Data Safety Monitoring (DSM) plan, and complying with all reporting 
requirements to the Sponsor, local and federal authorities.  
15.6. DATA SAFETY MONITORING BOARD 
A Data Safety Monitoring Board (DSMB) will be established with a primary function to 
protect the safety and welfare of study subjects. The DSMB will meet to examine 

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comprehensive safety data, which will be provided to the DSMB at regular intervals 
(quarterly) as defined by their charter, but may meet with greater frequency at their 
discretion. DSMB members will receive automatic electronic notification as soon as an SAE 
is reported at the study site. The DSMB members will have access to needed subject clinical 
data for complete documentation of all SAEs. All pertinent safety data including information 
on deaths, tumor progressions, adverse events and laboratory safety data will be reviewed. 
Subsequent to each meeting of the DSMB, the members will recommend in writing to the 
Sponsor that either the study continue in its current form, undergo protocol modification to 
deal with a critical emerging issue, or be stopped because of safety concerns. DSMB 
meetings will consist of an open session, which the Sponsor's representatives can attend, and 
a confidential closed session, which the Sponsor's representatives cannot attend. Minutes will 
be kept for both, the open and closed sessions of the DSMB meetings. The minutes of the 
closed sessions will not be revealed to the Sponsor until the study has been completed and the 
database has been locked. 
15.7. STOPPING RULES 
An external DSMB will oversee this study. The investigators and representatives of the 
Sponsor and DSMB will review and discuss subject data for all subjects enrolled by 
teleconference. The DSMB could recommend stopping the clinical trial for safety purposes. 
 
The development of dose limiting toxicity (DLT) in any subject will prompt a review of 
safety data by DSMB. The development of any DLT toxicity in ≥ 33% of the accumulated 
number of subjects at any dosing during the assessment period (28 days after last booster 
infusion) will result in protocol discontinuation. However, if DTLs only occur in the 
Activation or Booster phase, then a decision by DSMB may be made to continue enrolling 
subjects to receive only priming and in-situ vaccination phases. 
 
16. STATISTICAL METHODS 
16.1. GENERAL CONSIDERATIONS 
The Phase I/IIb study is primarily designed to assess the safety and tolerability of the study 
drug dosing schedule and the related immune response. Any evidence of clinical objective 
anti-tumor activity and/or symptomatic changes will be recorded. 
 
Safety analyses will be performed on all subjects who receive any dose of study medication. 
All summary data will be presented by dosing schedule (Schedule A-1 vs Schedule A-2 vs. 
Schedule A-3 vs. Schedule A-4 vs. Schedule B vs. Schedule C vs. Schedule D vs. Schedule E 
vs. Schedule F). Any evidence of clinical objective anti-tumor activity and/or symptomatic 
changes will be recorded.  
 
Descriptive statistics and/or subjects’ listings will be provided for demographic data, 
incidence of adverse events (overall, by intensity, and by relationship to study medication), 
incidence of clinically significant laboratory abnormalities, vital signs, medical history and 
physical exam, and tumor assessments.  
 
If subjects are administered steroids, the subject data will be censored at the date of steroid 
administration. 

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16.1.1. Demographics 
Demographic data will be summarized with descriptive statistics for gender, age, date of 
diagnosis of disease, prior treatments and ECOG status (e.g. N, mean, median). 
16.1.2. Concomitant Medications or Treatments 
Concomitant medications will be presented in data listings. 
16.1.3. Primary Endpoint 
Safety is the primary endpoint. AEs and SAEs will be coded, graded and summarized by 
attribution. Safety analysis will be performed on all subjects who receive any dose of study 
medication. AEs that occur after the Safety Evaluation Period will not be included in safety 
evaluations. 
16.1.4. Adverse Events  
All reported terms (investigator descriptions) for AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The incidence of AEs will be summarized 
for those events that occur on or after the date of the first treatment (TEAE: Treatment-
Emergent Adverse Events). All SAEs and TEAEs leading to withdrawal, and or other 
significant TEAEs will be listed separately. The data will be summarized as follow: 
• all TEAEs, 
• TEAEs related to Study drug,  
• Serious TEAEs,  
• Serious TEAEs related to Study drug,  
• TEAEs resulting in death, 
• TEAEs leading to withdrawal.  
 
The incidence of TEAEs will be summarized by system organ classification and preferred 
term by severity and relationship to study medication. All AEs will be included in the data 
listings. 
Laboratory results will be classified according to NCI-CTCAE Version 4.03. Incidence of 
laboratory abnormalities will be summarized; laboratory results not corresponding to an NCI-
CTCAE Version 4.03 term will not be graded. Laboratory toxicity shifts from baseline to 
worst grade will also be provided. 
The results from medical history, physical examination, and vital signs measurements will be 
tabulated. 
16.1.5. Secondary Endpoint (Part 2 only) 
Health-Related Quality of Life will be measured at baseline, during the treatment (for 
subjects enrolled to schedules A1-4 at day 35 and for subjects in schedules B-F at day 28) 
and after completion of treatment (28 days following the last booster dose). Analysis will be 
performed to compare quality of life differences over the time. 

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16.1.6. Exploratory Endpoints 
All data will be summarized using descriptive statistics by dosing schedule. All subjects who 
received any study medication will be included in the analysis.  
 
If the subject is alive at the end of the follow-up period or is lost to follow-up, OS will be 
censored on the last date the subject is known to be alive. 
16.1.7. Missing and Spurious Data 
Every effort will be made to obtain required data at each scheduled evaluation from all 
subjects who have been enrolled. There will be no imputation for missing data. 
16.1.8. Determination of Sample Size 
The planned sample size of at least 3 subjects at each dose schedule was considered sufficient 
to assess and to detect major safety and tolerability problems.  
17.  REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
17.1. DECLARATION OF HELSINKI 
The study will be conducted in accordance with the Declaration of Helsinki and GCP 
according to International Conference on Harmonisation (ICH) guidelines. Specifically, the 
study will be conducted under a protocol reviewed by an IRB or IEC; the study will be 
conducted by scientifically and medically qualified persons; the PI and Sponsor believe the 
benefits of the study are in proportion to the risks; the rights and welfare of the subjects will 
be respected; and all the physicians conducting the study do not find the hazards to outweigh 
the potential benefits; and each subject will give his or her written, informed consent in their 
native language before any protocol-driven tests or evaluations are performed. Consent to 
serial biopsies will be asked for separately from the consent to participate in the study. This 
consent must also be written and in the native language of the subject. A subject can consent 
to the study and not consent to the serial biopsies and will not be excluded for not consenting 
to the biopsies. 
17.2. INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES  
The Investigator will submit this protocol to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) and will maintain a record of IEC/IRB 
review/approval at the site. During the clinical trial, any amendment or modification to the 
protocol will be sent to the IEC/IRB. The IEC/IRB will also be informed of any event likely 
to affect the safety of subjects or the continued conduct of the study, in particular any change 
in safety and all updates to the Investigator’s Brochure will be sent to the IEC/IRB.  
The IEC/IRB will approve all protocol amendments, written informed consent documents and 
document updates, subject recruitment procedures, written information to be provided to the 
subjects, available safety information, information about payment and compensation 
available to subjects, the investigator’s curriculum vitae and/or other evidence of 
qualifications, and any other documents requested by the IEC/IRB and regulatory authority, 
as applicable. 

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17.3. ETHICAL CONDUCT OF THE STUDY 
The investigator is responsible for ensuring that the clinical study is conducted in accordance 
with the protocol and to Standard Operating Procedures (SOPs), Food and Drug 
Administration (FDA) Good Clinical Practice (GCP) guidelines, FDA Financial Disclosure 
regulations, as well as the ICH guidelines and any other regional/national requirements for 
clinical trials, as applicable. 
17.4. PROTOCOL AMENDMENTS 
Any amendment to the protocol requires written approval/favorable opinion by the IEC/IRB 
prior to its implementation, unless there are overriding safety reasons.  
In some instances, an amendment may require a change to the Informed Consent Form. The 
Investigator will obtain an IEC/IRB approval/favorable opinion concerning the revised 
Informed Consent Form prior to implementation of the change. The investigator understands 
that subjects must be consented using the most current IEC/IRB approved version of the 
Informed Consent Form. If the Informed Consent Form is updated, subjects who are still 
receiving therapy will be re-consented, or at the direction of the IEC/IRB. 
17.5. COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS 
The investigator must comply with all requirements of the protocol. When a situation occurs 
that requires a temporary departure from the protocol, the Investigator or other physician in 
attendance should contact the sponsor or designee as soon as possible in order to discuss the 
situation and agree on an appropriate course of action. The investigator will describe the 
departure from the protocol and the circumstances requiring it on the CRF/eCRF and will 
notify the IRB/IEC as appropriate. 
17.6. INFORMED CONSENT 
The investigator or his/her designee will inform the subject of all aspects pertaining to their 
participation in the study. The process for obtaining subject informed consent will be in 
accordance with all applicable regulatory requirements (e.g., CFR Part 50 and ICH E6 
Section 4.8).  
 
Prior to the beginning of the study, the investigator must have the IRB/IEC’s written 
approval/favorable opinion of the written informed consent form and any other information to 
be provided to the subjects.  
 
The subject must have been given a copy of the informed consent form (ICF) at least 24 
hours prior to being asked to sign the document. The investigator or his/her designee and the 
subject must both sign and date the ICF before the subject can participate in the study. The 
subject will receive a copy of the signed and dated form, and the original will be retained in 
the site’s study records. The decision to participate in the study that is made by the subject 
must be entirely voluntary. The investigator or his/her designee must emphasize to the subject 
that consent for study participation may be withdrawn at any time without penalty or loss of 
benefits to which the subject is otherwise entitled.  
 

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The informed consent and any other information provided to subjects or the subject’s legally 
acceptable representative should be revised whenever important new information becomes 
available that is relevant to the subject’s consent and should receive IRB/IEC 
approval/favorable opinion prior to use. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject’s legally acceptable representative 
of all pertinent aspects of the study and of any new information relevant to the subject’s 
willingness to continue participation in the study. This communication should be 
documented. During a subject’s participation in the trial, any updates to the consent form and 
any updates to the written information will be provided to the subject. 
17.7. CONFIDENTIALITY AND DISCLOSURE 
Confidentiality will be maintained within legal limits in the review of the medical records and 
consent forms, which may contain the identity of the subject. All subjects’ identities will be 
restricted to their initials and a unique subject number. 
Regulatory agencies or ethics committees may review medical records, and other study 
documentation for auditing or inspection purposes. Investigators and their affiliated 
institutions that are considered covered entities (CE) under the Health Insurance Portability 
and Accountability Act (HIPAA) will request that the subject sign a fully informed 
Authorization that will accompany the consent form. The Authorization will include the 
Authorization Core Elements (see Privacy Rule, 45 CFR §164.508(c)(1)) and the 
Authorization Required Statements (see Privacy Rule, 45 CFR §164.508(c)(2)). These 
activities are intended to ensure that subjects understand how their Protected Health 
Information (PHI) arising from this research study is to be handled. The Privacy Rule is an 
additional but similar obligation to those that have been required under the Department of 
Health and Human Services (DHHS) or the Food and Drug Administration (FDA) Protection 
of Human Subjects Regulations (e.g., 45 CFR part 46 or 21 CFR parts 50 and 56, 
respectively) to take measures to protect such PHI from inappropriate use or disclosure. 
The investigator and other study site personnel will keep confidential any information 
(including this protocol) related to this study and all data and records generated in the course 
of conducting the study, and will not use the information, data, or records for any purpose 
other than conducting the study. These restrictions do not apply to (1) Information that 
becomes publicly available through no fault of the investigator or study site personnel; (2) 
information that it is necessary to disclose in confidence to an IRB/IEC solely for the 
evaluation of the study; (3) information that it is necessary to disclose in order to provide 
appropriate medical care to a study subject; or (4) study results that may be published as 
described under the Publication Section. 
17.8. MONITORING AND AUDITING STUDY DOCUMENTATION 
The Sponsor (or designee) of this study is responsible to Health Authorities for taking all 
reasonable steps to ensure the proper conduct of the study in regards to ethics, protocol 
compliance, and integrity and validity of the data recorded on the CRFs. The Sponsor is also 
responsible for monitoring data quality and subject safety. Thus, the main duty of the Sponsor 
is to help the investigator to maintain a high level of ethical, scientific, technical and 
regulatory quality in all aspects of the study. 
 

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For the purposes of ensuring compliance with the protocol, GCP, and applicable regulatory 
requirements, the investigator will permit monitoring and auditing by the Sponsor or designee 
and inspection by applicable regulatory authorities.  
 
The investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, 
and as such will not disclose any personal identity or personal medical information. 
 
The confidentiality of the data verified and the anonymity of the subjects should be respected 
during these inspections. 
17.9. STUDY REPORT, PUBLICATION POLICY AND ARCHIVING OF STUDY 
DOCUMENTATION 
All data and records generated during the study and all inventions discovered in the course of 
conducting the study are the property of Immunovative Therapies, Ltd. 
Immunovative Therapies, Ltd. will retain ownership of all data. Data derived from the trial 
are the exclusive property of Immunovative. All proposed publications based on this study 
will be subject to the Sponsor’s approval requirements. Any publication or presentation 
related to the trial must be reviewed and approved by the Sponsor before submission of the 
manuscript. If the Sponsor publishes a manuscript, each PI and sub-investigator (as 
appropriate) will be named as an author and will have an opportunity to review and approve 
the submission of the manuscript. 
The investigator (or designee) will be responsible for preparing the Clinical Study Report for 
the site. An integrated clinical study report for all sites will be prepared by the Sponsor in 
accordance with ICH E3 guidance. 
17.10.  DATA CAPTURE  
17.10.1. 
  Case Report Forms 
The CRF is an integral part of the study and subsequent reports. The CRF must be kept 
current to reflect subject status during the course of the study. Only the subject number and 
an alpha code will be used to identify the subject.  
After obtaining written source document information from each subject at each visit, the site 
will enter the data onto a paper CRF or directly into an internet –based data collection system 
(as described under section 11.50.2; Electronic Data Capture). 
Source documents are where subject data are recorded and documented for the first time. 
They include, but are not limited to hospital records, clinical and office charts, laboratory 
notes, evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate and 
records kept at the pharmacy, laboratories, and other departments involved in a clinical trial. 
 
Source documents that are required to verify the validity and completeness of data 
transcribed on the CRFs must never be obliterated or destroyed. 
 

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The investigator will maintain a Delegation of Authority Page to document all persons 
authorized to make entries and/or corrections on CRFs. The CRF should be reviewed, signed, 
and dated by investigator. 
 
In case of paper CRF, all CRFs should be completed in a neat, legible manner to ensure 
accurate interpretation of data. Black ink is required to ensure clarity of reproduced CRF 
copies. When making changes or corrections, original entries will be crossed out with a single 
line, and the changes will be initialed and dated. DO NOT ERASE, OVERWRITE OR USE 
CORRECTION FLUID ON THE ORIGINAL CRF ENTRY. 
 
According to the GCP guidelines, the investigator (or designee) will check the CRF entries 
against the source documents, except for the pre-identified source data directly recorded in 
the CRF.  
The following table identifies what are source vs. CRF data in this study: 
 
Table 10 Source vs. CRF Data  
Type of Data 
Source/CRF  
Comment 
Informed consent 
Source documents 
Signature date is captured on CRF 
Demographics 
Source documents and 
CRF 
 
Inclusion/Exclusion 
Criteria 
Source documents and 
CRF 
 
Medical History (incl. 
Disease History) 
Source documents and 
CRF 
 
Physical Examination 
Source documents 
Performance date and clinically 
significant results are documented on 
CRF 
Vital Signs 
Source documents 
Performance date and clinically 
significant results are documented on 
CRF 
ECOG 
Source documents and 
CRF 
 
EKG 
Source documents 
Source documents/CRF and clinically 
significant results are documented on 
CRF 
CT Scan 
Source documents (CD 
and printed radiology 
reports) 
Performance date is captured on CRF 
Ultrasound 
Source documents 
Performance date is captured on CRF 
Cryoablation 
Source documents 
Performance date is captured on CRF 
Biopsy 
Source documents 
(Pathology reports) 
Performance date is captured on CRF 
Clinical Laboratory 
Reports (CBC, CMP, 
CRP, coagulation) 
Source documents 
(Printed report forms) 
Performance date and clinically 
significant results are documented on 
CRF 
Pregnancy test 
Source documents 
Performance date is captured on CRF 
Autoimmune profile 
Source documents 
Performance date and clinically 

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Type of Data 
Source/CRF  
Comment 
(Printed report forms) 
significant results are documented on 
CRF 
Research blood 
(Cytokines and 
TH1/TH2 balance) 
Source documents 
(Printed report forms) 
Performance date and clinically 
significant results are documented on 
CRF 
HLA Test  
Source documents and 
CRF 
 
Date & time of blood 
sampling 
Source documents 
(Printed report forms) 
Dates are documented on CRF 
Study drug 
administration details  
Source Documents 
(Drug administration 
Form) and CRF 
 
Drug accountability 
Folder in Pharmacy/ 
Investigator’s Site File 
 
HRQoL Questionnaires 
CRF 
 
Adverse events 
Source documents and 
CRF 
 
Concomitant 
Medication 
Source documents and 
CRF 
 
Protocol Deviations 
Source documents 
 
Trial Termination 
details 
CRF 
 
 
The ICF will include a statement by which the subject allows the Sponsor, or designee, the 
Ethics Committee (IRC/IEC), and the regulatory authorities to have direct access to source 
data which supports the data on the CRFs (e.g. subject’s medical file, appointment books, 
original laboratory records, etc.).  
It is the responsibility of the investigator to maintain adequate and accurate CRFs to record 
all observations and other data pertinent to the clinical investigation.  
The Clinical Monitor (CM) is responsible for performing on-site monitoring at regular 
intervals throughout the study to verify adherence to the protocol; verify adherence to local 
regulations on the conduct of clinical research; and ensure completeness, accuracy, and 
consistency of the data entered in the CRF.  
Data review may generate requests for clarifications (Queries) from the Sponsor to which the 
investigator is obliged to respond by confirming or modifying the data questioned.  
17.10.2. 
Electronic Data Capture 
If Electronic Data Capture (EDC) will be used for electronic data acquisition and storage, 
electronic case report forms (eCRFs) will be provided for transfer of all research data by site 
personnel from data source documentation to a computer database. Each responsible person 
at a site will have user access with a unique username and password, with permissions 
providing each person their needed access. Some personnel will have data entry, data review, 
and query resolution permissions, while others may only have data read permissions, based 
on their individual trial roles. 

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CMs will verify all computerized data against its source. Monitoring will be enhanced by 
computer assisted data management, identifying missing or possibly erroneous data as soon 
as data are computerized. This approach will allow initial remote monitoring, and 
communication between CMs and site personnel before and between site visits, and will 
expedite data review and cleaning. As each subject’s data computerization is completed and 
fully monitored with all queries resolved, that subject’s data set will be locked by the CM to 
only allow read access for the remainder of the trial. 
All trial data are to be housed in a secure computing environment. The EDC system will 
include a complete audit trail of all data entry, monitoring, and query activity that is 
compliant with HIPAA (and/or equivalents at each participating country) and meets all 
requirements for 21 CFR Part 11.  
Trial data as required by CMs, other authorized representatives of the Sponsor, and 
appropriate regulatory authority inspectors will be available through the EDC.  
All required trial information must be entered into the EDC system. eCRFs are considered 
complete when all data fields are complete and acknowledged as correct by the CM. In 
addition, the investigator, as the person ultimately responsible for the accuracy of all CRF 
data, must sign the investigator’s statement at trial completion for each subject.  
Final monitored and/or audited eCRFs will be provided by the Sponsor to the sites at the end 
of the study in the format of PDF file. 
17.11.  STUDY DOCUMENTS  
17.11.1. 
Curricula Vitae 
An updated copy of the curriculum vitae limited to the experience, qualification and training 
for the investigator and sub-investigators (and completed FDA 1572 form and Financial 
Disclosure Forms) will be maintained with the site regulatory documents.  
17.11.2. 
Financial Disclosure 
Financial disclosure information must be provided by all investigators and sub-investigators 
and will be collected by the Sponsor prior to the start of the study. 
17.11.3. 
Archiving of Documents 
ICF, source documents, drug accountability and retention records, and other study related 
documents will be retained in the permanent archives of the study site. These will be 
available for inspection at any time by the FDA per 21 CFR 312. Records retention for this 
study is required for a period of 2 years following the date on which this study agent is 
approved by the FDA for the marketing purposes; or, if no application is to be filed or if the 
application is not approved for such indication, until two years following the date on which 
the entire study is completed, terminated, or discontinued, and the FDA is notified. 
 

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Colorectal Cancer. N Engl J Med 2015; 372: p.1909-1919.  
44. 
Rosenberg, S.A., J.C. Yang, and N.P. Restifo, Cancer immunotherapy: moving 
beyond current vaccines. Nat Med, 2004. 10(9): p. 909-15. 
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Rivoltini, L., et al., Escape strategies and reasons for failure in the interaction 
between tumour cells and the immune system: how can we tilt the balance towards 
immune-mediated cancer control? Expert Opin Biol Ther, 2005. 5(4): p. 463-76. 
46. 
Demanet, C., et al., Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, 
allospecificities in leukemic cells: an escape mechanism from CTL and NK attack? 
Blood, 2004. 103(8): p. 3122-30. 
47. 
Iijima, J., K. Konno, and N. Itano, Inflammatory alterations of the extracellular 
matrix in the tumor microenvironment. Cancers (Basel), 2011. 3(3): p. 3189-205. 
48. 
Filaci, G. and N. Suciu-Foca, CD8+ T suppressor cells are back to the game: are they 
players in autoimmunity? Autoimmun Rev, 2002. 1(5): p. 279-83. 
49. 
Ben-Baruch, A., Inflammation-associated immune suppression in cancer: the roles 
played by cytokines, chemokines and additional mediators. Semin Cancer Biol, 2006. 
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50. 
Elliott, R.L. and G.C. Blobe, Role of transforming growth factor Beta in human 
cancer. J Clin Oncol, 2005. 23(9): p. 2078-93. 
51. 
Liu, V.C., et al., Tumor evasion of the immune system by converting CD4+CD25- T 
cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J 
Immunol, 2007. 178(5): p. 2883-92. 
52. 
Zhou, J., et al., The expression of interleukin-10 in patients with primary ovarian 
epithelial carcinoma and in ovarian carcinoma cell lines. J Int Med Res, 2007. 35(3): 
p. 290-300. 
53. 
Khazaie, K. and H. von Boehmer, The impact of CD4+CD25+ Treg on tumor specific 
CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol, 2006. 16(2): p. 124-36. 
54. 
Kosmaczewska, A., et al., The significance of Treg cells in defective tumor immunity. 
Arch Immunol Ther Exp (Warsz), 2008. 56(3): p. 181-91. 

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55. 
Xie, Y., et al., Tumor apoptotic bodies inhibit CTL responses and antitumor immunity 
via membrane-bound transforming growth factor-beta1 inducing CD8+ T-cell anergy 
and CD4+ Tr1 cell responses. Cancer Res, 2009. 69(19): p. 7756-66. 
56. 
Terabe, M., et al., Transforming growth factor-beta production and myeloid cells are 
an effector mechanism through which CD1d-restricted T cells block cytotoxic T 
lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor 
recurrence. J Exp Med, 2003. 198(11): p. 1741-52. 
57. 
Ostrand-Rosenberg, S. and P. Sinha, Myeloid-derived suppressor cells: linking 
inflammation and cancer. J Immunol, 2009. 182(8): p. 4499-506. 
58. 
Serafini, P., I. Borrello, and V. Bronte, Myeloid suppressor cells in cancer: 
recruitment, phenotype, properties, and mechanisms of immune suppression. Semin 
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59. 
Nefedova, Y., et al., Hyperactivation of STAT3 is involved in abnormal differentiation 
of dendritic cells in cancer. J Immunol, 2004. 172(1): p. 464-74. 
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regulatory cytokines or inflammatory cytokine inhibitors. J Gene Med, 2000. 2(4): p. 
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61. 
Pakravan, N., A.T. Hassan, and Z.M. Hassan, Naturally occurring self-reactive 
CD4+CD25+ regulatory T cells: universal immune code. Cell Mol Immunol, 2007. 
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62. 
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T-cell activation. Immunol Rev, 1999. 169: p. 263-72. 
63. 
Matzinger, P., Tolerance, danger, and the extended family. Annu Rev Immunol, 1994. 
12: p. 991-1045. 
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Har-Noy, M. and S. Slavin, The anti-tumor effect of allogeneic bone marrow/stem cell 
transplant without graft vs. host disease toxicity and without a matched donor 
requirement? Med Hypotheses, 2008. 70(6): p. 1186-92. 
66. 
Aglietta, M., et al., Reduced-intensity allogeneic hematopoietic stem cell 
transplantation in metastatic colorectal cancer as a novel adoptive cell therapy 
approach. The European group for blood and marrow transplantation experience. 
Biol Blood Marrow Transplant, 2009. 15(3): p. 326-35. 
67. 
Ueno, N.T., et al., Allogeneic peripheral-blood progenitor-cell transplantation for 
poor-risk patients with metastatic breast cancer. J Clin Oncol, 1998. 16(3): p. 986-93. 
68. 
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regimen with ifosfamide, carboplatin and etoposide (ICE). Bone Marrow Transplant, 
1997. 20(5): p. 421-3. 
69. 
Ueno, N.T., et al., Rapid induction of complete donor chimerism by the use of a 
reduced-intensity conditioning regimen composed of fludarabine and melphalan in 
allogeneic stem cell transplantation for metastatic solid tumors. Blood, 2003. 
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Biol Blood Marrow Transplant, 2002. 8(1): p. 32-9. 
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Epple, 
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73. 
Janikashvili, N., et al., Allogeneic effector/memory Th-1 cells impair FoxP3+ 
regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to 
treat leukemia. Blood, 2011. 117(5): p. 1555-64. 
74. 
Har-Noy, M., et al., Allogeneic CD3/CD28 cross-linked Th1 memory cells provide 
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Har-Noy, M., et al., Completely mismatched allogeneic CD3/CD28 cross-linked Th1 
memory cells elicit anti-leukemia effects in unconditioned hosts without GVHD 
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peripheral blood of colorectal cancer patients and involvement in cancer 
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Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, 
Bohnsack O, Nichol G, et al: Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clinical cancer research: an official 
journal of the American Association for Cancer Research 2009, 15:p. 7412-7420. 
 

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19. APPENDICES 
APPENDIX 1 
BIOPSY, CRYOABLATION SURGICAL PROCEDURE 
Subjects will be referred to a sponsor dedicated radiology center for the cryoablation and 
voluntary biopsy procedures and intratumoral injections.   
Preferably, the lesion selected for biopsy will not be the same lesion as is targeted for 
ablation. However, if a second lesion is not available then the lesion for ablation will be 
biopsied prior to ablation. The cryoablation and biopsy procedures are conducted under CT 
and/or ultrasound guidance. Visual documentation of probe placement for the cryoprobe 
probe will be provided and placed in the source documents. In addition, visual documentation 
of the kill zone after the ablation will also be provided for cryoablation. The tumor biopsy 
specimen will be placed in formalin in a pre-labeled specimen container. The tumor biopsy 
specimen will be sent to the Sponsor for pathological analysis.  
Subjects will have a target tumor lesion cryoablated under local or conscious sedation 
followed by an intratumoral AlloStim® injection at a dose of 1 x 107 cells formulated in 1 ml 
of Plasma-LyteA/1% HAS or 3 x 107 cells formulated in 3 ml of Plasma-LyteA/1% HSA. 
The intent of the ablation procedure is not to completely ablate the target lesion, but only to 
cause an area of necrosis within the tumor. Therefore, it is not necessary to have perfect 
margins. The intratumoral injection will occur after the ablation area has warmed to 370C.  
It is preferred that an interventional radiologist, CT technician, and physician trained in 
anesthesia or emergency medicine be present during the procedure. A Registered Nurse (RN), 
medical assistant and a cryoablation technician should also be present to support these 
procedures (same individual may function in two of these roles). The Sponsor may also have 
a medical/scientific consultant present. If the ablation target is in or near the lungs, it is 
recommended that the procedure be conducted in a hospital or near a hospital with the 
capability to diagnose and treat pneumothorax or related complications.   
Cryoablation will be performed by a licensed interventional radiologist or other experienced 
physician using a CryoCare-28 Percutaneous Probe System (Endocare, CA, USA) or the 
SeedNet™ System (Galil Medical, Israel). Generally, the Galil system is preferred for 
approach of lesions in the lungs due to the smaller 17g probe size having less of a chance of 
pneumothorax complications. These systems use the Joule-Thomson effect to cool the end of 
a cryoprobe in a closed system. In accordance with the gas coefficient and the dimension of 
the nozzle, different gaseous elements generate different thermal exchange events at the area 
close to the nozzle. Argon gas is used for cooling (-1870C), and helium is used for heating 
(670C).  
Subjects will be observed for 1-4h prior to release.   
 
Pre-Procedure Assessments 
Subjects may be hydrated prior to the procedure with normal saline or equivalent. All 
subjects requiring IV conscious sedation will have a pre-procedure assessment which will be 
documented in the medical records including: 
• A medical evaluation (history and physical based) by the interventional radiologist 
(this should include documentation of current medications and a history of any 
adverse or allergic drug reactions, including anesthesia or sedation, other allergies, 
NPO status, and an ASA assessment). 

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• Assessment of the subject’s ability to tolerate conscious sedation 
• Review of laboratory studies including coagulation studies. PT/PTT within normal 
range and INR must be ≤ 1.5. Review with subject the previously signed informed 
consent for the procedure and plan for sedation. 
• Age appropriate assessment, including baseline set of vital signs and a pre-procedure 
SPO2. 
• Note that subjects exhibiting hemodynamic instability, oxygen desaturation, or 
respiratory depression/failure are not appropriate candidates for IV conscious 
sedation. 
 
Any of the following drugs (or combination) can be used for conscious sedation at the 
discretion of the treating physician and administered intravenously (IV) or intramuscularly 
(IM): 
• Diazepam (Valium) adult dose: 2-10 mg.;  >60yo: 2-5 mg  
• Lorazepam adult dose: 0.5 mg/kg;  >60yo: .02-0.05 mg/kg  
• Midazolam (Versed) adult dose: .07 - 0.08 mg/kg; >60yo:  .02-0.05 mg/kg  
• Morphine adult dose: 0.025-0.2 mg/kg; >60yo:  0.05-0.2 mg/kg (Max. of 15 mg) 
• Meperidine (Demerol) adult dose: 1-1.5 mg/kg; >60yo: 1-1.5 mg/kg 
• Fentanyl (Sublimaze) adult dose: 1-2 mcg/kg; >60yo: 1 mcg/kg 
 
Care must be taken to assure that the total dose does not obtund protective pharyngeal 
reflexes or render the subject unresponsive to verbal stimuli.  
For some procedures, where subject breath movements may affect the ability to accurately 
place the cryoprobe, DIPRIVAN® (propofol) or similar sedation medication is allowed during 
the interval of probe placement. 
The following equipment/emergency drugs shall be immediately available (Code Cart) prior 
to IV conscious sedation being administered: 
• Oxygen source 
• Ambu bag 
• Laryngoscope 
• Endotracheal Tubes (i.e. sizes 5.0 mm, 6.0 mm, 7.0 mm, 8.0 mm) 
• Oral and nasal airways 
• Emergency drugs (Narcan, Romazicon) 
• Cardiac monitor/defibrillator and suction equipment 
• Pulse Oximeter 
 
Immediately Prior to Initiation of Conscious Sedation 
• Place the subject on monitoring device for heart rate, pulse oximetry and blood 
pressure. 
• Prior to the initiation of conscious sedation, the following assessments are 
determined, monitored, and documented:  
o Level of consciousness and mental status 
o Vital signs: heart rate, blood pressure, respiratory rate, temperature and 
oxygen saturation 
o NPO Status 
o Baseline Aldrete scale  

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• Peri-procedure monitoring, subject care, and treatment including medications 
administered will be documented on the Sedation Record Form and included in the 
medical records. 
 
Intra-Procedure Monitoring and Care 
• The physician will order the sedation medication and administer the initial dose. The 
RN may administer subsequent medications. 
• Cardiac monitoring and oxygen saturation are to be monitored continuously and 
documented every 5 minutes. 
• Blood pressure, pulse, respiration and heart rate/rhythm will be taken and documented 
at least every five minutes, or more frequently depending upon changes in the 
subject’s condition. 
• The subject will also be monitored for potential adverse reactions to the medications 
being administered. Any signs or symptoms of adverse reactions are to be reported 
immediately to the attending physician and documented. 
• Level of consciousness will be monitored and documented. 
• Supplemental oxygen will be administered if oxygen saturation is less than 95%. 
• Administered drugs should be recorded, including route, time and dosage. 
• If subject demonstrates persistent oxygen desaturation (SaO2 less than 90%) despite 
the use of supplemental oxygen, or requires airway support, the case should be 
terminated. 
 
Biopsy and Cryoablation  
• Once the percutaneous approach is determined, a sterile field will be created and local 
anesthesia administered to the planned probe insertion site.  
• A guide probe will be inserted percutaneously and verified by CT to be within the 
target tumor lesion. A needle biopsy system will be used to obtain a sample of tumor 
to verify ablation of live tumor. Preferably, this determination will be made "real-
time" by an on-site pathologist. If a pathologist is not available, the tumor sample will 
be placed in formalin in a pre-labeled container and sent for retrospective pathological 
analysis.   
• If the subject is undergoing cryoablation, a cryoprobe will be inserted through the 
guide tube into the tumor. One or two freeze-thaw cycles will be performed. A single 
probe of 2- or 5-mm will be used according to the size of the target tumor. The time 
of freezing will be approximately 5-20 minutes dependent on the achievement of an 
"ice-ball", visible on CT or ultrasound. In the case of a Galil probe, a thermosensor 
may also be placed in or near the tumor lesion. Thawing will be achieved by input of 
helium during a period equivalent to the freezing time before the second freezing 
process will be initiated. The procedure requires ablation of a sample of the tumor 
lesion and does not require complete tumor ablation with tumor-free margins.  
• The lesion will be allowed to cool for approximately 10 min to 1 hour following the 
second freezing or heating cycle before injection of AlloStim®. AlloStim® is 
formulated in Plasma-LyteA in a syringe with a locked needle.  The needle will be 
inserted through the guide tube and into the ablated tumor. AlloStim® will be 
administered intratumorally by injection.  The syringe will be flushed into the tumor 
with additional Plasma-LyteA or saline after injection.   
• Following injection, the guide tube will be removed. Hemostasis of the insertion hole 
will be obtained by Spongel application to the tract of the guide tube and by suture of 
the insertion site (if necessary). 
 

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Immediate Post Procedure Management 
• Subjects will go to an appropriate post-anesthesia care observation area, transported 
by a registered nurse. 
• Vital signs (which include: heart rate, blood pressure, respiratory rate, level of 
consciousness, and oxygen saturation) will be taken every five to fifteen minutes until 
the subject reaches the defined discharge criteria. Heart rate/rhythm will be monitored 
by a cardiac monitor. Post sedation assessment shall also include subject’s orientation. 
• Significant variations in physiologic parameters are to be reported to the physician 
immediately. These shall include, but not be limited to: 
o A variation of plus or minus 20% in vital signs 
o Serious arrhythmia 
o Oxygen saturation greater than 5% below baseline 
o Dyspnea, apnea, or hypoventilation 
o Diaphoresis, inability to arouse subject , or the need to maintain the subject’s 
airway 
o Other untoward or unexpected subject responses 
• Blood is drawn for post-ablation blood tests: CBC, CMP, and inflammation markers.  
Blood must be drawn within 2 hours after ablation treatment to identify any acute 
changes. 
 
Discharge Criteria 
The RN or medical assistant managing the care of the subject should provide continuous 
monitoring until a judgment is made by a physician that the subject is ready to be discharged. 
Any subject receiving a reversal agent must be observed for 2 hours after the last dose of the 
reversal agent. 
The decision for discharge will be guided by the following criteria which will be documented 
in the medical records and the discharge order will be written by a physician when the subject 
reaches a score of seven (7) on the Aldrete scale: 
• Subject is able to be aroused 
• Blood pressure, heart rate and respiration rate are stable for at least two sets (q 15 
min.) and have returned to pre-procedure status 
• Oxygen saturation is back to or near baseline 
• Subject is oriented to person, place, time and situation and ambulates without 
difficulty (if these were skills prior to procedure) 
• Subject is able to verbalize appropriately; stands and dresses self (if these were skills 
prior to procedure) 
• Subject has minimal/tolerable pain level  
• Subject has no nausea, vomiting, or bleeding 
• Subject must have a responsible adult to accompany home. In no case should the 
subject be allowed to drive himself/herself home. For the purpose of this section, a 
cab or bus driver is not considered a responsible adult 
• Subject has received written discharge instructions related to procedure, limitations, 
etc. and prescription for pain medication 
The interventional radiologist will provide the referring PI with a written report of the 
cryoablation and biopsy procedures within 48h. 
 

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APPENDIX 2 
CLINICAL HOLD 
The FDA placed a clinical hold on IND 13936 in May 2010.  The clinical hold was placed 
after the Sponsor notified FDA that an employee had made allegations regarding the conduct 
of the trial to the IRB that had oversight and that the IRB had initiated an investigation of the 
allegations.  The IRB subsequently filed a report with FDA finding most allegations without 
merit.  This report is available upon request. The FDA subsequently conducted their own on-
site investigation which resulted in a Form 483 being issued to the PI and the Sponsor. 
 
The major issue with respect to the PI related to “planned protocol deviations”.  This was a 
process whereby the Investigator would notify the IRB of a planned change in dosing 
frequency for a small number of subjects. The protocol was sub-divided into sections 
including intradermal dosing, intraturmoral dosing and intravenous dosing.  After intradermal 
dosing an increased in allo-specific Th1 was expected.  After intraturmoral dosing, an 
increase in tumor-specific Th1 cells was expected and after intravenous dosing, a cytokine 
storm was expected.  When the expected immunological response was not detected, the PI 
petitioned the IRB to continue the dosing section until the response was noted before 
advancing to the next part of the protocol.  The PI conducted these planned protocol 
deviations upon obtaining IRB clearance. This resulted in some subjects receiving more 
doses than others.  During the inspection, FDA maintained that the protocol deviations were 
safety issues that required FDA protocol amendments. The IRB disagreed and argued that 
they had the authority to authorize this change in a few subjects to determine if a protocol 
amendment should be submitted.  
 
Numerous other issues were raised and were finally resolved as follows: 
 
1. Sponsor agreed that no protocol deviations would be made without an approved 
protocol amendment 
2. Sponsor agreed to form a DSMB to monitor the safety using an FDA-approved 
charter 
3. Sponsor agreed to have an independent clinical monitor conduct inspections of 
clinical sites under a FDA-approved charter. The independent monitor will report to 
FDA monthly on compliance with GCP. 
The major issue with the Sponsor was related to the QC release testing of the final formulated 
lots of study drug.  The intermediate of the drug was stored frozen and underwent USP 
sterility and rapid test for endotoxin.  When needed in the clinic, released intermediate was 
thawed and formulated in a clean room located in the clinic. Since the study drug at the time 
had only a 4-6h shelf life and USP sterility testing required 14 days, it was not possible to 
know if a formulated dose was sterile before it was infused. This put increased emphasis on 
release testing for safety. The release test of greatest concern was a rapid test for endotoxin 
using an FDA-approved device.  The device had internal quality tests to determine that a 
sample met pre-determined criteria before presenting a result.  Because the device used optics 
and the study drug contained microbeads, occasionally the beads interfered with the device 
optics requiring re-testing.  The FDA expressed that the repeat testing was a safety concern. 
 
This issue was addressed in multiple ways. First, the rapid test assay underwent a rigorous 
validation protocol with the validation experimental design pre-approved by FDA. This was 
successfully completed.  Second, the endotoxin testing of the intermediate product was 
changed to a validated gel clot method conducted in a licensed lab.  Lastly, a rapid 

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microbiological test method capable of detecting all organisms in the USP 71 sterility test 
within 48h was validated and incorporated in the release criteria. 
 
The GMP issues were finally resolved by: 
 
1. Donors for the source blood will be screened and tested in accordance with 21 CFR 
1271 tissue regulations which are more stringent than the blood regulations. 
2. Sponsor agreed to an independent GMP monitor that will report monthly to FDA.  
The monitoring will be conducted in accordance with an FDA-approved charter.  
 
 
 
 
 

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APPENDIX 3 
CLINICAL TOXICITY DATA 
1. Introduction 
 
This appendix presents clinical data for all studies conducted under IND 13,936 
(cleared by FDA on August 13, 2009) from September 2009 to May 2010 with 
follow-up to May 2011. The following table presents an overview of the studies 
under the IND: 
 
Protocol Number  
Objective  
Study Status  
ITL-001-HM  
To evaluate the safety, toxicity, and anti-tumor 
effect 
of 
administration, 
of 
AlloStim® 
in 
hematological malignancies  
Withdrawn  
ITL-002-CRYO  To determine the safety and feasibility of creating 
an individualized in-situ anti-tumor vaccine in 
subjects with refractory or metastatic cancer  
Completed  
 
2. Study Summary ITL-001-HM 
 Title of Study: 
A Phase I/II Study of Polyclonally Activated, Intentionally Mis-
Matched, Allogeneic Th1 Memory Cells (AlloStim®) in Subjects 
with Relapsed or Refractory Hematological Malignancy without 
Prior Conditioning  
Protocol Number: 
ITL-001-HM 
Study Design: 
Subjects meeting eligibility criteria receive an initial 
intravenous priming infusion of 1 x 108 AlloStim® on day 0 and 
booster infusions of 1 x 108 AlloStim® cells on days 7, 14, and 
21 (+/- 3 days) as tolerated. 
Study Purpose: 
To evaluate the safety of administration, toxicity and anti-
tumor effect of intravenous AlloStim® infusions. 
Study Population: 
The study population was to consist of up to 50 Subjects with 
hematological malignancy refractory to standard therapy, or 
that recurred after standard therapy, or hematological 
malignancy Subjects referred for allogeneic stem cell 
transplantation that were unable to locate a suitable donor. 
Study Duration: 
Subjects were to be evaluated at 30 days, 60 days and 90 days 
post last infusion for tumor response. Subjects with complete 
response were to be followed for an additional 180 days and 
re-evaluated to determine durability of the response. Subjects 
with stable disease or partial response will be offered an 
additional cycle of 1 x 108 AlloStim® infusions weekly for up 
to 3 consecutive weeks and then will be re-evaluated for tumor 
response at 30 days following the 3rd infusion. Subjects 
showing disease progression at day 90 were to be taken off 
protocol. The protocol was planned to accrue subjects over a 
period of approximately 2 years. 
Study Status: 
Withdrawn (2 subjects completed the treatment) 
 
 
 

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3. Study Summary ITL-002-CRYO 
Title of Study: 
A Phase I/II study of an experimental therapeutic cancer 
vaccine created in-situ in subjects with progressive metastatic 
cancer refractory to standard therapy.  
Protocol Number: 
ITL-002-CRYO  
Study Design: 
This is a single-arm, open label, single institution Phase I/II 
study to determine the safety and feasibility of creating an 
individualized in-situ anti-tumor vaccine. The study protocol 
has three separate steps: (1) priming step; (2) in-situ 
vaccination step; and (3) immune stimulation step. Subjects 
meeting eligibility criteria were primed with at least three and 
up to nine intradermal AlloStim® injections at a frequency of 
every 2-8 days at doses between 1 x 107 to 4 x 107 cells.  
After priming, a selected tumor lesion was cryoablated using a 
percutaneous, image-guided technique followed by an 
intratumoral injection of 1-6 x 107 AlloStim®. Subjects with 
palpable tumors also were eligible to receive at least one and 
up to three alcohol ablation procedures to palpable lesions 
followed by intratumoral AlloStim®. This was in addition to 
the cryoablation procedure or in replacement of the 
cryoablation procedure.  
At the same time as the intratumoral injections, and/or up to 
eight days following, the subjects were administered 
intravenous AlloStim® at doses between 1 x 107 to 1 x 109 
cells.  
Some subjects with ascites and/or carcinomatosis received 
intraperitoneal AlloStim® at a dose of 0.5 to 5 x 108. Subjects 
also received intravenous AlloStim® at 1 x 107 to 1 x 109 cells 
at the same time or up to 8 days following.  
Study Purpose: 
This Phase I/II clinical study was designed to investigate the 
safety and anti-effect of a personalized anti-tumor vaccine 
created within the body of subjects with advanced cancers.  
Study Population: 
The study population was to consist of up to 50 subjects, 18 
years or older, with progressive metastatic cancer refractory to 
all standard therapy with at least one lesion accessible for 
percutaneous cryoablation.  
Study Duration: 
Total duration of the treatment period for each subject was 90 
days. Subjects were evaluated at 30 days after the last 
AlloStim® treatment for tumor response and again at 60 days 
and at 90 days. 
Study Status: 
Completed (42 subjects completed the treatment) 
 
 
 
 
 
 

Protocol: ITL-019-CORK-CRYVAC v.2, Amendment 8.0        Immunovative Therapies Ltd. 
 
 
Protocol Date: December 23, 2014    Amendment Date: September 12, 2017          Page 94 of 94 
 
       Study ITL-002-CRYO – Tumor Locations: 
 
Tumor Location  
No. of Subjects  
%  
Colorectal  
8  
19.0  
Liver  
22  
52.4  
Esophagus  
2  
4.8  
Soft tissue  
7  
16.7  
Lymph node  
20  
47.6  
Lung  
22  
52.4  
Pancreas  
5  
11.9  
Ovary  
3  
7.1  
Spleen  
3  
7.1  
Bone  
24  
57.1  
Breast  
16  
38.1  
Adrenal  
3  
7.1  
Brain  
2  
4.8  
Omentum/mesentery  
5  
11.9  
Prostate  
1  
2.4  
Gallbladder  
1  
2.4  
Skin  
3  
7.1  
Uterus  
1  
2.4  
Vagina  
2  
4.8  
 
4. Toxicity Results 
 
 
4.1. Study ITL-001-HM 
 
No dose limiting toxicity, no adverse events > grade 2 and no adverse events requiring 
adjustment of dose or medical intervention. 
 
 
4.1.1. Subject 001:  
27 year old male diagnosed with stage IV Hodgkin's disease refractory to chemotherapy. 
Progressed after myeloablative autologous stem cell transplant performed at UCSD in 
June 2009. Subject was accrued in study March 2010. Presented at baseline with large 
mediastinal/pleural mass. No acute toxicity >grade 2 noted. Subject deceased August 20, 
2010 due to complications related to surgical procedure. Autopsy revealed significant 
immune-mediated tumor lysis and fibrosis. 
 
 
4.1.2. Subject B002:  
66 year old male diagnosed with stage IV mantle cell non-hodgkin's lymphoma in May 
2009. Underwent 6 cycles of R-hyper CVAD chemotherapy. Disease recurrence in 
October 2009 in head, chest, abdomen, pelvis and bone marrow. Underwent 2 cycles of 
R-ICE chemotherapy and did not respond. Started salvage Velcade and acyclovir but 
discontinued due to HSV encephalitis and severe pancytopenia. Deceased July 15, 2010 
from disease complications.