Safety and Immunologic Activity of Multiple Infusions of APN401
Phase: PHASE1
Conditions: Metastatic Malignant Neoplasm in the Brain, Metastatic Solid Neoplasm, Recurrent Colorectal Carcinoma, Recurrent Pancreatic Carcinoma, Recurrent Solid Neoplasm, Stage IV Colorectal Cancer, Stage IV Pancreatic Cancer, Stage IVA Colorectal Cancer, Stage IVA Pancreatic Cancer, Stage IVB Colorectal Cancer, Stage IVB Pancreatic Cancer, Unresectable Solid Neoplasm
Sponsor: Wake Forest University Health Sciences

Safety and Immunologic Activity of Multiple Infusions of 
APN401 Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
ClinicalTrials.Gov:  NCT03087591
Protocol version date: 05/10/19     
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Principal Investigator: 
Co-Investigators: 
Biostatistician: 
Research Nurse: 
Pierre L. Triozzi, MD 
Wake Forest School of Medicine 
Internal Medicine - Hematology and Oncology 
Rhonda Bitting, MD 
Wake Forest School of Medicine 
Internal Medicine - Hematology and Oncology 
Rodwige Desnoyers, MD 
Wake Forest School of Medicine 
Internal Medicine - Hematology and Oncology 
Paul Savage, MD 
Wake Forest School of Medicine 
Internal Medicine - Hematology and Oncology 
Christopher Y. Thomas, MD 
Wake Forest School of Medicine 
Internal Medicine – Hematology and Oncology 
George Yacoub, MD 
Wake Forest School of Medicine 
Internal Medicine - Hematology and Oncology 
Ralph B. D’Agostino Jr, PhD 
Wake Forest School of Medicine 
Biostatistical Sciences - Biostatistics 
Angela Howell, RN 
Comprehensive Cancer Center of Wake Forest University 

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Study Coordinator: 
Data Manager: 
Wilson Brooks 
Comprehensive Cancer Center of Wake Forest University 
Margie Hauser 
Comprehensive Cancer Center of Wake Forest University 
Regulatory Coordinator: 
Cindy Miller 
Funding Sponsor: 
IND Number:  
Comprehensive Cancer Center of Wake Forest University 
Apeiron Biologics 
15989 

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STUDY SYNOPSIS 
IND AGENT 
• APN401 is a suspension of autologous peripheral blood mononuclear
cells (PBMCs) transfected with siRNA that reduces Cbl-b.
INDICATION 
• Advanced solid tumors
PRIMARY 
OBJECTIVES 
• Determine toxicities
• Determine immunologic effects
SECONDARY 
OBJECTIVE 
• Document clinical response and survival
STUDY PHASE 
• Phase I
STUDY DESIGN 
• Open-label
MAIN INCLUSION 
CRITERIA 
• Signed written informed consent
• Histologically confirmed metastatic or inoperable solid tumor no
longer responding to standard therapies
• Must be at least 4 weeks since prior systemic therapy, radiation
and/or surgery
• ECOG performance status 0-1
• Hematocrit ≥28%, WBC >3000/µl, and platelets >100,000/µl
• Creatinine ≤ 1.6 mg/dl
• ALT and AST<2.5 fold the upper limit of normal and total bilirubin ≤
1.6 mg/dl
MAIN EXCLUSION 
CRITERIA 
• Pregnant or breastfeeding patients
• Untreated, progressing, or symptomatic brain metastasis
• HIV, hepatitis B, or hepatitis C (active) infection
• Active autoimmune disease
• Ongoing requirement for an immunosuppressive treatment
• Significant cardiovascular or pulmonary disease
TREATMENT PLAN • PBMC for infusions will be collected by leukapheresis the day prior to
infusion.
• Patients will be administered three infusions separated by 4 weeks
• Blood will be drawn pre-therapy and at 3, 5, 9, and 10 weeks, and
then every 8 weeks for immune assessments
• Imaging will be performed pre-therapy and 2 weeks after infusion 3
and then every 8 weeks for clinical response
• Six patients will be treated initially. If a dose limiting toxicity (DLT) is
observed in ≤ 1/6, than an additional four patients will be enrolled to
allow evaluation of laboratory correlates.  Enrollment will be
suspended if >1/6 or >3/12 patients manifest DLT
LABORATORY 
CORRELATES 
• PBMC cytokine response
• Circulating immunocytes
POPULATION SIZE 
• Two to 12 eligible and evaluable patients
STUDY DURATION 
• Patients will be followed for toxicity until objective disease
progression or 1 year, whichever occurs first.

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Contents 
1.0 
Background ........................................................................................................................ 6 
1.1 
Adoptive cellular immunotherapy ................................................................................ 6 
1.2 
Cbl-b ........................................................................................................................... 6 
1.3 
APN401 ....................................................................................................................... 7 
1.4 
Phase 1 study of single infusion of APN401 ............................................................... 7 
1.5 
Study rationale ............................................................................................................ 7 
2.0 
Objectives .......................................................................................................................... 8 
2.1 
Primary ........................................................................................................................ 8 
2.2 
Secondary ................................................................................................................... 8 
3.0 
Selection of Patients .......................................................................................................... 8 
3.1 
Inclusion criteria .......................................................................................................... 8 
3.2 
Exclusion criteria ......................................................................................................... 9 
4.0 
Patient Registration .......................................................................................................... 10 
5.0 
Treatment Plan ................................................................................................................. 11 
5.1 
Dosing ....................................................................................................................... 11 
5.2 
Leukapheresis ........................................................................................................... 11 
5.3 
Infusion ..................................................................................................................... 11 
5.4 
Supportive care guidelines ........................................................................................ 12 
5.5 
Nursing implications .................................................................................................. 13 
5.7 
Duration of follow-up ................................................................................................. 14 
6.0 
Study Calendar ................................................................................................................ 15 
7.0 
Drug information ............................................................................................................... 17 
7.1 
Description ................................................................................................................ 17 
7.2 
How supplied ............................................................................................................ 17 
7.3 
Side effects ............................................................................................................... 17 
7.4 
Storage and handling ................................................................................................ 17 
7.5 
Administration ........................................................................................................... 17 
7.6 Cell Processing .............................................................................................................. 17 
8.0 
Toxicity Criteria and Adverse Event Reporting ................................................................ 17 
8.1 
Adverse event definition ............................................................................................ 17 
8.2 
Dose limiting toxicity (DLT) ....................................................................................... 18 
8.3 
Safety and toxicity reporting requirements ................................................................ 18 
8.4 
WFUHS IRB AE reporting requirements ................................................................... 18 
8.5 
FDA reporting requirements ...................................................................................... 19 
9.0 
Clinical Response ............................................................................................................ 20 
9.1 
Definitions ................................................................................................................. 20 
9.2 
Measurable disease guidelines ................................................................................. 21 
9.3 
Response criteria ...................................................................................................... 22 
9.4 
Confirmatory measurement/duration of response ..................................................... 23 
10.0 
Laboratory Correlates ...................................................................................................... 24 
10.1 Sample collection ......................................................................................................... 24 
10.2 Immune Response Outcomes ................................................................................... 24 
11.0 
Statistical Considerations ................................................................................................. 24 
11.1 Study Outcomes ......................................................................................................... 24 
11.1 Study parameters ......................................................................................................... 24 
11.2 Sample size .................................................................................................................. 25 
11.3 Analyses ....................................................................................................................... 25 
11.3.1 Study parameters ...................................................................................................... 25 
11.3.2 Sample size ............................................................................................................... 25 

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11.4 Analyses ....................................................................................................................... 25 
11.5 Interim Analysis ............................................................................................................ 26 
As described above an interim analysis will occur after 6 patients are enrolled ................... 26 
11.6 Accrual Rate ................................................................................................................. 26 
12.0 
Data Management Procedures ........................................................................................ 26 
13.0 
References ....................................................................................................................... 27 
Appendix A – Subject Eligibility Checklist ................................................................................... 28 
Appendix B – Protocol Registration Form ................................................................................... 32 
Appendix C – STRC Reporting Guidelines ................................................................................. 33 
Appendix E – RECIST Measurement Form ................................................................................ 38 
Appendix F – Response Criteria ................................................................................................. 40 
Appendix G – Apheresis Unit SOP ............................................................................................. 43 
Appendix H – Interferon Production ............................................................................................ 46 
Appendix I – Frequency Counts from Flow Cytometry ............................................................... 47 
Appendix J – Neutrophil/Lymphocyte Data Form ....................................................................... 48 

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1.0 
Background 
1.1 Adoptive cellular immunotherapy 
One approach of addressing immune deficiencies preventing an antitumor response in vivo 
effectively applied to improve survival is to infuse immune cells activated ex vivo. Sipuleucel-
T, an autologous cellular immunotherapy, has been approved for the treatment of metastatic 
prostate cancer [1]. Sipuleucel-T is manufactured from peripheral blood mononuclear cells 
(PBMCs) isolated during leukapheresis that are cultured ex vivo with PA2024, a fusion 
protein consisting of prostatic acid phosphatase and granulocyte macrophage colony 
stimulating factor, and then infused back into the patient. Other strategies of activating, 
expanding, and/or engineering immune cells ex vivo to mediate antitumor effects have 
exhibited considerable promise in a variety of malignancies [2,3]. Cellular immunotherapy 
has not been reproducibly effective, and several obstacles remain, including sustaining the 
in vivo survival and function of transferred cells and generating high-avidity tumor-reactive T 
cells. T-cell persistence can be transiently maintained by administering interleukin (IL-) 2, 
but this is often associated with significant toxicity and may also promote expansion of 
regulatory T (Treg) cells that limit antitumor immunity [4]. The poor T-cell function often 
observed has been more difficult to address, as it, in part, reflects deficient expression of 
costimulatory proteins and/or increased expression of inhibitory ligands or suppressive 
cytokines by tumor cells [5]. Thus, strategies to improve T cell survival, function, and avidity 
are needed.  
Cell processing is performed per FDA approved SOPs.  They include several tests of 
sterility. 
1.2 Cbl-b 
Cbl-b (Casitas B-lineage lymphoma b), an E3 ubiquitin ligase, is a major negative regulator 
of lymphocyte function. It increases the threshold for naive T-cell activation by regulating 
T-cell receptor and CD28 costimulatory signaling [6]. Abrogating Cbl-b expression rescues
IL-2 production and proliferation by naive CD28–/– T cells. Following target recognition,
interferon (IFN-) γ production is enhanced, and target avidity is increased. Importantly,
neither proliferation or cytokine production is induced in unstimulated T cells, indicating that
Cbl-b silencing enhances T cell activities only in the context of antigen stimulation and does
not lead to an unwanted general activation of all lymphocytes. Tumors lack the costimulatory
proteins that bind CD28, and CD28 expression is often lost on T cells that have
differentiated to effector cells during repetitive stimulations [7]. Thus, disrupting Cbl-b
expression in tumor-reactive T cells may provide a unique strategy for increasing autocrine
IL-2 production for promoting proliferative responses and survival following tumor
recognition in the absence of costimulation and may also reduce the threshold for T cell
activation to allow low-avidity T cells to respond to tumors expressing limiting amounts of
antigen. Cbl-b–/– knock-out mice are resistant to outgrowth of transplantable and
spontaneous tumors [8,9]. Adoptive transfer of Cbl-b–/– CD8+ T cells into tumor-bearing wild-
type mice resulted in detectable therapeutic activity [9-11]. Tumor resistance has been
attributed to the increased responsiveness of the small number of naive tumor-reactive
Cbl-b–/– CD8+ T cells present in the polyclonal repertoire. Genetic deletion of Cbl-b or
targeted inactivation of its E3 ligase activity also have been shown to license natural killer
(NK) cells to spontaneously reject metastatic tumors in mouse models [12]. Cellular
immunotherapy with Cbl-b–/– cells or inactivation of Cbl-b E3 ligase activity does not result in

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significant inflammation or in autoimmunity. Thus, abrogating Cbl-b expression in effector 
immune cells may improve the efficacy of adoptive cellular immunotherapy of human 
malignancies without significant clinical toxicity. 
1.3 APN401 
APN401 is a suspension of viable autologous human PBMCs that have been transiently 
transfected with siRNA in order to reduce Cbl-b protein levels, for autologous cellular 
immunotherapy applications. A highly efficient transfection protocol using a commercial 
electroporation device is used to simultaneously transfect T, B, NK cells and monocytes with 
the siRNA with minimal cell damage. Using this protocol shut down of Cbl-b expression can 
be achieved for more than seven days in stimulated human T cells, resulting in strong 
enhancement of T-cell activation, cytokine production, and proliferation. Cbl-b-silenced 
PBMCs display a clear increase in proliferation and IL-2 and IFN-γ production in response to 
anti-CD3/28 stimulation. In addition, Cbl-b silencing also increases secretion of tumor 
necrosis factor (TNF) α and IL-17. Adoptive transfer of Cbl-b silenced murine CD8 T cells 
using a similar transient siRNA silencing procedure as for human cells significantly 
decreased tumor burden [13]. Moreover, T cells isolated from tumor-draining lymph nodes 
displayed sustained activated T cell function five days after Cbl-b silencing and transfer. 
Little toxicity was observed. No unwanted effects of autoimmunity in other tissues were 
observed. Thus, APN401 is a novel approach to enhance antitumor immune responses. 
Moreover, because of potential of limited toxicity and synergy with other cancer therapies 
that have a mechanistic component of immune activation, APN401 has high potential to be 
included in combination programs. 
1.4 Phase 1 study of single infusion of APN401 
The feasibility and safety of a single intravenous infusion of APN401 were evaluated in 
patients with refractory metastatic solid tumors [14]. Patients with active autoimmune 
disease or a requirement for immune suppressive drugs were excluded. PBMC were 
collected by leukapheresis. The following day PBMCs were transfected with Cbl-b siRNA by 
electroporation to produce APN401 and then infused intravenously over 30 minutes. Three 
to ten patients were treated in each of the three dosing cohorts in which they received a 
single intravenous infusion of 5, 10, or 50 x105 cells/kg APN401. PBMC were successfully 
collected and transfected with Cbl-b siRNA in all patients enrolled. CD3 T cell, CD56 NK 
cell, CD19 B cell, and CD14 monocytes were transfected with similar efficiencies. 
Transfected PBMCs produced 4-fold more IFN-γ 2-fold more IL-2 in response to CD3/CD28 
stimulation than PBMC that were processed and electroporated without siRNA. From 27.0 to 
467 X 106 siRNA transfected PBMCs were infused. Infusions were well tolerated. Mild to 
moderate chills developed in most patients at the completion of the infusion. Dose-limiting 
toxicities were not observed. There was no immediate hypersensitivity and no evidence of 
autoimmune adverse effects. Stable disease observed in two patients with pancreatic 
cancer and one with colorectal cancer was associated with increases in PBMC responses to 
stimulation with CD3/CD8 and tumor-associated peptides.  
1.5 Study rationale 
Adoptive cellular immunotherapy with ex vivo manipulated autologous immune cells has 
been an attractive approach to refractory cancers. Cbl-b is a major negative regulator of 
immune function. Adoptive cellular immunotherapy with Cbl-b silenced cells significantly 

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decreased tumor burden in mouse models without toxicity. Multiple infusions were applied in 
these studies. APN401 is a suspension of autologous human PBMCs transfected ex vivo 
with a siRNA that silences Cbl-b developed for adoptive cellular immunotherapy 
applications. A phase I clinical trial to determine the toxicities of a single intravenous 
administration of APN401 established feasibility and safety. This clinical trial will examine 
multiple infusions and also provide an initial estimate of immunologic activity. The overall 
goal is to determine if there is sufficient evidence of safety and immunologic activity to 
proceed to phase II clinical trials, alone or in combination with other antitumor agents.  
2.0 
Objectives 
2.1 Primary 
2.1.1 To determine the toxicities and establish the safety of multiple infusions of 
APN401 
2.2 Secondary 
2.2.1    To determine the immunologic effects of multiple infusions of APN401 
2.2.2 To document clinical response and survival 
3.0 
Selection of Patients 
3.1 Inclusion criteria 
3.1.1 Patients with histologically confirmed inoperable, recurrent or metastatic 
malignant solid tumors, deemed incurable, and who have either: 
• failed to respond to standard therapy or
• for whom no standard therapy is available or
• refuse to receive standard therapies
The study is intended to enroll patients with pancreatic and colorectal cancer. 
Patients with other types of solid tumors will require approval by the Principal 
Investigator. 
3.1.2 Measurable disease as defined by RECIST (see Section 9.0) 
3.1.3 Patients with treated, stable, and asymptomatic brain metastases are eligible 
3.1.4 Patients on every 2, 3 or 4 week systemic therapy programs must be off the 
treatment program for at least 2, 3, or 4 weeks, respectively, and must have 
recovered from any clinically significant toxicity experienced.  Patients on weekly 
or daily systemic therapy programs and patients receiving radiation must be at 
least 1 week since treatment and recovered from any clinically significant toxicity 
experienced.  Must be at least 4 weeks and have recovered from major surgery 

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3.1.5 Age ≥ 18 years 
3.1.6 ECOG performance status 0 or 1 
3.1.7 Patients must have the following lab values obtained < 4 weeks prior to starting 
treatment: 
• WBC ≥ 3000/µL
• Platelets ≥ 100,000/µL
• Hematocrit ≥ 28%
• Creatinine ≤ 1.6 mg/dL
• AST and ALT < 2.5 x upper limit of normal
• Bilirubin ≤ 1.6 mg/dL (except patients with Gilbert’s Syndrome, who must have
a total bilirubin less than 3.0 mg/dL)
• Albumin ≥ 3.0 g/dL
• INR ≤ 1.5
3.2 Exclusion criteria 
3.2.1 Women must not be pregnant or breastfeeding due to unknown effects of the 
study treatments on the unborn fetus. All women of childbearing potential must 
have a blood test within 72 hours to rule out pregnancy. Women of childbearing 
potential and sexually active males must be strongly advised to use an accepted 
and effective method of contraception. Women of childbearing potential 
(WOCBP) must be using an adequate method of contraception to avoid 
pregnancy throughout the study and for 26 weeks after the last dose of 
investigational product, in such a manner that the risk of pregnancy is minimized. 
Sexually mature females who have not undergone a hysterectomy or who have 
not been postmenopausal naturally for at least 24 consecutive months (i.e., who 
have had menses at some time in the preceding 24 consecutive months) are 
considered to be of childbearing potential. Women who are using oral 
contraceptives, other hormonal contraceptives (vaginal products, skin patches, or 
implanted or injectable products), or mechanical products such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, or are practicing abstinence or where their partner is sterile (e.g., 
vasectomy) should be considered to be of childbearing potential. 
3.2.2 Untreated, progressing, or symptomatic brain metastases 
3.2.3 Autoimmune disease, as follows: Patients with a history of inflammatory bowel 
disease are excluded as are patients with a history of symptomatic disease (e.g., 
rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic 
lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s granulomatosis]). 
Patients with motor neuropathy considered of autoimmune origin (e.g., Guillain-
Barre Syndrome and myasthenia gravis) are excluded. Patients with a history of 
autoimmune thyroiditis are eligible if their current thyroid disorder is treated and 
stable with replacement or other medical therapy. 
3.2.4 Any other malignancy from which the patient has been disease-free for less than 
2 years, with the exception of adequately treated and cured basal or squamous 
cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix. 

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3.2.5  Other ongoing systemic therapy for cancer, including any other experimental 
treatment. These include concomitant therapy with any of the following: IL-2, 
interferon, ipilimumab, pembrolizumab, nivolumab, or other immunotherapy; 
cytotoxic chemotherapy; and targeted therapies.  
3.2.6 Ongoing requirement for an immunosuppressive treatment, including the use of 
glucocorticoids or cyclosporine, or with a history of chronic use of any such 
medication within the last 4 weeks before enrolment. Patients are excluded if 
they have any concurrent medical condition that requires the use of systemic 
steroids (the use of inhaled or topical steroids is permitted). 
3.2.7 Infection with HIV. Due to the mechanism of action of APN401, activity and side 
effects in an immune compromised patient are unknown. 
3.2.8 Active infection with Hepatitis B. Active or chronic infection with Hepatitis C. 
3.2.9 Clinically significant pulmonary dysfunction, as determined by medical history 
and physical examination. Patients with a history of pulmonary dysfunction must 
have pulmonary function tests with a FEV1 ≥ 60% of predicted and a DLCO ≥ 
55% (corrected for hemoglobin) 
3.2.10 Clinically significant cardiovascular abnormalities (e.g., congestive heart failure or 
symptoms of coronary artery disease), as determined by medical history and 
physical examination. Patients with a history of cardiac disease must have a 
normal cardiac stress test (treadmill, echocardiogram, or myocardial perfusion 
scan) within the past 6 months of study entry. 
3.2.11 Active infections within 48 hours of study entry 
3.2.12 Systemic infection requiring chronic maintenance or suppressive therapy 
3.2.13 Patients are excluded for any underlying medical or psychiatric condition, which 
in the opinion of the investigator, will make treatment hazardous or obscure the 
interpretation of adverse events, such as a condition associated with frequent 
rashes or diarrhea. 
4.0 
Patient Registration 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer control, 
must be registered with the WFBCCC Protocol Registrar or entered into the Oncology Research 
Information System (ORIS) Screening Log within 24 hours of Informed Consent.  
In order to ensure prompt registration of your patient: 
1.
Complete the Eligibility Checklist (Appendix A)
2.
Complete the Protocol Registration Form (Appendix B)

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3.
Alert the WFUHS registrar by phone, and then send the signed Informed
Consent Form, Eligibility Checklist and Protocol Registration Form to the
registrar, either by fax or e-mail. Ensure that the “source documents” column of
the checklist is complete and that the form is signed by either the research nurse
or CRA. Patients will not be registered if forms are incomplete.
Protocol Registrar Contact Information: 
PHONE (336) 713-6767 
FAX (336) 713-6772 
E-MAIL (registra@wakehealth.edu)
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday.
To complete the registration process, the Registrar will assign a patient study number, 
randomize the patient, and register the patient to the study.  
5.0 
Treatment Plan 
5.1 Dosing 
5.1.1 Leukapheresis to collect PBMC for infusion will be performed the day prior to 
infusion. Patients will be administered three infusions of APN401 at 50 x105 
cells/kg IV, separated by 4 weeks (reference Appendix I).  Leukapheresis and 
administration of APN401 can be delayed up to 3 weeks at the physician’s 
discretion.  Subsequent treatment must occur 28 days after prior treatment.   
5.1.2 Six patients will be treated initially. Should >1/6 subjects experience greater than 
grade 3 or 4 toxicity, further enrollment of study subjects and further 
administration of the study agent will stop pending assessment of the risk. 
5.1.3 If DLT is observed in ≤ 1/6, than an additional four patients (a total of 12) will be 
enrolled to allow evaluation of laboratory correlates. Enrollment will be 
suspended if >1/6 or >3/12 patients manifest DLT 
5.2 Leukapheresis 
5.2.1 PBMC will be harvested from the peripheral blood by a standard 1.5 to 2.0 blood 
volume mononuclear cell leukapheresis. 
5.2.2 Mobilization with a colony-stimulating factor is not required. 
5.3 Infusion  
5.3.1 Confirm patient identity: APN401 is intended solely for autologous use. Confirm 
the proper product has been received according to the label on the outside of the 
insulated polyurethane container. Prior to APN401 infusion, match the patient’s 
identity with the patient identifiers on the cell product disposition form and the 
APN401 infusion bag. 

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5.3.2 Confirm expiration date and time: Infusion must begin prior to the expiration date 
and time indicated on the cell product disposition form and Product Label. Do not 
initiate infusion of expired APN401. 
5.3.3 Inspect the infusion bag: Inspect the bag for signs of leakage. Do not administer if 
the bag leaks. Contents of the bag will be slightly cloudy, with a cream-to-pink 
color. Gently mix and re-suspend the contents of the bag, inspecting for clumps 
and clots. Small clumps of cellular material should disperse with gentle manual 
mixing. Do not administer if the bag leaks during handling or if clumps remain in 
the bag.  
5.3.4 Vital signs will be recorded at screening, prior to infusion and at 30 and 60 
minutes after infusion.  
5.3.5 Administer APN401 via intravenous infusion over a period of approximately 30 
minutes. Do not use a cell filter. The entire volume of the bag should be infused. 
5.3.6 Observe the patient for at least 60 minutes following each infusion. 
5.4 Supportive care guidelines 
5.4.1 
Patients should receive full supportive care, including transfusions of blood and 
blood products, antibiotics, antiemetics, etc. when appropriate. The reason(s), 
the drugs and dosage, and the dates of supportive treatments should be 
recorded on flow sheets. 
5.4.2 
Patients may receive the following to abrogate APN401 infusion toxicity: 
• Acetaminophen 650 mg po q 4 hr. May be given as pre-treatment at
physician’s discretion.
• Hydroxyzine hydrochloride or diphenhydramine may be used for generalized
erythematous rash. May be given as pre-treatment at physician’s discretion.
• Demerol 25-75 mg intravenously q 20 min can be administered concurrently to
control chills and rigors.
• Antiemetics and antidiarrheal agents as required.
5.4.3 
Treatment with hormones or other chemotherapeutic agents may not be 
administered except for steroids given for pre-existing adrenal failure; hormones 
administered for non-disease-related conditions (e.g., insulin for diabetes). Use 
of dexamethasone and other steroidal antiemetic or anti-inflammatory drugs is 
prohibited. 
5.4.4 
In the event of an acute infusion reaction, the infusion may be interrupted or 
slowed, depending on the severity of the reaction. Appropriate medical therapy 
should be administered as needed. If the infusion of APN401 must be 
interrupted, the infusion should not be resumed if the APN401 infusion bag will 
be held at room temperature for more than 3 hours.  
5.4.5 
APN401 is released for infusion based on the microbial and sterility results from 
several tests: microbial contamination determination by Gram stain, endotoxin 
content, and mycoplasma testing.  Sterility sampling will be performed by the 

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research technologist. APN401 is also cultured for microbial growth. The final 
(14-day incubation) sterility test results are not available at the time of infusion. If 
the sterility results become positive for microbial contamination after APN401 
has been approved for infusion, the treating physician will be informed and 
testing to identify the microorganism as will antibiotic sensitivity testing on 
recovered microorganisms will be performed. The clinical investigator should 
evaluate the subject for any signs of infection that may be attributable the 
product sterility failure. Additional information from the physician in order to 
determine the source of contamination may be necessary. See section 8.5.1 for 
the reporting requirement for sterility failure. 
5.5 Nursing implications 
5.5.1 It is important to maintain all scheduled appointments and arrive at each 
appointment on time because the leukapheresis and infusions must be 
appropriately spaced, and the APN401 expiration time must not be exceeded. 
5.5.2 If the patient is unable to receive an infusion of APN401 within the required time, 
the patient will need to undergo an additional leukapheresis procedure if the 
treatment is to be continued.  
5.5.3 Counsel the patient on the importance of adhering to preparation instructions for 
the leukapheresis procedure, the possible side effects of leukapheresis, and post-
procedure care.  
5.5.4 If the patient does not have adequate peripheral venous access to accommodate 
the leukapheresis procedure and infusion of APN401, inform the patient about the 
need for a central venous catheter. Counsel the patient on the importance of 
catheter care. Instruct the patient to tell their doctor if they are experiencing 
fevers or any swelling or redness around the catheter site, because these 
symptoms could be signs of an infected catheter. 
5.5.5 Report signs and symptoms of acute infusion reactions such as fever, chills, 
fatigue, breathing problems, dizziness, high blood pressure, nausea, vomiting, 
headache, or muscle aches.  
5.5.6 Report any symptoms suggestive of a cardiac arrhythmia. 
5.5.7 Inform the treating doctor if the patient is taking immunosuppressive agents. 
5.6 
Duration of therapy 
Patients will receive protocol therapy unless: 
5.6.1 Extraordinary medical circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. This includes any clinical adverse event, laboratory abnormality or 
intercurrent illness which, in the opinion of the investigator, indicates that 
continued treatment with study therapy is not in the best interest of the subject. 

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5.6.2 Patient withdraws consent 
5.6.3 Pregnancy: All WOCBP should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. Pregnancy tests should 
be conducted as clinically indicated. 
5.6.4 Disease progression: Patients who progress clinically before week 9 will be 
removed from study if other therapy (surgery, radiation, chemotherapy) is needed 
urgently.  
When a patient is removed from study, the Off-Study Form/Early Termination must be 
completed within seven days. 
5.7 Duration of follow-up 
All patients, including those who discontinue protocol therapy early, will be followed for 
response until progression or one year from registration, whichever occurs first.Patients 
will then be followed for survival for five years from the date of registration. All patients 
must also be followed through completion of all protocol therapy. 

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6.0 
Study Calendar 
Baseline evaluations, including imaging, are to be conducted within 4 weeks prior to initiation of treatment (Day 0). In the event that the 
patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. 
Treatment Phase 
Follow-Up Phase 
Early 
Termination 
Pre- 
StudyJ 
Day 0 
Week 1 
Day 1 
Week 1 
Day 15 
Week 3 
(± 1 day) 
Day 28 
Week 5  
(± 3 
days) 
Day 
29N 
Week 5 
Day 56 
Week 9  
(± 3 
days) 
Day 57N
Week 9 
Day 71 
Week 10 
(± 3 days) 
Week 18 and 
every 8 
weeks 
( ± 1 week)L 
Off Study 
Visit/Early 
Termination 
VisitL,M 
LeukapheresisA 
X 
X 
X 
APN401B 
X 
X 
X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
XO
X 
Vital signsC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examQ 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diffD 
X 
X 
X 
X 
X 
X 
X 
X 
ChemistriesE 
X 
X 
X 
X 
X 
X 
X 
X 
PT, PTT 
X 
HIV, HBV, HCV 
X 
βhCGF 
X 
Adverse events
X 
X 
X 
X 
X 
X 
X 
X 
X 
ImagingG 
X 
XL
XK 
XL
Tumor markerH 
X 
X 
X 
X 
Immune responseI 
X 
X 
X 
X 
X 
X 
A. PBMC will be harvested from the peripheral blood by a standard 1.5 to 2.0 blood volume mononuclear cell leukapheresis.
B. APN401 is infused 50 x105/kg IV over 30 minutes
C. Vitals signs should include blood pressure, heart rate, temperature, and respiratory rate. At the administration visits, vitals signs should also be
performed before infusion and 30 and 60 minutes after the end of the infusion.
D. Hemoglobin, hematocrit, white blood cell count, and platelets. The CBC differential includes enumeration of neutrophils, lymphocytes, eosinophils,
monocytes, basophils and any abnormal blood cells.
E. Serum albumin, urea or BUN, creatinine, ALT, AST, LDH, alkaline phosphatase, direct and total bilirubin, glucose, total protein, sodium, potassium,
chloride, CO2, calcium, phosphorus, and uric acid. These labs should be obtained less than 36 hours prior to the treatment.
F. Women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) at
screening. A pregnancy test should also be obtained at any time if there are clinical concerns for possible pregnancy.
G. Imaging should include a chest and abdomen CT. Other types of imaging and/or imaging of other sites should be obtained as clinically indicated to
document extent of cancer. If restaging imaging indicates partial or complete response, repeat confirmatory imaging should be obtained in 4 weeks (but

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no sooner than 4 weeks). 
H. CA19-9 in patients with pancreatic cancer, CEA in patients with colorectal cancer, and other standard-of-care tumor markers as clinically indicated.
Repeat assessment not required if completed within 2 months of pre-study or early termination visit.
I. On Days 0, 28 and 56, the immune response testing will be taken from the leukapheresis product. On Day 15 and in the follow-up phase, collect 30 ml
of blood (3 vials) into 10 ml EDTA tubes. If immune response labs have been collected within 4 weeks prior to the off study/ termination visit, re-
collection is not required.
J. Peripheral blood laboratory studies performed in order to determine patient eligibility must be performed within 28 days of study entry. Radiographic
and other tests performed in order to determine patient eligibility must be performed within 28 days of study entry.
K. Follow-up radiologic procedures used to assess outcome should be performed within 7 working days of the scheduled time.
L. Patients will be observed until objective disease progression or 1 year, whichever occurs first.
M. Off study/early termination assessments are only indicated for patients who do not complete all study visits (until week 58) /Follow-Up phase. These
assessments should occur no more than 4 weeks after the discontinuation of study treatment. If the subject had not undergone imaging within the past 6
weeks re-imaging is indicated. If a patient discontinues treatment for any reason other than progression, imaging will be done every 12 weeks until
progression.
N. Must occur the day following leukapheresis day.
O. Following the week 18 visit only documentation of anti-cancer treatment.
P. Adverse events will be recorded on an ongoing basis and up to 2 months following the administration of the test drug.
Q. Physical Exam may be completed +/- 2 days of visit.

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7.0 
Drug information 
7.1 Description 
The drug product, APN401, is a suspension of viable PBMCs transfected with siRNA in 
order to reduce Cbl-b protein levels of the respective patient (autologous administration) in 
saline 
7.2 How supplied 
Each dose of APN401 contains autologous PBMCs transfected with siRNA in order to 
reduce Cbl-b protein levels suspended in saline  
7.3 Side effects 
Infusions of APN401 have been well tolerated. Grade 3 or 4 toxicities attributable to 
treatment were not observed. Chills are the most common toxicity. These manifested at the 
completion of the 30 minute infusion and responded to meperidine. Transient lymphopenia, 
attributed to the leukapheresis, was also observed. Anemia, anorexia, dyspnea, fatigue, 
fever, hyponatremia, nausea, and myalgia have also been observed.  
7.4 Storage and handling 
Storage is not recommended. The infusion bag can be maintained at room temperature for 
up to three hours after release from the laboratory. APN401 should not be infused if 
maintained more than three hours at room temperature. APN401 is not routinely tested for 
transmissible infectious diseases and may transmit diseases to health care professionals 
handling the product. Universal precautions should be followed.  
7.5 Administration 
APN401 is administered at 50 x105/kg via intravenous infusion over a period of 
approximately 30 minutes. Do not use a cell filter.  
7.6 Cell Processing 
Cell processing is performed in the Blood and Bone Marrow Transplant Lab in the North 
Tower at WFBMC. The BMT lab is not accredited for this purpose and does not have 
responsibility for the procedures as part of this study within the laboratory. The research 
team, which includes the PI and an experienced technician, is responsible for the safety, 
purity and potency of the cellular products under protocol.  
8.0 
Toxicity Criteria and Adverse Event Reporting 
8.1 Adverse event definition 
An adverse event is any physical or clinical change or disease experienced by the subject at 
any time during the course of the study, whether or not considered related to the use of the 
study drug. This includes the onset of new illness and the exacerbation of pre-existing 

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conditions. Disease-related symptoms that do not increase in severity or frequency from 
baseline are not considered adverse events. 
All toxicity should be graded according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. Adverse events will be recorded on an ongoing basis and up 
to 2 months following the administration of the test drug. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 
can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
•
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.3
above) for expedited reporting purposes only.
•
Attribution of the AE:
Definite – The AE is clearly related to the study treatment.
Probable – The AE is likely related to the study treatment.
Possible – The AE may be related to the study treatment.
Unlikely – The AE is doubtfully related to the study treatment.
Unrelated – The AE is clearly NOT related to the study treatment.
8.2 Dose limiting toxicity (DLT) 
DLT is defined as 
8.2.1 CTCAE grades 3-5 allergic reactions related to study cell infusion 
8.2.2 CTCAE grades 3 and greater autoimmune reactions other than that vitiligo 
8.2.3 CTCAE grades 3 and greater organ toxicity (cardiac, dermatologic, 
gastrointestinal, hepatic, pulmonary, renal/genitourinary or neurologic) not pre-
existing or due to the underlying malignancy and occurring within 30 days of 
study product infusion 
8.2.4 Treatment-related death within 8 weeks of the study cell infusion 
8.3 Safety and toxicity reporting requirements 
The Safety and Toxicity Reporting Committee (STRC) is responsible for reviewing SAEs for 
WFBCCC Institutional studies as outlined in Appendix C. STRC currently requires that all 
unexpected 4 and all grade 5 SAEs on these trials be reported to the STRC for review. Any 
grade 3 to 5 product infusion reactions must also be reported. All WFBCCC Clinical 
Research Management (CRM) staff members assisting a Principal Investigator in 
investigating, documenting and reporting an SAE that qualifies for STRC reporting are 
responsible for informing a clinical member of the STRC – as well as the entire committee – 
via the email notification procedure of the occurrence of an SAE.  
8.4 WFUHS IRB AE reporting requirements 
Any unanticipated problems involving risks to subjects or others and adverse events shall be 
promptly reported to the IRB, according to institutional policy. Reporting to the IRB is 

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required regardless of the funding source, study sponsor, or whether the event involves an 
investigational or marketed drug, biologic or device. Reportable events are not limited to 
physical injury, but include psychological, economic and social harm. Reportable events 
may arise as a result of drugs, biological agents, devices, procedures or other interventions, 
or as a result of questionnaires, surveys, observations or other interactions with research 
subjects. 
All members of the research team are responsible for the appropriate reporting to the IRB 
and other applicable parties of unanticipated problems involving risk to subjects or others. 
The Principal Investigator, however, is ultimately responsible for ensuring the prompt 
reporting of unanticipated problems involving risk to subjects or others to the IRB. The 
Principal Investigator is also responsible for ensuring that all reported unanticipated risks to 
subjects and others which they receive are reviewed to determine whether the report 
represents a change in the risks and/or benefits to study participants, and whether any 
changes in the informed consent, protocol or other study-related documents are required. 
Any unanticipated problems involving risks to subjects or others occurring at a site where 
the study has been approved by the WFUHS IRB (internal events) must be reported to the 
WFUHS IRB within seven calendar days of the investigator or other members of the study 
team becoming aware of the event. 
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external events) 
must be reported to the WFUHS IRB within seven calendar days of the investigator or other 
members of the study team becoming aware of the event. 
Any event, incident, experience, or outcome that alters the risk versus potential benefit of 
the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
8.5 FDA reporting requirements 
IND sponsors are responsible for compliance with the Federal Food, Drug, and Cosmetic 
Act and the implementing regulations (Title 21 of the Code of Federal Regulations). Those 
responsibilities include: (1) reporting any unexpected fatal or life threatening adverse 
experience associated with use of the drug by telephone or fax no later than 7 calendar 
days after initial receipt of the information [21 CFR 312.32(c)(2)]; (2) reporting any adverse 
experience associated with use of the drug that is both serious and unexpected in writing no 
later than 15 calendar days after initial receipt of the information [21 CFR 312.32(c)(1)]; and 
(3) submitting annual progress reports (21 CFR 312.33).
8.5.1  Sterility failure, result of investigation of the cause and any corrective actions,
must be reported in an information amendment submitted to the FDA in a timely 
manner, within 30 calendar days after initial receipt of the positive culture test (21 
CFR 312.31).  If the patient experiences any serious and unexpected adverse 
experience that could be from administration of the sterility failure of the cellular 
product, then this information must reported to the FDA in an IND safety report 
no more than 15 calendar days after the initial receipt of the information (21 CFR 
312.32).  

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8.5.2  If study stopping rules are met and if it is determined that the investigational drug 
presents an unreasonable and significant risk to subjects, all investigations are to 
be discontinued and the FDA, all Institutional Review Boards, and all 
investigators need to be notified (21 CFR 312.56(d). 
9.0 
Clinical Response 
9.1 Definitions 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) 
of the tumor lesions are used in the RECIST criteria. Note: lesions are either measurable or 
non-measurable using the criteria provided below. The term “evaluable” in reference to 
measurability will not be used because it does not provide additional meaning or accuracy. 
9.1.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >20 mm with conventional techniques (PET, CT, MRI, x-ray) or as >10 mm 
with spiral CT scan.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
9.1.2 Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter <20 mm with conventional techniques or <10 mm using 
spiral CT scan), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 
9.1.3 Target lesions: All measurable lesions up to a maximum of five lesions per organ 
and 10 lesions in total representative of all involved organs should be identified 
as target lesions and recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be 
used as reference by which to characterize the objective tumor response. 
9.1.4 Non-target lesions: All other lesions (or sites of disease) should be identified as 
non-target lesions and should also be recorded at baseline.  Non-target lesions 
include measurable lesions that exceed the maximum numbers per organ or total 
of all involved organs as well as non-measurable lesions.  Measurements of 
these lesions are not required but the presence or absence of each should be 
noted throughout follow-up.  

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9.2 Measurable disease guidelines 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than four weeks before the beginning of the treatment. 
•
The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during follow-up.
Imaging-based evaluation is preferred to evaluation by clinical examination when
both methods have been used to assess the antitumor effect of a treatment.
•
Clinical lesions. Clinical lesions will only be considered measurable when they are
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin
lesions, documentation by color photography, including a ruler to estimate the size of
the lesion, is recommended.
•
Chest X-ray. Lesions on chest x-ray are acceptable as measurable lesions when
they are clearly defined and surrounded by aerated lung.  However, CT is preferable.
•
Conventional CT and MRI. These techniques should be performed with cuts of 10
mm or less in slice thickness contiguously. Spiral CT should be performed using a 5
mm contiguous reconstruction algorithm. This applies to tumors of the chest,
abdomen, and pelvis. Head and neck tumors and those of extremities usually require
specific protocols.
•
PET-CT. At present, the low dose or attenuation correction CT portion of a combined
PET-CT is not always of optimal diagnostic CT quality for use with RECIST
measurements. However, if the site can document that the CT performed as part of a
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral
contrast), then the CT portion of the PET-CT can be used for RECIST
measurements and can be used interchangeable with conventional CT in accurately
measuring cancer lesion over time. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not routinely or
serially performed.
•
Ultrasound (US).  When the primary endpoint of the study is objective response
evaluation, US should not be used to measure tumor lesions.  It is, however, a
possible alternative to clinical measurements of superficial palpable lymph nodes,
subcutaneous lesions, and thyroid nodules.  US might also be useful to confirm the
complete disappearance of superficial lesions usually assessed by clinical
examination.
•
Endoscopy, laparoscopy. The utilization of these techniques for objective tumor
evaluation has not yet been fully and widely validated.  Their uses in this specific
context require sophisticated equipment and a high level of expertise that may only
be available in some centers. Therefore, the utilization of such techniques for
objective tumor response should be restricted to validation purposes in reference
centers. However, such techniques can be useful to confirm complete pathological
response when biopsies are obtained.

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•
Tumor markers. Tumor markers alone cannot be used to assess response.  If
markers are initially above the upper normal limit, they must normalize for a patient
to be considered in complete clinical response.
•
Cytology, histology. These techniques can be used to differentiate between partial
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in
tumor types such as germ cell tumors, where known residual benign tumors can
remain).
9.3 Response criteria 
9.3.1 Evaluation of target lesions 
•
Complete Response (CR): Disappearance of all target lesions
•
Partial Response (PR): At least a 30% decrease in the sum of the longest
diameter (LD) of target lesions, taking as reference the baseline sum LD
•
Progressive Disease (PD): At least a 20% increase in the sum of the LD of
target lesions, taking as reference the smallest sum LD recorded since the
treatment started or the appearance of one or more new lesions
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor
sufficient increase to qualify for PD, taking as reference the smallest sum LD
since the treatment started
9.3.2 Evaluation of non-target lesions 
•
Complete Response (CR): Disappearance of all non-target lesions and
normalization of tumor marker level
•
Incomplete Response/Stable Disease (SD): Persistence of one or more non-
target lesion(s) or/and maintenance of tumor marker level above the normal
limits
•
Progressive Disease (PD): Appearance of one or more new lesions and/or
unequivocal progression of existing non-target lesions
•
Although a clear progression of “non-target” lesions only is exceptional, in
such circumstances, the opinion of the treating physician should prevail, and
the progression status should be confirmed at a later time by the review panel
(or study chair).
9.3.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria (see section 9.4.1). 

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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression, even after discontinuation of treatment. In some circumstances, it may be difficult 
to distinguish residual disease from normal tissue. When the evaluation of complete response 
depends on this determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
9.4 Confirmatory measurement/duration of response 
9.4.1 Confirmation: To be assigned a status of PR or CR, changes in tumor 
measurements must be confirmed by repeat assessments that should be 
performed four weeks after the criteria for response are first met. In the case of 
SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of eight weeks. 
9.4.2 Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. 
9.4.3 Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  

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10.0 
Laboratory Correlates 
10.1 Sample collection 
Peripheral blood will be obtained at baseline prior to the first infusion, on day 29 and 57 (four 
and eight weeks after the infusion) and every eight weeks thereafter. Twenty (20) ml of 
blood is collected in two 10ml EDTA-containing vacutainers and sent to Dr. Triozzi’s 
laboratory, Room 5029, Hanes Building. 
10.2 Immune Response Outcomes 
All research laboratory procedures will be performed per manufacturer’s recommendations with 
amendments (if needed) as necessary to adapt the protocol to the current applications. 
Procedures and results will be recorded in a laboratory notebooks but also recorded on 
Appendices L through N. 
10.2.1 PMBC IFNγ production in vitro (R&D Systems ELISA) in response to anti-CD3 
plus anti-CD28 antibody (BD) (Appendix L) 
10.2.2 PMBC IFNγ production in vitro (R&D Systems ELISA) in response NY-ESO, 
survivin, and telomerase peptide mixtures (Proimmune Promix) (Appendix L) 
10.2.3 Frequency (flow cytometry) of CD4+, CD8+, CD4+FoxP3+ regulatory, 
ICOS+CD4+ and ICOS+CD8+ effector, and CD45RO+CD4+ memory T cells and 
CD3-CD56+ NK cells and CD19 B cells  (Appendix M) 
10.2.4 Neutrophil to lymphocyte ratio (Appendix N) 
11.0 
Statistical Considerations 
11.1 Study Outcomes 
11.1.1 Primary Outcome 
•
Rate of Toxicities when patients are administered APN401 for one year
11.1.2 Secondary Outcome 
•
To determine the immunologic effects of multiple infusions of APN401 through
monitoring immune response in vitro by measuring IFN production, frequency of immune
cells, and neutrophil to lymphocyte ratio for one year.
•
To document clinical response and survival using from RECIST criteria and progression
free survival and overall survival for five years, respectively.
11.1 Study parameters 
The primary goals are to determine the toxicities and to determine effects on immune 
response. The secondary goal is to document clinical effects.   

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11.2 Sample size 
A total of up to 12 patients will be treated to allow evaluation of laboratory correlates. 
11.3 Analyses 
11.3.1 Study parameters 
The primary goal of this study is to estimate the rate of toxicities.  The secondary goals 
include   determining the effects of treatment on immune response and also to examine 
clinical effects (response (from RECIST criteria), progression free survival and overall 
survival)   
11.3.2 Sample size 
A total of up to 12 patients will be treated to allow evaluation of laboratory correlates.  The 
design allows for an interim analysis to occur after the first 6 patients are enrolled.  If 1 or 
less experience a grade 3-4 toxicity then 4 more will be enrolled, if 3 or less experience a 
grade 3-4 toxicity the agent will not be considered too toxic.  With this sample size, during 
the first stage of the trial, if the true toxicity rate is 10% (or less) the trial will stop with 11% 
probability, whereas if the true toxicity rate is 40% (or higher) then the trial will stop with 
76.7% probability.  Likewise, if the trial continues to 12 patients, if the true toxicity rate is 
10% or less the probability of observing more than 3 toxicities is 1.2% and if the true toxicity 
rate is 40% or more then the probability of observing more than 3 toxicities is 62%.  
11.4 Analyses 
Adverse events will be categorized by organ system and severity and summarized as 
frequency counts and percentages. Other categorical data, such as clinical response, will be 
summarized similarly. Measured data, such as immune response, will be summarized as 
medians and ranges.  All tests of statistical significance will be 2-sided and p-values will 
generally not be adjusted for multiple comparisons. 
11.4.1 Toxicity: APN401 will be considered tolerable if ≤1/6 or if overall ≤3/12 patients 
(i.e. an observed toxicity rate of at most 30%) experience grade 3-4 toxicity. With 
this design the likelihood of stopping early and rejecting the therapy as too toxic 
is ≤11.4% if the true grade 3-4 toxicity rate is ≤10% and >76.7% if it is >40%. The 
overall likelihood of declaring APN401 too toxic is ≤1.2% and >62%, respectively 
in these scenarios.  
11.4.2 Immune response: APN401 will be considered immunologically active if PBMC 
IFN-γ production in response to anti-CD3/28 stimulation or to one or more tumor 
antigens is significantly increased or if neutrophil to lymphocyte ratio is 
significantly decreased post-therapy (week 9) compared to pre therapy. Immune 
responses will be summarized as medians and ranges. The effects of treatment 
on these markers individually will be analyzed using paired t-tests or the non-
parametric counterpart. With 12 patients there will be statistical power equal to 
80% to detect 1 1 standard deviation change  in these markers following 
treatment. All tests will be 2-sided and P <0.05 will be considered significant. 

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11.4.3 Clinical response and survival: Clinical response will be assessed by RECIST and 
summarized as frequency counts and percentages. Progression-free survival and 
overall survival are calculated from the initial infusion to confirmation of 
progression or death.  Exploratory survival plots will be estimated using the 
Kaplan Meier approach and median PFS and OS will be estimated if enough 
events occur. 
11.5 Interim Analysis  
As described above an interim analysis will occur after 6 patients are enrolled 
11.6 Accrual Rate  
Accrual is anticipated to be 1-2 patients per month.  However, since accrual will stop after 
the first 6 patients are enrolled, the total time for the study is anticipated 12-15 months. 
12.0 
Data Management Procedures 
Informed Consent Form 
ORIS 
Subject Eligibility Checklist (Appendix A) 
ORIS 
Protocol Registration Form (Appendix B) 
ORIS 
Concurrent Medications Form 
Sponsor Database 
Specimen Accountability Log (Appendix D) 
Laboratory Use 
RECIST Measurement Form (Appendix E) 
ORIS 
Response Criteria (Appendix F) 
ORIS 
Survival Data 
Sponsor Database 
Off-Study Form 
Sponsor Database 
Interferon Production Data Form (Appendix H) 
Laboratory use 
Frequency Count Data Form (Appendix I) 
Laboratory use 
Neutrophil/Lymphocyte Ratio Form (Appendix J) 
Laboratory use 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 27 of 48 
13.0 
References 
1.
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari
AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study
Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J
Med. 2010;363:411-22.
2.
Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a
clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299-308.
3.
Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH. Adoptive Immunotherapy for
Cancer or Viruses. Annu Rev Immunol. 2014 Jan 9. [Epub ahead of print].
4.
Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+
regulatory T cells in cancer patients. Blood. 2006;107:2409-14.
5.
Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science.
2004;305:200-5.
6.
Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A,
Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H,
Lipkowitz S, Penninger JM. Negative regulation of lymphocyte activation and autoimmunity
by the molecular adaptor Cbl-b. Nature. 2000;403:211-6.
7.
Topp MS, Riddell SR, Akatsuka Y, Jensen MC, Blattman JN, Greenberg PD. Restoration of
CD28 expression in CD28- CD8+ memory effector T cells reconstitutes antigen-induced IL-2
production. J Exp Med. 2003;198:947-55.
8.
Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, Beissert S, Melief
CJ, Penninger JM. Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. J Exp Med.
2007;204:879-91
9.
Chiang JY, Jang IK, Hodes R, Gu H. Ablation of Cbl-b provides protection against
transplanted and spontaneous tumors. J Clin Invest. 2007;117:1029-36.
10. Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, Beissert S, Melief
CJ, Penninger JM. Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. J Exp Med.
2007;204:879-91.
11. Stromnes IM, Blattman JN, Tan X, Jeevanjee S, Gu H, Greenberg PD. Abrogating Cbl-b in
effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. J Clin
Invest. 2010;120:3722-34.
12. Paolino  M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon
WY, Ikeda F, Fededa JP, Cronin SH, Nitsch R, Schultz-Fademrecht C, Eickhoff J,
Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl
BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural
killer cells. Nature. 2014;507:508-12
13. http://www.apeiron-biologics.com/
14. Salzberg M, Triozzi PL, Kooshki M, Alistar A, Bitting R, Fenstermaker J, Lametschwandtner
G, Loibner H. Adoptive Cellular Immunotherapy with APN401, Autologous Cbl-b-Silenced
Peripheral Blood Mononuclear Cells, in Patients with Solid Tumors. J Clin Oncol 34, 2016
(suppl; abstr e14541).

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 28 of 48 
Appendix A – Subject Eligibility Checklist 
IRB Protocol No. 00041173 
CCCWFU Protocol No. 03716 
Study Title: Safety and Immunologic Activity of Multiple Infusions of APN401 
Principal Investigator:  Pierre L. Triozzi, MD 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria 
is NOT 
met 
Source Used to 
Confirm * 
3.1.1  Patients with histologically confirmed inoperable, 
recurrent or metastatic malignant solid tumors, deemed 
incurable, and who have either: 
• failed to respond to standard therapy or
• for whom no standard therapy is available or
• refuse to receive standard therapies
The study is intended to enroll patients with pancreatic and 
colorectal cancer. Patients with other types of solid tumors will 
require approval by the Principal Investigator. 
□ 
□ 
3.1.2 Measurable disease as defined by RECIST (see Section 
9.0) 
□ 
□ 
3.1.3 Patients with treated, stable, and asymptomatic brain 
metastases are eligible  
□ 
□ 
3.1.4 Patients on every 2, 3 or 4 week systemic therapy 
programs must be off the treatment program at least 2, 3, or 4 
weeks, respectively, and must have recovered from any 
clinically significant toxicity experienced. Patients on weekly or 
daily systemic therapy programs and patients receiving radiation 
must be at least 1 week since treatment and recovered from any 
clinically significant toxicity experienced.  Must be at least 4 
weeks and have recovered from major surgery 
□ 
□ 
3.1.5 Age ≥ 18 years 
□ 
□ 
3.1.6 ECOG performance status 0 or 1 
□
□ 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 29 of 48 
3.1.7 Patients must have the following lab values obtained < 4 
weeks prior to starting treatment: 
 • WBC ≥ 3000/µL
 • Platelets ≥ 100,000/µL
 • Hematocrit ≥ 28%
 • Creatinine ≤ 1.6 mg/dL
 • AST and ALT < 2.5 x upper limit of normal
 • Bilirubin ≤ 1.6 mg/dL (except patients with Gilbert’s Syndrome,
who must have a total bilirubin less than 3.0 mg/dL)
• Albumin ≥ 3.0 g/dL
• INR ≤ 1.5
□ 
□ 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria 
is 
present 
Source Used to 
Confirm * 
3.2.1 Women must not be pregnant or breastfeeding due to 
unknown effects of the study treatments on the unborn fetus. All 
women of childbearing potential must have a blood test within 
72 hours prior to randomization to rule out pregnancy. Women 
of childbearing potential and sexually active males must be 
strongly advised to use an accepted and effective method of 
contraception. Women of childbearing potential (WOCBP) must 
be using an adequate method of contraception to avoid 
pregnancy throughout the study and for 26 weeks after the last 
dose of investigational product, in such a manner that the risk of 
pregnancy is minimized. Sexually mature females who have not 
undergone a hysterectomy or who have not been 
postmenopausal naturally for at least 24 consecutive months 
(i.e., who have had menses at some time in the preceding 24 
consecutive months) are considered to be of childbearing 
potential. Women who are using oral contraceptives, other 
hormonal contraceptives (vaginal products, skin patches, or 
implanted or injectable products), or mechanical products such 
as an intrauterine device or barrier methods (diaphragm, 
condoms, spermicides) to prevent pregnancy, or are practicing 
abstinence or where their partner is sterile (e.g., vasectomy) 
should be considered to be of childbearing potential. 
□ 
□ 
3.2.2 Untreated, progressing, or symptomatic brain metastases 
□
□ 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
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3.2.3 Autoimmune disease, as follows: Patients with a history 
of inflammatory bowel disease are excluded as are patients with 
a history of symptomatic disease (e.g., rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus 
erythematosus, autoimmune vasculitis [e.g., Wegener’s 
granulomatosis]). Patients with motor neuropathy considered of 
autoimmune origin (e.g., Guillain-Barre Syndrome and 
myasthenia gravis) are excluded. Patients with a history of 
autoimmune thyroiditis are eligible if their current thyroid 
disorder is treated and stable with replacement or other medical 
therapy. 
□ 
□ 
3.2.4 Any other malignancy from which the patient has been 
disease-free for less than 2 years, with the exception of 
adequately treated and cured basal or squamous cell skin 
cancer, superficial bladder cancer or carcinoma in situ of the 
cervix. 
□ 
□ 
3.2.5  Other ongoing systemic therapy for cancer, including any 
other experimental treatment. These include concomitant 
therapy with any of the following: IL-2, interferon, ipilimumab, 
pembrolizumab, nivolumab or other immunotherapy; cytotoxic 
chemotherapy; and targeted therapies.  
□ 
□ 
3.2.6 Ongoing requirement for an immunosuppressive 
treatment, including the use of glucocorticoids or cyclosporine, 
or with a history of chronic use of any such medication within the 
last 4 weeks before enrolment. Patients are excluded if they 
have any concurrent medical condition that requires the use of 
systemic steroids (the use of inhaled or topical steroids is 
permitted). 
□ 
□ 
3.2.7 Infection with HIV. Due to the mechanism of action of 
APN401, activity and side effects in an immune compromised 
patient are unknown. 
□ 
□ 
3.2.8 Active infection with Hepatitis B. Active or chronic 
infection with Hepatitis C. 
□ 
□ 
3.2.9 Clinically significant pulmonary dysfunction, as 
determined by medical history and physical examination. 
Patients with a history of pulmonary dysfunction must have 
pulmonary function tests with a FEV1 ≥ 60% of predicted and a 
DLCO ≥ 55% (corrected for hemoglobin) 
□
□ 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
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3.2.10 Clinically significant cardiovascular abnormalities (e.g., 
congestive heart failure or symptoms of coronary artery 
disease), as determined by medical history and physical 
examination. Patients with a history of cardiac disease must 
have a normal cardiac stress test (treadmill, echocardiogram, or 
myocardial perfusion scan) within the past 6 months of study 
entry. 
□ 
□ 
3.2.11 Active infections within 48 hours of study entry 
□ 
□ 
3.2.12 Systemic infection requiring chronic maintenance or 
suppressive therapy  
□ 
□ 
3.2.13 Patients are excluded for any underlying medical or 
psychiatric condition, which in the opinion of the investigator, will 
make treatment hazardous or obscure the interpretation of 
adverse events, such as a condition associated with frequent 
rashes or diarrhea. 
□ 
□ 
This subject is      
 eligible / 
 ineligible     for participation in this study. 
ORIS Assigned PID: __________________  
Research professional confirming eligibility: 
Signature_______________________________ Date: ____________ 
Treating Physician:   
Signature_______________________________ Date:  ____________ 
Principal Investigator**:   
Signature_______________________________ Date:  ____________ 
* Examples of source documents include clinic note, pathology report, laboratory results, etc.
When listing the source, please specifically state which document in the medical record was
used to assess eligibility. Please also include the date on the document. Example: “Pathology
report, 01/01/14” or “Clinic note, 01/01/14”
**Principal Investigator signature can be obtained following registration if needed 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 32 of 48 
Appendix B – Protocol Registration Form 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: 
____________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
Zip Code:  ___ ___ ___ ___ ___ 
SEX:  
Male
Female
Ethnicity (choose one):   Hispanic 
Non-Hispanic
Race (choose all that 
apply): 
WHITE
BLACK
ASIAN
PACIFIC ISLANDER
NATIVE AMERICAN
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2
Primary Diagnosis: 
_____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, 
Monday – Friday. 
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or 
e-mailed to the registrar at 336-7136772 or registra@wfubmc.edu.
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________      
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
YES   NO
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
PID # (to be assigned by ORIS): 
___ ___ ___ ___ ___ ___ ___ ___ 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 33 of 48 
Appendix C – STRC Reporting Guidelines 
Safety and Toxicity Review Committee (STRC; 
previously known as CROC)  Serious Adverse Event 
(SAE) Notification SOP 
 Date: 11/17/2016 
Mandatory STRC SAE Reporting Requirements 
This document describes STRC reporting and use of the electronic submission form that is submitted for 
unexpected grade 4 and any grade 5 (death during protocol intervention) SAEs on CCCWFU Institutional 
interventional trial patients. There are multiple entities that require reporting of SAEs. Each entity has different 
rules for what is reported, and how it is reported.  
Rules used by other entities (Institutional Review Board (IRB), AdEERS, MedWatch, etc.) should NOT be used to 
evaluate whether an event should be reported to STRC. Only the rules for reporting described in this document 
should be considered. 
As defined in the NCI Data Table 4 reporting guidelines, CCCWFU Institutional Interventional studies covered by 
these reporting requirements are defined as: In-house, internally reviewed trials, including those collaborative 
studies conducted with industry sponsorship in which the center is a primary contributor to the design, 
implementation, and monitoring of the trial, or participation in a multi-site trial initiated by an institutional 
investigator at another center.  Institutional trials are almost always authored by a researcher here at CCCWFU. 
Institutional protocols are labeled NCI Code=”I” for Institutional on the protocol screen in ORIS. Cooperative group 
protocols are not considered Institutional, but Research Base trials are classified as Institutional. 
The STRC is responsible for reviewing SAEs for CCCWFU Institutional Interventional studies, as defined above. STRC 
currently requires that unexpected grade 4 and all grade 5 SAEs on these trials be reported to the STRC for review. 
All Clinical Protocol and Data Management (CPDM) staff members assisting a PI in documenting and reporting an 
SAE that qualifies for STRC reporting are responsible for informing a clinical member of the STRC by phone (or in-
person), followed by informing the entire committee via the required email notification. 
THESE REPORTING REQUIREMENTS APPLY TO any faculty or staff member on the study team for a CCCWFU 
Institutional Interventional trial. Once an event is observed, it is the responsibility of the person who observed 
the event to be sure that it is reported. 
What is considered an SAE under this mandatory procedure? 
Any unexpected grade 4 event and all grade 5 events (death during protocol intervention) should be reported. 
These events should be reported if they occur while a patient is on study treatment or if they occur within 30 days 
of last study treatment (even if patient begins a new treatment during the 30 days). This window of 30 days should 
be the standard window to be used in all protocols unless a specific scientific rationale is presented to suggest that 
a shorter window can be used to identify events.  In addition, if it is not clear whether the Grade 4 is unexpected it 
should be reported. 
Top of Form 
Bottom of Form 
Table 1: Summary of STRC Reporting Requirements for Institutional Pilot, Phase 1, Phase 2 
and Phase 3 Interventional Trials  

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 34 of 48 
STRC reporting may not be appropriate for specific expected adverse events for protocols. In those situations the 
adverse events that will not require STRC reporting must be specified in the text of the approved protocol. 
STRC notification responsibilities of the person handling the reporting/documenting of the SAE: 
Make a phone call (or speak in person) to the appropriate clinical member of the STRC as listed below (page if 
necessary)—see note 2 below 
Submit the STRC Notification Form WITHIN 24 HOURS of first knowledge of the event. This form is found at either 
the ORIS main menu page or by going to http://ccc.wfubmc.edu/oris/strc.aspx. 
This will ensure that all persons that need to be made aware of the event (i.e., study team members and STRC 
members) will be notified; remember to file a copy of your confirmation. (Form instructions will walk you through 
the required fields, consult the help page for further instructions.) 
Ensure that you document that the appropriate person(s) on the STRC has been contacted.  This documentation is 
placed on the STRC Notification form described above. 
Follow up with/update the clinical member(s) of STRC regarding any new developments or information obtained 
during the course of the SAE investigation and reporting process. 
Elements to complete the electronic STRC form: 
Please use ‘reply to All’ when responding with one of these terms:  Definite, Probable, Possible, Unlikely, or 
Unrelated 
Patient ID (ORIS PID) 
Patient Name 
Patient MR# 
CCCWFU(ORIS) Study Number 
Title 
PI Name 
PI Contact Number 
PI Comments 
STRC Clinician notified by Phone 
Notified Date 
Notified Time 
STRC Clinician Comments 
Category [This is the Grade – Either Unexpected Grade 4 or Grade 5 should be entered] 
Additional Information (IRB Reporting)(after discussion with PI or STRC Clinician 
Is This Event Related to Protocol Treatment? 
Is Suspension of the Protocol Needed? 
ADVERSE EVENT 
Grade 1, Grade 2, Grade 3 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Not Required 
Not Required 
REPORT TO 
STRC 
Not Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Unlikely 
Not Required 
Not Required 
REPORT TO 
STRC 
Not Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Possible 
Not Required 
Not Required 
REPORT TO 
STRC 
Not Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Probable 
Not Required 
Not Required 
REPORT TO 
STRC 
Not Required 
REPORT TO 
STRC 
REPORT TO 
STRC 
Definite 
Not Required 
Not Required 
REPORT TO 
STRC 
Not Required 
REPORT TO 
STRC 
REPORT TO 
STRC 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
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Any Changes to Consent or Protocol Needed? 
Was Nature or Severity of Event Unexpected? 
Date of the event.  
Brief description (include brief clinical history relevant to this event, including therapies believed related to event). 
Date of Last Dose before event 
Relevant tests/labs.  
Other Relevant Treatment Information 
Other Comments/Notes (include regimen of chemo and dates the patient received them if known). 
Cc (email) (include treating Physician; separate email list with comma”,”) 
Your Name 
Your Email 
Confirm Your Email 
The Clinical Members of STRC to Notify by Phone or Page: 
Bayard Powell, MD – Director-at-Large, CCCWFU; Section Head, Hematology/Oncology 
6-7970 / 6-2701 / Pager 336-806-9308
Glenn Lesser, MD – Hematology Oncology 6-9527 / 6-7972 / Pager 336-806-8397
Stefan Grant, MD, JD-Hematology Oncology 3-5172/ 6-5772 Pager 336-806-6453
Jimmy Ruiz, MD-Hematology Oncology 6-0230/ Pager 336-806-9710
Kathryn Greven, MD – Vice Chair – Radiation Oncology
3-3600 / 3-6505 / Pager 336-806-8314
Marissa Howard-McNatt, MD – General Surgery 6-0545 / Pager 336-806-6438
Mercedes Porosnicu, MD- Hematology Oncology 6-7980 / 6-0230 / Pager 336-806-9150
Definition of Unavailable:
As a general guideline if the first clinician that is contacted does not respond to the phone call or page within a
reasonable amount of time, then initiate contact with their backup.  Give the back-up a reasonable amount of time
to respond to a phone call or page before contacting another member. This is a general guideline.  You must use
your best judgment as a clinical research professional given the time of day, severity of the SAE, and other
circumstances as to when it is appropriate to contact backup clinicians.  If the event occurs near the end of day,
then leave messages (voice or email) as appropriate and proceed with submitting your STRC notification form.  The
important criteria is that you have taken reasonable steps to notify and document that you have initiated some
type of contact to one or more of the clinical members of STRC.
STRC CLINICAN RESPONSIBILITY: 
It is the responsibility of the STRC clinician to review all reported events, evaluate the events as they are reported; 
and communicate a response to the Investigator, event reporter and the members of STRC. The review will include 
but not be limited to the information reported; there may be times when additional information is needed in order 
for an assessment to be made and further communication directly with the investigator may be warranted. STRC 
reserves the right to agree with the investigator’s assessment if STRC does not agree with the investigator. STRC 
reserves the right to suspend the trial pending further investigation. 
Is there any immediate danger or harm that could be present for a future patient based on the information 
provided in the STRC report – and if so an immediate suspension of enrollment should take place. 
AMENDMENTS TO PREVIOUS REPORTS 
If you are not able to supply all pertinent information with the initial submission, once the additional information is 
available do not submit a new report. Go to the original email that was received by STRC and others “reply to all” 
and entitle your email “Amendment for (list date of event and patient ID) this will avoid duplications of the same 
event. List the additional information which you are reporting. 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 36 of 48 
Acronyms and Definitions 
STRC-Safety and Toxicity Review Committee 
SAE-Serious Adverse Event 
IRB-Institutional Review Board 
CCCWFU-Comprehensive Cancer Center Wake Forest University 
ORIS-Oncology Research Information System 
NCI-National Cancer Institute 
CPDM-Clinical Protocol and Data Management 
Interventional Trials-Therapeutic Level 1 and Level 2 trials 
Therapeutic Level 1-A cancer treatment protocol aimed at directly treating/curing the patient’s cancer. 
Therapeutic Level 2-A therapeutic protocol not cancer treatment involves clinical activity to treat symptoms, 
improve the patient’s quality of life, or prevent cancer. 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 37 of 48 
Appendix D – Specimen Accountability Log 
Protocol WFBCCC 03716: Safety and Immunologic Activity of Multiple Infusions of APN401 
Subject 
Identifier 
Description 
of Specimen 
Date and 
Time of 
Collection 
Visit 
Number 
Storage 
Location 
Date and 
Time of 
Shipping/ 
Release 
Name of 
Person 
Specimen 
Released to 
Initials 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
Protocol version date: 05/10/19     
  Page 38 of 48 
Appendix E – RECIST Measurement Form 
TUMOR RESPONSE WORKSHEET (Modified RECIST ) 
    CCCWFU # _______________ 
Patient Name: ________________________________________                     Patient MRN: ______________________________ 
Has patient had localized RT @ baseline? □ No □ Yes If yes, which lesions? :____________________________________ 
Target Lesions 
TARGET Lesions 
Lesion 
Site 
Imaging 
(ie,CT, MRI)
Baseline 
Date: 
(Se, Im)
Cycle_____ 
Date: 
(Se, Im) 
Cycle_____ 
Date: 
(Se, Im)
Cycle_____ 
Date: 
(Se, Im)
Cycle_____ 
Date: 
(Se, Im)
01 
mm 
mm 
mm 
mm 
mm 
02 
mm 
mm 
mm 
mm 
mm 
03 
mm 
mm 
mm 
mm 
mm 
04 
mm 
mm 
mm 
mm 
mm 
05 
mm 
mm 
mm 
mm 
mm 
Sum of Diameters 
mm 
mm 
mm 
mm 
mm 
% Change (% ∆)  from Baseline or Nadir* & 
absolute value (AbV) 
NA 
  NA 
% ∆ 
   AbV 
Target Lesion Response
      N/A 
Non-Target Lesions 
NON-TARGET Lesions 
Lesion 
Site 
Imaging 
Baseline 
Cycle_____ 
Cycle_____ 
Cycle_____ 
Cycle_____ 
01 
02 
03 
04 
05 
Non-Target Lesion Response 
N/A

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 39 of 48 
 
 
*Terms & Calculations 
 
 
 
Baseline: The set of data collected prior to randomization 
 Nadir: The lowest point
 
New Lesions 
New 
1 
 
 
 
N/A 
 
 
 
 
2 
 
 
 
N/A 
 
 
 
 
3 
 
 
 
N/A 
 
 
 
 
Overall Tumor Response 
Cycle_____ 
Cycle_____ 
Cycle_____ 
Cycle_____ 
 
Radiologist Signature/Date: 
 
 
 
 
 
Treating Physician Signature/Date: 
 
 
 
 
 
PI Signature: 
 
 
 
 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 40 of 48 
 
Appendix F – Response Criteria 
 
ORIS Assigned PID: __________________    Date Completed: ____ ___ / ___ ___ / ___ ___ 
 
Study Visit: 
 Week 10, Day 71 ( ± 3 Days) 
 Week 18 ( ± 1 week) 
 Week 26 ( ± 1 week) 
 Week 34 ( ± 1 week) 
 Week 42 ( ± 1 week) 
 Week 50 ( ± 1 week) 
 Week 58 ( ± 1 week) 
 Off Study 
 Other visit: (please specify) ________________ 
 
Evaluation of target lesions 
 
   Complete Response (CR): Disappearance of all target lesions 
 
   Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 
   Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
 
   Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
 
 
Evaluation of non-target lesions 
 
   Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level 
 
   Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) 
or/and maintenance of tumor marker level above the normal limits 
 
   Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail, and the progression status should be 
confirmed at a later time by the review panel (or study chair). 
 
 
Treating Physician Signature: ________________________   Date: ___ ___ / ___ ___ / ___ __ 
 
PI Signature: ____________________________      
   Date: ___ ___ / ___ ___ / ___ ___ 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 41 of 48 
 
 
BEST OVERALL Response Criteria for  
 
ORIS Assigned PID: __________________    Date Completed: ____ ___ / ___ ___ / ___ ___ 
 
Study Visit: 
 
 Week 10, Day 71 ( ± 3 Days) 
 Week 18 ( ± 1 week) 
 Week 26 ( ± 1 week) 
 Week 34 ( ± 1 week) 
 Week 42 ( ± 1 week) 
 Week 50 ( ± 1 week) 
 Week 58 ( ± 1 week) 
 Off Study 
 Other visit: (please specify) ________________ 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria (see section 
9.4.1). 
 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
   Complete Response (CR): Disappearance of all target lesions 
 
   Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 42 of 48 
 
   Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the treatment started or the 
appearance of one or more new lesions 
 
   Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum LD since the treatment started 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression, even after discontinuation of treatment. In some circumstances, it may be difficult 
to distinguish residual disease from normal tissue. When the evaluation of complete response 
depends on this determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
Confirmatory Measurement/Duration of Response 
 
Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed four weeks after the criteria for 
response are first met. In the case of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of eight weeks. 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). The duration of 
overall CR is measured from the time measurement criteria are first met for CR until the first 
date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started.  
 
 
Treating Physician Signature: ________________________   Date: ___ ___ / ___ ___ / ___ __ 
 
PI Signature: ____________________________      
   Date: ___ ___ / ___ ___ / ___ ___ 
 
 
 
 
 
 
 
 
 
 
 
 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 43 of 48 
 
Appendix G –  Research Study Product Chain of Custody- Apheresis/ BMT Lab 
 
Collection of Study Product in Apheresis: 
 
I. 
Identification of Research Study Participant in Apheresis  
a. Identification 
• Patient(s) is/are scheduled for PBMC collection by Research RN or 
coordinators as ordered by PI (Dr. Triozzi) 
•  Coordinators notify Apheresis staff of date of collection.  
• Apheresis staff validates that the patient is on the proper associated 
research protocol (CCCWFU03716) in the EMR  
• Once study status is verified the apheresis staff enter the apheresis 
collection plan into EMR 
•  Dr. Triozzi reviews and signs EMR Apheresis orders 
• Patients’ name is placed on Apheresis calendar and designated 
bed/cubicle assigned and protocol apheresis orders reviewed.  
• Two registered nurses are assigned to each patient the day prior to 
collection 
o 1) Collection (CRN)-responsible for assigned patient and 
collection procedure including: labeling of product, blood tubes, 
Apheresis Unit\ Cellular Product Hand-off Log, and care of 
patient during collection of product,  
o 2) Verifier (VRN) - responsible for confirming and validating 
accuracy of labeling of ISBT 128 Labeling of collection bag and 
Related Samples (Apheresis) Product, blood tubes, and 
Apheresis Unit Cellular Product Hand-off Log as performed by 
the collection RN.   
• Time Out is performed at the bedside within the confines of the cubicle 
space in full view and earshot of the patient.  
• The CRN and VRN: Verbally and visually identify patient and verify that 
the patient’s Name, MRN, and DOB match the protocol collection orders.  
 
b. Labeling  
• Research Protocol Specific Label provided by BMT Processing Lab:  
ISBT 128 research specific label placed on product bag following 
completion of patient and protocol order verification; both CRN and VRN 
sign and date the ISBT 128 product label(s) with a validated permanent 
marker.  
• CRN then exposes adhesive backing of label and securely applies ISBT 
128 product Label to the Spectra Optia IDL set collection bag. 
Product collection bag(s) is labeled in full view of patient and VRN, 
ensuring correct patient collection bag has been labeled 
c. Collecting  
• Collection is performed per research protocol orders. Collection via 
Spectra Optia Apheresis System 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 44 of 48 
 
•  Collection performed with Optia IDL set using continuous mononuclear 
cell collection with whole blood processed with goal of 1.5 – 2.0 
TBV or greater to obtain at least 200 mL of product, collection rate 
of 1.0 ml/min.  
 
 
d. Chain of Custody 
• 
Research RN/coordinator is contacted prior to completion of collection 
and given an exact time procedure will be complete.  
• 
Research RN/Coordinator coordinates the product retrieval time with Dr. 
Triozzi or Research designee to ensure that they  are on the apheresis 
unit to retrieve the product from the apheresis RN immediately upon 
disconnection from Optia machine.  
• 
Study Principal Investigator (PI) is on unit to receive collected product and 
completes the cellular product hand off log signaling the end of the 
Apheresis Unit chain of custody and the assumption of the Research 
Protocol for subsequent chain of custody procedure adherence. 
• 
The research personnel then remove the product from the apheresis unit 
as deemed appropriate by Dr. Triozzi. 
  
ll. 
Minimum Processing Standards within a shared space 
BMT lab Requirements: 
o A meeting of all individuals including the requestors will be arranged to discuss 
each section of the BMT program’s involvement in the research project. 
o For BMT lab, discussion will include use of reagents, solutions, equipment, 
space, storage, time, days of the week needed for product processing, training 
needed for the research techs. 
o Donors must be negative for infectious disease markers (IDMs) 
o Transfections with viral, bacterial or any infectious agents will not be allowed in 
the BMT lab- Changed to Transfection will be performed in an assigned biologic 
safety cabinet not currently in use by the BMT lab. 
o Researchers must have at least 2 identifiers on products and samples brought 
into the BMT lab- Product label, patient label containing MRN/CSN numbers, 
and an alphanumeric number. BMT lab do not provide labels. 
o Any project study or IRB protocols will not be under our current BMT FDA 
registrations. If an FDA registration is needed, consult with BMT program and 
BMT lab directors. FDA registration should not be stated on the protocol without 
approval from the BMT program  
o Any equipment that is needed from BMT Processing Lab will require training 
and documentation of training including decontamination procedures of the 
equipment. (Biologic safety cabinets, centrifuge, incubators, and controlled rate 
freezers). 
o Prevention of Cross-Contamination Guideline: Research product will not be 
processed during BMT lab processing of patient products to avoid 
contamination. Research products should not be stored in any refrigerator used 
for storage of BMT patient products/samples.  
o Equipment training checklist will include: 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 45 of 48 
 
o Preparation of equipment: decontamination procedures of the equipment before 
use, settings, specimen prep, use of tools, check for cross contamination 
o Operation of equipment: procedure 
o Post operation of equipment: removal of specimen, check for contamination, 
decontamination procedures of the equipment after use. 
o Work counter space 
o Research specimens and documentation will be isolated to one workstation next 
to biologic safety cabinet assigned. 
o BMT operations will take priority over any research operations. Researchers 
need to schedule their use of BMT lab space with the BMT lab well in advance 
before the date of use. If there is a conflict BMT lab operations takes priority. 
o Any changes to the IRB protocol must be reviewed by all sections of the BMT 
program. 
o  Any violations in the agreement for the use of BMT lab space, equipment, 
cross-contamination, etc will be immediately brought to the attention of the BMT 
Laboratory Processing Medical Director.  
 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 46 of 48 
 
 
Appendix H – Interferon Production 
DATA COLLECTION FORM 
ORIS PID: _______________________ 
Date Completed: ____ / ____ / ____ 
 
PI: Pierre Triozzi, M.D.  
 
Study Number: CCCWFU 03716 
 
Interferon Production 
Sample ID 
Date 
Stimulator (#1: anti-CD3 plus anti-CD28 
antibody) or (#2: NY-ESO, survivin, and 
telomerase peptide mixtures) 
IFN 
production 
Notes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 47 of 48 
 
 
Appendix I – Frequency Counts from Flow Cytometry 
DATA COLLECTION FORM 
ORIS PID: _______________________ 
Date Completed: ____ / ____ / ____ 
 
PI: Pierre Triozzi, M.D.  
 
Study Number:_______________ 
 
Cell Frequency Counts 
Sample ID 
Date 
Cell type 
Count/Frequency 
Notes 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
/ 
 
 
 

Safety and Immunologic Activity of Multiple Infusions of APN401 
Wake Forest Baptist Comprehensive Cancer Center 
CCCWFU 03716 
 
 
Protocol version date: 05/10/19                                                                Page 48 of 48 
 
 
Appendix J – Neutrophil/Lymphocyte Data Form 
DATA COLLECTION FORM 
ORIS PID: _______________________ 
Date Completed: ____ / ____ / ____ 
 
PI: Pierre Triozzi, M.D.  
 
Study Number: CCCWFU 03716 
 
Neutrophil/Lymphocyte Data Collection Form 
Sample ID 
Date 
Neutrophil 
Lymphocytes 
Ratio