Conditions: Metastatic Pancreatic Adenocarcinoma Recurrent Pancreatic Carcinoma Stage III Pancreatic Cancer Stage IV Pancreatic Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This phase Ib/II trial studies the side effects and best dose of bispecific antibody armed activated T-cells when given together with aldesleukin and sargramostim and to see how well they work in treating patients with pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Bispecific antibody armed activated T-cells are the patient's own T cells that are coated with a bispecific antibody comprising 2 antibodies chemically joined together. These antibodies have specific targets and binding properties that may give the T cells a greater ability to seek out, attach to, and kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. Confirm in a single dose phase I (3 to 6 patients \[pts\]) that 8 infusions of 10\^10 epidermal growth factor receptor (EGFR) bispecific antibody armed activated T cells (BATs) given twice per week in combination with interleukin (IL)-2 (aldesleukin) (300,000 IU/m\^2/day) and granulocyte-macrophage colony stimulating factor (GM-CSF) (sargramostim) (250 ug/m\^2/twice weekly) beginning 3 days before the 1st infusion and ending on the day of the last infusion is safe.

II. Perform a phase II clinical trial to estimate the clinical efficacy of 8 infusions of 10\^10 EGFR BATs in combination with IL-2 and GM-CSF in 39 evaluable pts (including the 3-6 pts in the single dose phase I).

SECONDARY OBJECTIVES:

I. Determine if infusions of EGFR BATs significantly increase cellular or humoral anti-pancreatic cancer (PC) responses by peripheral blood mononuclear cells (PBMC) at different time points after last EGFR BATs infusion and if those responses persist beyond 2 months (mos).

II. Obtain original tumor paraffin blocks prior to treatment and evaluate blocks for cluster of differentiation (CD)3, CD4, CD8, programmed cell death (PD)1/programmed cell death ligand (PDL)1, monocytes subpopulations, myeloid-derived suppressor cells (MDSC), and cytoplasmic interferon (IFN)-gamma and IL-10 by immunohistochemical staining to quantitate type and number of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment to estimate whether the type and number correlate with clinical responses.

III. To determine the time to progression (TTP).

OUTLINE: This is a phase Ib, dose-escalation study of anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells followed by a phase II study.

Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride intravenously (IV) over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin subcutaneously (SC) and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion.

After completion of study treatment, patients are followed up for 18 months.

Arms:
arm 1: Patients receive one of the following standard chemotherapy regimens at the discretion of the treating physician: gemcitabine hydrochloride IV over 30 minutes; gemcitabine hydrochloride IV over 30 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30-40 minutes; oxaliplatin IV over 2 hours, fluorouracil IV over 46 hours and leucovorin calcium IV over 2 hours; or fluorouracil IV over 46 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV, and oxaliplatin IV over 2 hours. Approximately 2 weeks after standard chemotherapy completion, patients receive anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV over 5-30 minutes twice weekly for 4 weeks. Patients also receive aldesleukin SC and sargramostim SC on day -3 before the first anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells infusion and continuing twice weekly until the final infusion.

Interventions: intervention 1: Aldesleukin intervention 2: Antibody Therapy intervention 3: Fluorouracil intervention 4: Gemcitabine Hydrochloride intervention 5: Irinotecan Hydrochloride intervention 6: Laboratory Biomarker Analysis intervention 7: Leucovorin Calcium intervention 8: Oxaliplatin intervention 9: Paclitaxel Albumin-Stabilized Nanoparticle Formulation intervention 10: Sargramostim
Intervention descriptions: intervention 1: Given SC intervention 2: Given anti-CD3 x anti-EGFR-bispecific antibody armed activated T-cells IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Correlative studies intervention 7: Given IV intervention 8: Given IV intervention 9: Given IV intervention 10: Given SC

Protocol document:
Prot_SAP_000.pdf: 
Protocol version: 6/22/2015, 8/25/201505/27/2016 
 
 
2015-100  
Title:  Phase Ib/II Treatment of Advanced Pancreatic Cancer with anti-CD3 x anti-EGFR-Bispecific 
Antibody Armed Activated T-Cells (BATs) in Combination with Low Dose IL-2 and GM-CSF 
 
Phase of Study:  Phase II 
IND Number: 13091 
Version: 6/5/15, 8/25/15, 5/27/16 
 
Study Center:  Karmanos Cancer Institute 
 
PRINCIPAL INVESTIGATOR 
Anthony F. Shields, M.D., Ph.D. 
HW04HO 
4100 John R 
Detroit, MI 48201 
Tel # 313-576-8735 
Fax # 313-576-8767 
E-mail: shieldsa@karmanos.org 
 
 
CO-INVESTIGATORS 
Lawrence G. Lum, MD, DSc 
Philip Philip, MD, PhD 
Abhinav Deol, MD 
Archana Thakur, PhD 
 
BIOSTATISTICIAN 
Greg Dyson, PhD 
 
PROGRAM STAFF 
Kristie Fields, RN, BSN, OCN 
 
 
DATA MANAGER: 
Tina Guthrie 
 
REGULATORY COORDINATOR: 
Kendra Mellert, M.S.A., CCRP 
 


Protocol version: 06/22/201508/25/2015 
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2
SUMMARY 
 
Epidermal Growth Factor Receptor (EGFR) is expressed on pancreatic cancer (PC). Our recent phase I 
study on patients with colorectal cancer and advanced pancreatic showed encouraging results. This 
protocol will confirm toxicities and estimate the clinical efficacy of combining anti-CD3 x anti-EGFR 
bispecific antibody (EGFRBi) armed activated T cells (EGFR BATs) given to patients (pt) with locally 
advanced or metastatic PC who have received at least first line chemotherapy  and may have 
responding, stable or progressive disease.  In the phase I study, 5 patients received 3-4 infusions of 2 x 
1010 BATs per infusion with total 8 x 1010 per course of treatment without dose limiting toxicities (DLTs) 
with a median overall survival (OS) of 14.5 mos.   
 
One treatment of chemotherapy will be given 1-2 weeks before immunotherapy to create immunologic 
space before the infusions of EGFR BATs.  In the single dose phase I portion of this study involving 3-6 
pt, we will confirm the safety of twice weekly infusions of up to 1010 EGFR BATs infusions in combination 
with 300,000 IU of interleukin 2 (IL-2)/m2/day and 250 µg granulocyte-macrophage colony stimulating 
factor (GM-CSF)/m2/twice weekly beginning 3 days before the 1st infusion and ending on the day of the 
last infusion.  If there is toxicity in 1 of 3 pt, 3 additional pt will be added to the dose level of 1010.  If 2 of 6 
patients experience DLTs, then the dose will be reduced to 7.5 x 109 per infusion.  If only 1 pt has toxicity 
in the first 6, then the study will proceed to enroll the remaining cohort of pt in the phase II. In the phase II 
portion of this study, we will estimate the clinical efficacy of 8 infusions of 1010 EGFR BATs in 
combination with IL-2 and GM-CSF in 39 evaluable pt (including the 3-6 pt in the above mentioned single 
dose phase I). The primary endpoint is an improvement in median OS from historical data of 7 mos to 
10.5 mos. 
 
Immune evaluations will be performed to determine if: a) infusions of EGFR BATs significantly increase 
cellular or humoral anti-PC responses and if those responses persist and b) immune responses correlate 
with clinical responses.  The original tumor paraffin blocks prior to treatment will be evaluated for the 
presence of CD3, CD4, CD8, PD1/PDL1, monocytes subpopulations, MDSC, and cytoplasmic IFN-γ and 
IL-10 by Immunohistochemical staining. The type and number of tumor infiltrating lymphocytes (TILs) in 
the tumor microenvironment will be correlated with clinical responses (secondary objective). 
 
If the pt does not have rapidly progressive disease 2 months after the last infusion, the treatment may be 
repeated. If the pt has significant progression of disease, the pt will receive oncologist’s choice of 
chemotherapy. Such chemotherapy may be given starting 30 days after the last BATs infusion. The pts 
will receive 3 months of chemotherapy and continue to be evaluated on protocol.  
 
In summary, the primary objective of the study is to evaluate clinical efficacy after confirming the safety at 
a dose up to 1010 EGFR BATs per infusions for 8 infusions in combination with IL-2 and GM-CSF. The 
primary endpoint is OS with the design to determine whether infusions of BATs in PC pts could improve 
the median OS from 7 months to 10.5 mos. Given the poor prognosis for pt with metastatic or locally 
advanced PC, we will also follow the pt to determine if immunotherapy followed by chemotherapy 
improve clinical responses over historical responses and improves time to progression free survival 
(PFS). Patients who are stable, partial responders, or complete responders by Wolchok criteria are 
eligible for re-treatment with BATs. The secondary objectives are: 1) immune evaluation studies to 
determine if infusions of BATs significantly increases cellular or humoral anti-PC responses and if those 
responses persist and correlate with clinical responses and 2) determine whether the type and number of 
T cells, Th1/Th2 secreting T cells, activation markers in the original biopsy paraffin block correlates with 
clinical outcomes. 
 
 


Protocol version: 06/22/201508/25/2015 
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3
TABLE OF CONTENTS 
Summary ............................................................................................................................................ 2 
1.0  Objectives .......................................................................................................................................... 4 
2.0  Background And Significance ............................................................................................................ 4 
3. Eligibility .............................................................................................................................................. 11 
4. Treatment Plan ................................................................................................................................... 12 
5.0 Toxicities, Dose Modifications And Management .............................................................................. 16 
6.0 Drug Formulation .............................................................................................................................. 18 
7.0 Preparation Of EGFRBi-Armed Activated T-Cells ............................................................................. 20 
8.0 Registration And Required Data ........................................................................................................ 21 
9.0 Criteria For Response, Progression, And Relapse ............................................................................ 24 
10.0 Criteria For Removal Of Patients From Study ................................................................................. 26 
11.0 Adverse Event (Ae) Reporting......................................................................................................... 27 
12.0 Statistical Considerations ................................................................................................................ 29 
13. Human Subjects ............................................................................................................................... 31 
14.0 References ..................................................................................................................................... 33 
 
 
 
 


Protocol version: 06/22/201508/25/2015 
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4
1.0  OBJECTIVES 
 
1.1   Primary Objectives: 
 
In patients who have received at least first line chemotherapy:  
 
a)  Confirm in a single dose phase I (3 to 6 pts) that 8 infusions of up to  1010 EGFR BATs given 
twice per week in combination with IL-2 (300,000 IU /m2/day) and granulocyte-macrophage colony 
stimulating factor (GM-CSF) (250 µg/m2/twice weekly) beginning 3 days before the 1st infusion and 
ending on the day of the last infusion is safe.  
 
 
b) Perform a phase II clinical trial to estimate the clinical efficacy of 8 infusions of 1010 EGFR BATs in 
combination with IL-2 and GM-CSF in 39 evaluable pts (including the 3-6 pts in the single dose 
phase I). The primary endpoint is an improvement in median overall survival (OS) from historical 
data of 7 mos to 10.5 mo. The trial will accrue 39 evaluable pts (including those in the single dose 
phase I.  
 
1.2  Secondary Objectives: 
 
1.2.1. Determine if infusions of EGFR BATs significantly increase cellular or humoral anti-PC 
responses by peripheral blood mononuclear cells (PBMC) at different time points after last EGFR 
BATs infusion and if those responses persist beyond 2 mos  
 
1.2.2 Obtain original tumor paraffin blocks prior to treatment and evaluate blocks for CD3, CD4, 
CD8, PD1/PDL1, monocytes subpopulations, MDSC, and cytoplasmic IFN-γ and IL-10 by 
Immunohistochemical staining  to quantitate type and number of tumor infiltrating lymphocytes (TILs) 
in the tumor microenvironment to estimate whether the type and number correlate with clinical 
responses. 
 
 
 
1.2.3 To determine progression free survival (PFS).  
 
2.0  BACKGROUND AND SIGNIFICANCE 
 
2.1 Metastatic and Locally Advanced Pancreatic Cancer:  
PC is the fourth most common cause of cancer-related death in the United States with over 48,960 newly 
diagnosed cases expected in 2015 and an expected mortality rate of approximately 40,5601. Most pt  
diagnosed with PCs have unresectable disease and usually die of metastatic disease even after 
treatment with chemo and radiation therapy. Despite the recent remarkable advancements in many 
malignancies, little success has been reflected in the outcome of PC. This malignancy is still considered 
among the most aggressive and the least curable of all human malignancies. Unfortunately, late 
diagnosis of PC in most pts with LAPC or MPC is associated with poor prognosis. Without effective 
treatment, the median survival of less than one year is expected for those with MPC. 
2.2 Chemotherapy for the treatment of PC.  
Single-agent gem became the first-line treatment of MPC after the pivotal 1997 report, where Burris et al2 
compared gem with 5-FU. The response rate was 5.4% in pt treated with gem alone whereas none of the 
5-FU treated pts responded (p = NS). Gem was associated with a statistically significant improvement in 
pain control, weight loss and functional impairment leading to FDA approval based on improvements in pt 
performance status. Many other combinations with gem failed to provide any further benefit and.3 and clinical 
outcomes remained alarmingly low2,4-18. More recently, the combination of nab-paclitaxel plus gem improved OS 
to 8.5 months compared to 6.7 mos for gem alone. 20 The cocktail of 5-FU, oxaliplatin, irinotecan and 
leucovorin (FOLFIRINOX) improved OS in the first line setting to 11.1 mos when compared to gem.19 In 
34 second-line chemo clinical trials reviewed by Rahma et al in 2013, pts who received treatments had a 
OS of 6 mos compared to those who received supportive care of 4 mos. Gem and platinum-based 
combinations provided a PFS and OS of 4 and 6 mos, respectively' and the combination of 5 FU and 


Protocol version: 06/22/201508/25/2015 
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5
platinum agents provided a PFS and OS of 2.9 and 5.7 mos, respectively.21 With dismal response 
rates, PFS, and OS in clinical trials, innovative and novel therapeutic approaches are desperately 
needed to improve OS in pts with LAPC and MPC.   
 
2.3 EGFR (ERBB-1 Receptor, HER1) as target.  
EGFR is over-expressed in 30-50% of PC. In clinical trials, small molecule inhibitors that target the 
intracellular tyrosine kinase signaling pathways of EGFR, such as gefitinib (Iressa®) or erlotinib 
(Tarceva®) have been tested without major impact on disease.  Though cetuximab was approved by the 
FDA in 2004 for the treatment of metastatic colon cancer, results from a study in PC with gem and 
cetuximab were disappointing.22 Therefore, cetuximab alone is not effective. Alternative strategies that 
exploit and directly target EGFR over-expression using the targeting ability of cetuximab circumvent the 
activational or mutation status of EGFR may be more 
effective at killing tumor cells than antibody alone. 
2.4. EGFR BATs:  
Arming anti-CD3 activated T cells (ATC) with anti-CD3 
x anti-EGFR bispecific antibody (EGFRBi) makes every 
T cell into a non-MHC restricted EGFR-specific 
cytotoxic T lymphocyte (CTL).23,24 Anti-CD3 x anti-
HER2 bispecific antibody (BiAb) armed ATC (HER2 
BATs) showed repeated killing, proliferation, and 
release of Th1 cytokines, Regulated on Activation 
Normal T Expressed and Secreted (RANTES=CCL5), 
macrophage 
inhibitory 
protein-1 
alpha 
(MIP-1α), 
interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-
α),and GM-CSF that induce DC maturation. Dying 
tumor cells release tumor associated antigens (TAA), 
that can lead to increased cross-presentation of TAA 
by antigen presenting cells (DC). This mechanism, 
illustrated in Fig 1, may vaccinate pts against their own 
TAAs. Preclinical studies showed that EGFRBi armed 
ATC (EGFR BATs) killed pancreatic cancer cell line MiaPaCA, secreted cytokines, and inhibited tumor 
growth in mice.24  
2.5. Unarmed ATC as mobile serial killers and immunokine factories.  
Cross-linking the T cell receptor with anti-CD3 triggers activation, proliferation, cytokine synthesis, and 
non-MHC restricted cytotoxicity directed at tumor targets.25-28 The tumoricidal cytokines produced include 
IFN-γ, TNF-α, and GM-CSF.29-39 In animals, infusions of ATC provide anti-tumor effects40-43 and improve 
engraftment when limiting doses of stem cells were given after lethal total body irradiation.44 In humans, a 
phase I trial treating pts with cyclophosphamide followed by infusions of activated CD4+ cells resulted in 1 
complete, 2 partial and 8 minor responses in 31 advanced cancer pts.45,46 If nonspecific ATC had 
enhanced cancer-directed activity after chemoT, BATs may have even greater anti-tumor activity. 
Fig 1: Infusion of targeted T cells induces anti-tumor immune 
responses. T cells kill tumor cells releasing cytokines and 
chemokines that induce DC maturation followed by antigen 
presentation of unknown tumor antigens to “vaccinate” the patient 
against their own TAAs. 
EGFRBi


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6
2.6. HER2 BATs Target high HER2 SK-BR-3 and 
low HER2 SUM 1315 expression cell lines.  
Our preclinical studies showed that HER2 BATs 
killed breast cancer cells lines that expressed not 
only high amounts of HER2 (SK-BR-3, high 3+ 
expression) but, more importantly, target and lyse 
cell lines that express little (MCF-7, a negative 
control for IHC)47 or essentially no HER2 expression 
(Sum 1315). Using goat anti-HER2/neu Ab to detect 
HER2/neu receptors on the cells, we showed that 
Sum 1315 was only 6.7% HER2 positive by flow 
cytometry 
(Fig 
2b) 
and 
negative 
for 
HER2 
expression by Western blotting (Fig 2a).  Fig 2c 
shows high levels of specific cytotoxicity of HER2 
BATs directed at both Sum 1315 and SK-BR-3 cells 
using an arming dose of 50 ng/106 ATC at the 
effector:target (E:T) ratios depicted in Fig 2a. This is 
consistent with the observation that as few as 10-30 
T 
cell 
receptor 
(TCR)-ligand 
interactions 
are 
sufficient to mediate T cell killing.48 Arming doses of 
50, 1.0, and 0.05 ng of BiAb/106 ATC led to 4000, 80, 
and 4 dimers/cell, respectively (assuming 20% dimer 
and 20% of BiAb actually binding to the T cells). 
Therefore, it is clear that only a few molecules of 
HER2Bi on ATC and a few HER2 on 
the surface of tumor cells are 
sufficient to allow binding and 
triggering of high levels of specific 
cytotoxicity.     
2.7. Phase I Safety, Immune and 
Clinical Responses in Metastatic  
Breast Cancer (MBC).  
HER2 
BATs 
exhibit 
anti-HER2 
cytotoxicity, proliferate, and secrete 
immunokines 
upon 
tumor 
engagement. In our phase I trial, 23 
women with HER2 0-3+ MBC 
received 8 infusions of HER2 BATs 
(twice a week for 4 weeks) in 
combination with IL-2 and GM-CSF 
to evaluate safety, feasibility, PFS, 
OS, T cell trafficking and immune 
responses. The median OS for 8 
HER2 3+ pts, 14 HER2 0-2+ pts, 
and all pts was 57.4, 27.4, and 36.2 
mos, respectively (Fig 3c). One 
HER2 1+ pt who was progressing 
on Femara developed a very good 
partial response (nearly complete 
response) that persisted at 7 mos 
(Fig 3d). BATs persisted in the 
Fig 3. a) Mean Ratio of Th1/Th2 cytokine as a function of infusion #, where Th1/Th2 = 
[IL-2+IFN-γ]/[IL-4+IL-5] ; b) IL-12 levels as a function of infusion # with means denoted as 
horizontal bars; c) the median OS is 59.4 months for the HER2 3+ group (red), 27.4 months 
for the HER2 0-2+ (blue) group, and is 36.2 months for the entire group (black); d) HER2-ve  
partial responder showing 2-liver mets preIT (left) PET/CT which disappeared postIT (right).  


Protocol version: 06/22/201508/25/2015 
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7
blood for at least a week and trafficked to tumors. Targeting HER2 positive and negative tumors induced 
cytotoxic anti-tumor responses, increases in Th1 cytokines, and IL-12 serum levels. These robust immune 
responses suggest HER2 BATs infusions may provide a clinical benefit.49,50 
2.7.1. 
Evidence 
for 
activation 
and 
Immunization of endogenous immune cells in 
MBC pts. Peripheral blood mononuclear cells 
(PBMC) exhibited high levels of cytotoxicity 
directed at SK-BR-3 that persisted up to 4 mos 51. 
Fig 4 shows specific cytotoxicity mediated by 
endogenous 
lymphocytes 
(IgG2a 
negative 
population) directed against SK-BR-3 in two 
representative pts. PBMC from these pts were 
depleted of IgG2a+ bearing cells (ATC) using 
Miltenyi columns and the IgG2a negative 
population was used in the killing assay. The 
results 
strongly 
suggest 
that 
endogenous 
lymphocytes had developed robust immune 
responses to breast cancer antigens. There were 
significant increases in serum Th1 cytokines (Fig 
3a) and IL-12 (Fig 3b)50 during and after 
infusions. The marked increases in serum IL-12 (Fig 3b) show that 
monocytes are activated by BATs infusions and secrete high levels 
of IL-12. 
2.7.2. No Human Anti-Mouse Antibody (HAMA) responses. 
Because anti-CD3 mAb moiety comprising the BiAb is a murine 
IgG2a monoclonal antibody (mAb), we evaluated pts’ sera before 
and after HER2 BATs infusions for the development of HAMA to 
IgG2a in an ELISA and did not detect clinically significant levels of 
IgG anti-mouse. Of the 10 pts evaluated, none developed levels > 10 
ng/ml during or up to 8 weeks after immunotherapy.  
A.7.3. Vaccination with BATs infusions and Boost after Stem 
Cell Transplant (SCT) with ‘Immune’ ATC. In 5 evaluable MBC pts 
who had undergone the phase I clinical trial consisting of 8 infusions 
of HER2 BATs in combination with low dose IL-2 and GM-CSF, a 
second leukapheresis was performed to obtain "anti-breast cancer 
immune" PBMC. PBMC after 8 infusions of BATs before the second 
expansion exhibited specific cytotoxicity directed at SK-BR-3 ranged 
from 2 to 38% with a median of 26%.  ATC were produced and 
cryopreserved for multiple infusions (4-15 infusions) after high dose 
chemo and SCT. Two pts at Roger Williams Hospital received up to 
1010 immune ATC 3 times per week for 3 weeks and then once 
weekly infusions of 2 x 1010 ATC for 6 weeks and 4 pts at KCI 
received ATC once per week for 4 weeks. Fig 5a shows immediate 
non-MHC restricted specific cytotoxicity mediated by uncultured 
PBMC directed at SK-BR-3 targets at the designated time points for 
IT and post SCT for 5 pts. There were significant serum titers of anti-
SK-BR-3 that increased after the vaccination with 8 HER2 BATs 
infusions and high levels of anti-SK-BR-3 IgG antibody titers were 
present at the various time points after HDC and SCT up to 2 years after SCT (data not shown).  In order 
to confirm that transferred memory B cells were responsible for the serum antibodies were transferred in 
the stem cell product, fresh PBMC from 5 pts were re-stimulated in vitro with SK-BR-3 targeted T cells 
FG91801
0
20
40
60
80
100
Pheresis
aATC
ATC
5
8
1 Week
Post
3 Week
Post
1 Month
Post
IgG2a[-] Population
% Cytotoxicity
FG91792
0
20
40
60
80
100
Pheresis
aATC
ATC
5
8
1 Week
Post
IgG2a[-] Population
% Cytotoxicity
Fig 4:  Circulating PBMC depleted of IgG2a+ cells (IgG2a [-]) using Miltenyl 
beads exhibited cytotoxicity.  The IgG2a [-] population was tested for 
specific cytotoxicity directed at HER2-positive SKBR-3 (25:1 E:T) or HER2-
negative Raji as a function of treatment schedule.  The IgG2a [-] 
populations were compared to the pheresis product, unarmed ATC, armed 
ATC product. 
Fig 5: a) Multiple infusions of ATC after SCT 
promoted the development of cytotoxicity that 
could be detected during and at 2-4 weeks post 
IT (MidIT and PostIT), and  3 mos (3M), 6 mos 
(6M) and 12-24 mos (1-2Y) after SCT. b) Shows 
the anti-SK-BR-3 antibody levels in culture 
supernatants tested after 14 days of culture. 
These data suggest that pts had been immunized 
against her own tumor antigens by multiple 
infusions of BATs that can be transferred in ATC 
product after SCT. 
a 
b 


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8
and CpG using a new assay for inducing anti-tumor antibodies in 
vitro.52  The 14 day culture supernatants contained anti-breast 
cancer antibodies before and after SCT. In other words, the stem 
cell product contained memory B cells that produce anti-breast 
cancer antibodies when re-stimulated in vitro (Fig 5b). Together, 
this proof-of-concept pilot study shows that both cellular and 
humoral anti-tumor immune responses can be detected during and 
after IT, and these immune responses can be transferred via the 
"immune" ATC. 
2.7.4.Summary of HER2 BATs. The HER2 BATS infused into 
MBC pts in the phase I were safe and induced immune and clinical 
responses. BATs infusions induced endogenous immune cells to 
develop anti-breast cancer CTL and serum antibody activity that 
could be transferred in pts after autologous SCT in multiple 
infusions of immune ATC which provided anti-tumor specific helper 
activity for antibody synthesis. These studies provide PROOF of 
CONCEPT that BATs can vaccinate pt against their own tumor 
antigens and the memory effector T cells and 
specific antibody forming B cells can be 
transferred and be easily detected after HDC and 
SCT. 
2.8. Preclinical Data that support proposed 
research: 
A.8.1 EGFR BiAb redirects non-MHC restricted 
cytotoxicity of ATC. Based on the experience 
generated with HER2 BATs, EGFR directed BATs 
were generated. EGFR is expressed in several 
epithelial cancers including non-small cell lung 
cancer (NSCLC). In NSCLC addition of EGFR 
directed antibodies (cetuximab and necitumumab) 
to chemo has shown modest improvement in 
survival.53,54 The degree of binding of EGFR BATs 
to the EGFR-positive NSCLC cell line, A549, 
compared to an EGFR-negative cell line, MDA-
MB-453, was evaluated using phycoerythrin-
conjugated (PE) goat anti-mouse IgG2a to detect 
the OKT3 (anti-CD3) moiety of the BiAb (Fig 6). 
EGFR BATs binding to A549 cells 
was consistent with their expression 
of EGFR; in contrast, EGFR BATs 
bound just above the background of 
the isotype control to MDA-MB-453 
cells. A representative histogram of 
the background binding for an 
isotype control to A549 is also 
shown.  
Fig 7: 1) Anti-CD3 (OKT3, Centrocor Ortho-Biotech, Raritan, NJ) was 
cross-linked with Traut’s reagent (2-iminothiolane HCl, Pierce); 2) Anti-
EGFR was cross-linked with sulphosuccinimidyl 4-(N-maleimidomethyl) 
cyclohexane-1-carboxylate (Sulpho-SMCC); and 3) Cross linked 
monoclonal antibodies were desalted on PD-10 columns (Pharmacia, 
Uppsala, Sweden) to remove unbound cross-linker.  The cross-linked 
OKT3 and anti-EGFR will be heteroconjugated overnight. 
Fig 8 Antiproliferative effects of EGFR BATs 
compared with mAbs (cetuximab) or 
unarmed ATC against COLO356/FG cells. 
COLO 356/FG cells were treated with 
unconjugated OKT3 (anti-CD3) or 
cetuximab (500 ng/well), unarmed 
ATC (107/well), EGFR BATSs (107/well 
armed wi h 50 ng EGFRBi/106 ATC), or a 
combination of the mAbs with unarmed 
ATC. COLO 356/FG cells were counted 
after 72 hours. Results from three 
independent experiments are shown as the 
number of cells for each treatment as a % of 
the cells cultured with medium only. After 72 
hours, the cells in the control wells had 
gone through 1.5 doublings. Bars = SD. 
Fig 6 EGFRBi binding to EGFR-positive versus EGFR-
negative cells. A431cells (peak1) andMDA-MB-453 cells 
(peak 3) were incubatedwith EGFRBi (1 Ag/mL) for 30 
minutes at room temperature. EGFRBi binding was 
evaluated by flow cytometry using phycoerythrin-
conjugated (PE) goat anti-mouse IgG2a to detect the anti-
CD3 moiety of the BiAb. A representative histogram (peak 
2) of t he background binding for an isotype control 
(GIgG-PE) and unarmed ATC binding for each of the cell 
lines is also shown. 


Protocol version: 06/22/201508/25/2015 
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9
2.8.2 Production of EGFRBi.  The production of anti-CD3 x anti-
EGFR (OKT3 x cetuximab) BiAb by chemical heteroconjugation has 
been described (Fig 7).47 The heteroconjugated product is analyzed 
by non-reducing SDS-PAGE and quantified by densitometry using 
Quantity One software (Bio-Rad, CA). EGFR BATs are prepared and 
quality controlled and assured per SOP to be pathogen free, and 
endotoxin levels are quantitated and approved for use by the FDA (IND 
13091.47,55 
2.8.3. In vitro and in vivo characterization studies of EGFR BATs 
performed in a pancreatic cancer cell line. Much of the preliminary 
characterization of EGFR BATs was initially performed using the 
pancreatic carcinoma cell line, COLO 356/FG (FG), which 
demonstrates sensitivity to EGFR BATs-mediated cytotoxicity. We 
compared the anti-proliferative effect of EGFR BATs to cetuximab in 
cell proliferation assays. ATC alone, EGFR BATs (E:T of 10) or 
equivalent concentrations of unconjugated monoclonal antibodies 
(anti-CD3 or cetuximab) were co-cultured with FG cells. After 72-
hours, surviving FG cells were harvested and counted using a 
Coulter Particle Counter. Results (Fig 8), expressed as the number 
treated cells as a % of FG target cells plated alone (mean ± SD) from 
3 independent experiments, show that although cetuximab alone 
was ineffective (p > 0.05 compared to control) at inhibiting 
proliferation of FG, EGFR BATs induced significant killing 
(p<0.001) of the same target cells. When FG was grown as subcutaneous xenografts in a SCID-Beige 
mouse model (T-, B-, and NK cell deficient model), cetuximab (1 mg/week) administered intravenously for 
6 weeks significantly delayed tumor growth compared to 
ATC alone or medium administered on the same schedule, 
but EGFR BATs administered at a 1000-fold lower dose (20 
x 106 ATC armed with 50 ng EGFR BiAb/million cells ≈ 0.001 
mg cetuximab/week) produced comparable tumor growth 
inhibition (Fig 9). No gross toxicities were observed in any of 
the treated groups of mice. Body weights of mice over the 
course of treatments were significantly lower (6-8%) in the 
unarmed ATC treatment group (p < 0.001), but did not differ 
significantly between the other 3 treatment groups. Post-
mortem necropsy of vital organs showed significant 23-30% 
and 22-32% increases in liver and kidney weights, 
respectively, in the mice treated with cetuximab compared to 
the other 3 treatment groups; liver and kidney 
are the primary target organs for EGFR-
targeted 
toxicities. 
These 
findings 
are 
consistent with observations from preclinical 
and clinical studies exploring other EGFR-
targeted 
therapeutics.56,57 
 
Importantly, 
compared to cetuximab, EGFR BATs showed 
no evidence of organ toxicities in our preclinical 
studies and produced comparable tumor 
growth delay suggesting that EGFR BATs may 
offer a wider therapeutic window with regard to 
safety. The EGFR BATs total dose used in 
these mice is equivalent to a 3.2 x 1010 total 
Fig 11: Left panel shows the bar graph of cytotoxicity mediated by 
fresh PBMC of patient (IT20091) against pancreatic cancer cell line-
MiaPaCa-2 preIT, post EGFR BATs infusion #1, #3 and #4, pre and 
post boost infusion at 3 mos. Right panel shows the enhanced IFN-γ 
EliSpots by PBMC directed at MiaPaCa-2 cells at MiaPaCa-2 post 
immunotherapy (post) and boost at 3 mos.  
Fig 10 
Fig 9 EGFRBi-armed ATC and cetuximab 
delayed growth of pancreatic tumor 
xenografts, but only cetuximab delayed 
growth of colorectal tumor xenografts in 
SCID-Beige mice. COLO356/FG  tumor 
cells (5 x106) were implanted s.c.in  SCID-
Beige mice. When tumors measured 60 
mm3, treatments were initiated. Mice 
received EGFR BATs by tail vein injection 
once per week for 6 weeks, and tumor 
growth was monitored.   Points are median 
tumor volumes from each treatment group 
(n = 5mice/treatment group/tumor type); 
bars, SE. 


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10
dose in humans, but significantly higher doses of ATC armed with other BiAbs, such as HER2Bi, have 
been attained in humans without encountering  DLTs.58 
2.9. Phase I Clinical Trial targeting colorectal and 
pancreatic cancer with EGFR BATs.  
Five PC and 6 colorectal cancer pts received up to 78.8 x 1010 
(median of 43, range 20.4 - 78.8 x 109) EGFR BATs in 3-4 
doses given once per week for 3 weeks followed by a boost at 
12 weeks. There were no DLTs. The planned doses were 10, 
20, and 40 x 109 BATs/infusion. The OS for the entire group, 
the colorectal, and pancreatic cancer pts was 13.6, 13.2, and 
14.5 mos, respectively (Fig 10). Most remarkable are the PC 
pts. Three are alive at 664, 333, and 284 days after pheresis, 
and two died at 375 (IT20087) and 408 (IT20092) days after 
study enrollment (Table 1 as of 5/26/2015). Fig 11 shows the 
cytotoxicity mediated by fresh PBMC from pt against PC cell 
line-MiaPaCa-2 after each infusion as well as the pre and post 
booster (4th infusion) results for cytotoxicity (left panel) and IFN-
γ EliSpots (right panel).  Fig 12 shows cytotoxicity of PBMC from 9 of the pts before (preIT) and 2 weeks 
post infusions #3 directed at a colorectal cell line. These data suggest that IT may sensitize or make 
tumor cells more susceptible to chemo leading to remarkable complete responses. Pt IT20102 had an 
abdominal lymph node decrease in size at 3 mos, received his booster infusion, and decreased by 27% 
at 6 mos on CT scan. This pt was interviewed (with consent) by the local Fox News affiliate. His story is 
available at the link below.  
Table 1 
Pt 
Age 
Disease 
Prior Tx 
BATs x 
10
9
 
TTP (days) 
OS 
(days) 
Comments 
IT20087 
58 
Mets to 
liver 
Folfirinox 
47 
186 
Dead 
(409) 
Progressed 
IT20091 
63 
T3 
N1Mets 
to liver. 
Post 
Whipple 
5FU,Leuk/5FU 
Folfirinox 
9.3 
 
78.8 
CR, 138 
 
Alive 
(664) 
Chemo Induced 
CR after Treated 
Twice IT 
with Folfirinox, 
responding to 
Folfirinox again. 
IT20092 
64 
T2b Abd 
Nodes, 
post 
Whipple 
gemcitaine, 5FU, 
radiation, 
36 
211 
Dead 
(436) 
Had chronic 
diarrhea; 
Appendicitis 
With PC tumor 
IT20102 
56 
T4, 
Mets to 
liver, 
lungs 
Folfirinox 
74 
Stable 
(near PR) 
Alive 
(333) 
Lesion decreased 
by 27% at 6 mos, 
stable at 8 mos 
IT20104 
51 
T4, Abd 
Nodes 
FOLFOX stable 1 yr then Xeloda 
72 
71, CR 
Alive 
(284) 
Chemo Induced 
CR after IT 
Fig 12: Specific cytotoxicity mediated by PBMC 
from colorectal and pancreatic cancer pts before 
and after 3 infusions of EGFR BATs. 


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11
http://www.clickondetroit.com/lifestyle/h
ealth/a-new-cuttingedge-treatment-for-
a-deadly-disease/32488192 
 
2.9.1. Toxicity of EGFR BATs. There 
have been no DLTs and only eleven 
episodes of Grade 2 toxicities (Table 
2). There were no grade 3 or 4 
toxicities. Toxicities related to the 
cellular infusion typically resolved with 
medication within 24-48 hours after an 
infusion.59 
2.10. Summary of Preliminary Data 
on In vitro and Clinical Use of EGFR 
BATs.  
Our preclinical studies clearly show 
that EGFR BATs lyse EGFR positive 
colorectal and pancreatic cell lines in 
vitro and significantly inhibited the 
growth of EGFR positive tumors in 
immunodeficient mice.  The phase I 
clinical trial in colorectal and pancreatic 
cancer 
pts 
was 
particularly 
encouraging and remarkable in the PC 
pts who, as summarized in Table 1, 
had substantial amounts of metastatic disease.  A median survival of 14.5 mos with a near PR in IT20102 
without any other treatment, and complete responses (CR), and a persistent CR response to 
chemotherapy in IT20104 are striking.  It is not clear what the mechanism is for responses to 
chemotherapy in IT20091 and IT20104.  Our working hypothesis is that immunotherapy sensitized the 
tumor or modulated the tumor so that subsequent chemotherapy was more effective.  Studies to dissect 
and understand these results are underway.  
  
 
3. ELIGIBILITY  
 
3.1 Eligibility (Inclusion and Exclusion Criteria):  
 
Inclusion Criteria: 
• 
Histological or cytological proof of pancreatic adenocarcinoma. Must have locally advanced or 
metastatic pancreatic cancer who have received at least first line chemotherapy and may have 
responding, stable or progressive disease 
• 
Expected survival ≥ 3 months 
• 
KPS ≥ 70% or SWOG Performance Status 0 or 1 
• 
Absolute Neutrophil Count (ANC) ≥ 1,200/mm3 
• 
Lymphocyte count ≥ 400/mm3 
• 
Platelet Count ≥ 75,000/mm3 
• 
Hemoglobin ≥ 8 g/dL 
• 
Serum Creatinine  < 2.0 mg/dl, Creatinine Clearance ≥50 ml/mm (can be calculated or measured) 
• 
Total Bilirubin ≤ 2 mg/dl (biliary stent is allowed) 
• 
SGPT and SGOT < 5.0 times normal 


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12
• 
LVEF  ≥ 45% at rest (MUGA or Echo) 
• 
Age ≥ 18 years at the time of consent (Written informed consent and HIPAA authorization for 
release of personal health information) 
• 
Females of childbearing potential, and males, must be willing to use an effective method of 
contraception 
• 
Females of childbearing potential must have a negative pregnancy test within 7 days of being 
registered for protocol therapy 
 
Exclusion Criteria: 
 
• 
Any chemotherapy related toxicities from prior treatment.(>grade 2 per CTCAE v4.0) 
• 
Known hypersensitivity to cetuximab or other EGFR antibody 
• 
Treatment with any investigational agent within 14 days prior to being registered for protocol 
therapy  
• 
Symptomatic brain metastasis  
• 
Chronic treatment with systemic steroids or another immuno-suppressive agent  
• 
Serious non-healing wound, ulcer, bone fracture, major surgical procedure, open biopsy or 
significant traumatic injury within 28 days prior to being registered for protocol therapy  
• 
Active liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis  
• 
Known HIV infection 
• 
Active bleeding or a pathological condition that is associated with a high risk of bleeding 
(therapeutic anticoagulation is allowed)   
• 
Uncontrolled systemic disease like active infections  
• 
Nonmalignant medical illnesses that are uncontrolled or a controlled illness that may be 
jeopardized by the treatment with protocol therapy  
• 
Females must not be breastfeeding  
• 
Pt may be excluded if, in the opinion of the PI and investigator team, the pt is not capable of being 
compliant 
 
Minor changes from these guidelines will be allowed at the discretion of the attending team under special 
circumstances. The reasons for exceptions will be documented. 
 
3.2  Screening Assessment   
Medical history, physical examination, Karnofsky or SWOG performance status, EKG, tumor markers, 
MUGA or ECHO, laboratory tests (hematology, chemistry) and staging CT, MRI or PET/CT will be 
performed ≤ 4 weeks prior to registration.  
 
3.3 Informed Consent and Registration 
Each pt must be aware of the nature of his/her disease process and must willingly consent to treatment 
after being informed of alternatives, potential benefits, side effects, and risks. Patients will be evaluated, 
consented, and registered after meeting all eligibility criteria, and prior to leukopheresis.  Patient’s 
disease will be staged. Baseline studies will be completed within 4 weeks prior to registration. 
 
4. TREATMENT PLAN 
4.1 Treatment Summary 
One treatment of chemotherapy (see section 4.2) will be given 1-2 weeks before immunotherapy to 
create immunologic space before the infusions of EGFR BATs. In the single dose phase I portion of this 
study involving 3-6 pt, we will confirm the safety of twice weekly infusions of up to 1010 EGFR BATs 
infusions in combination with 300,000 IU of interleukin 2 (IL-2)/m2/day and 250 µg granulocyte-
macrophage colony stimulating factor (GM-CSF)/m2/twice weekly beginning 3 days before the 1st infusion 
and ending on the day of the last infusion.  The pt will receive a single treatment with chemotherapy up to 


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13
1-2 weeks prior to starting the BATs infusions.  If there is toxicity in 1 of 3 pt, 3 additional pt will be added 
to the dose level of up to  1010.  If 2 of 6 pt experience DLTs, then the dose will be reduced to 7.5 x 109 
per infusion.  If only 1 pt has toxicity in the first 6, then the study will proceed to enroll the remaining 
cohort of pt in the phase II.  
 
In the phase II portion of this study, we will estimate the clinical efficacy of 8 infusions of 1010 EGFR BATs 
in combination with IL-2 and GM-CSF in 39 evaluable pt (including the 3-6 pt in the abovementioned 
single dose phase I). The primary endpoint is an improvement in median OS from historical data of 7 mos 
to 10.5 mo. 
 
Immune evaluations will be performed to determine if: a) infusions of EGFR BATs significantly increase 
cellular or humoral anti-PC responses at 8 weeks after last EGFR BATs infusion and if those responses 
persist at 26 weeks or 52 weeks and b) immune responses correlate with clinical responses.  The original 
tumor paraffin blocks prior to treatment will be evaluated for the presence of CD3, CD4, CD8, PD1/PDL1, 
monocytes subpopulations, MDSC, and cytoplasmic IFN-γ and IL-10 by Immunohistochemical staining. 
The type and number of tumor infiltrating lymphocytes (TILs) in the tumor microenvironment will be 
correlated with clinical responses. 
 
If the pt does not have rapidly progressive disease 2 mos after the last infusion, the treatment may be 
repeated. If the pt has significant progression of disease, the pt will receive oncologist choice of 
chemotherapy. Oncologist choice chemotherapy will be given starting 30 days after the last BATs 
infusion if the repeat tumor evaluation shows progression of disease. (The MDT team will specially 
discuss the management of each pt at the time of progression). The pt will continue to be followed 
for disease and overall survival status and blood studies may be done optionally to continue evaluate 
immune responses to tumor every 3 months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The primary objective of the study is to evaluate clinical efficacy and to confirm the safety at a dose up to 
1010 EGFR BATs per infusions for 8 infusions. The primary endpoint is OS with the design to determine 
Figure 13 


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14
whether infusions of BATs in PC pts could impro ve the median OS from 7 mos to 10.5 mos. Given the 
poor prognosis for patients with metastatic or locally advanced PC, we will also follow the patients to 
determine if immunotherapy followed by chemotherapy improve clinical responses over historical 
responses and improves progression free survival. Patients who are stable, partial responders, or 
complete responders by RECIST criteria are eligible for re-treatment with BATs.  
 
The secondary objectives are: 1) immune evaluation studies to determine if infusions of BATs 
significantly increase cellular or humoral anti-PC responses at 8 weeks after last BATs infusion and if 
those responses persist at 26 weeks or 52 weeks; and 2) progression free survival. 
 
Each pt will be given two infusions per week with doses ranging up to 10 x 1091010 per infusions per 
week for 4 weeks in a row.  Restaging CT and immune evaluations will be done 8 weeks after the last 
BATs infusions and then every 2 months as per standard of care until disease progression.  
 
Baseline serum and cell will be aliquoted from the pheresis. Blood draws (4 green top tubes containing 
approximately 40 mls of anti-coagulated blood and 1 red top tube containing 8 mls of serum) will be pre-
BAT infusion, after the 4th infusion, and then approximately 2 weeks (14±4 days), 2 months (60 days±7 
days, optional), 4 months (120 days±7 days) and optionally every 6 months (180 days±7 days) after 
the last infusion.  Optional IEs will be done if there continue to be immune responses at 6 month (± 2 
weeks) intervals until the responses have disappeared.  
 
 
Given the poor prognosis for patients with advanced pancreatic cancer, we will also follow the patients to 
determine if immunotherapy has any impact on survival and response rate (secondary endpoint). Patients 
who are stable, partial responders, or complete responders by RECIST criteria are eligible for re-
treatment with EGFR BATs. Patients who show evidence of progression at 8 weeks after the last BATs 
infusion will be given oncologist’s choice chemotherapy. 
 
4.2 Chemotherapy 
The time from leukopheresis to harvest of ATC is about 3 weeks. One treatment of standard 
chemotherapy: 1) gemcitabine;  2) gemcitabine and nab-paclitaxel; 3) modified FOLFOX6 (oxaliplatin, 5-
fluorouracil and leucovorin); or 4) FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxalipalatin) to 
create immune space. In patients with advanced pancreatic cancer with no other standard chemotherapy 
available or allergy, immunotherapy may be given within 1 week after a single dose of cyclophosphamide 
(1 gram/m2). 
 
4.3 Immunotherapy   
4.3.1 EGFR BATs infusions:  EGFR BATs infusions will be done in an outpatient setting at KCI.  All 
appropriate assurances for identification of product, patient, sterility, etc. will be performed prior to 
infusion.  The identity of the frozen BATs will be verified with patient’s identifiers and thawed at the 
bedside of the pt just prior to infusion.  BATs will be infused intravenously (IV) with the rate of infusion 
based on the endotoxin content of the product.  All patients will be observed for at least 4 hours after an 
infusion.  If stable, patients will be discharged home. BATs infusions will begin approximately1- 2 weeks 
after chemotherapy and the subsequent doses will be administered twice weekly for 4 weeks.  
 
4.3.2 Subcutaneous IL-2 Injections:  All patients will receive SQ IL-2 (300,000 IU/m2/day), beginning 
3 days before the first ATC infusion and ending at the last BATs infusion. 
 
4.3.3 GM-CSF Injections:  All patients will receive SQ GM-CSF (150 µg/m2/daily), to start 3 days 
before the first ATC infusion and ending at the last BATs infusion. 
 


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15
4.4 Recommended Concomitant Medications:   
Anti-emetics such as ondansetron, dolasetron, or granisetron should be used prior to chemotherapy.   30 
minutes prior to each EGFR BATs infusions, all patients will be pre-medicated with Benadryl (50 mg IV or 
PO) and Tylenol 650 mg PO.  Demerol (25-50 mg IV) will also be administered post infusion if the pt 
develops grade 3 chills and then may be administered 30 minutes prior to subsequent BATs infusions 
dependent upon the severity of the initial reaction.  The pt will alternate ibuprofen 600 mg every 8 hours 
with acetominophen 650 mg every 8 hours for 24 hours after the BATs infusion.  
• 
Ancillary Therapy:   
Patients will receive full supportive care including transfusion of blood and blood products, antibiotics, 
and anti-emetics, when appropriate.  The reason(s) for treatment, dosage and the dates of treatment 
will be recorded. 
• 
Steroids/Other Therapy:   
With the exception of steroids for anti-emetic regimen, adrenal failure, septic shock, pulmonary 
toxicity or hormones administered for non-disease-related conditions (e.g. insulin for diabetes), 
steroids will not be administered.  The patients will stop hormonal therapy 1 week prior to 
immunotherapy.  Hydrocortisone (50-100 mg IV every 6 hrs) for severe adverse reactions related to 
BATs infusions is allowed. Life-threatening reactions may be treated with Situximab (anti-IL-6 mab to 
control cytokine storm).  
 
4.5  Quality Control and Assurance of BATs 
 
Lists and lots of suppliers of mAbs, heteroconjugation reagents, and culture reagents are maintained. 
Release criteria for armed products for clinical use include: negative results for sterility check with ID 
(7 days, negative for mycoplasma, endotoxin less than 2.5 EU/mL (otherwise a calculated infusion 
rate will be used to ensure the pt receives no more than 5 EU/kg/hr), ≥10% cytotoxicity directed at 
EGFR+ cancer cell line (25:1 E/T) compared to the respective unarmed ATC, >50% CD3+ cells and 
<10%: CD19, CD20, CD16; and CD56+ cells will be measured in ATC product.  
 
4.6 Tumor Measurements   
All tumors will be measured in millimeters or centimeters prior to initiation of therapy.  These 
measurements will consist of the longest diameter and the perpendicular diameter at the widest portion of 
the tumor and will be made and recorded by the physician or his designee.  An estimate of overall 
objective and subjective response will be made and recorded at the end of treatment.  Disease status will 
be evaluated in the patients and their responses will be confirmed a minimum of four (4) weeks after the 
first response has been recorded using standard RECIST 1.1 criteria. Responses will be noted as 
Complete Response (CR), Partial Response (PR), Minor Response (MR), Stable Disease (SD) or 
Progressive Disease (PD). Duration of response will be measured from first observation of the response.  
All patients will be staged before IT and at designated follow up times after IT (see section 8). 
 
4.7  Accrual and Duration of Study  
Our anticipated accrual rate is 11 patients per year. Thus, it should take approximately 4 years to accrue 
the 43 patients needed for the trial. Allowing for 18 months of follow-up to obtain the primary endpoint on 
the last pt enrolled and 6 months to assemble, analyze and interpret the data the total study duration is 
projected to be at most 6 years.  
4.8 Re-start Criteria   
    Patients removed from the study due to unrelated toxicity may be re-entered upon complete resolution 
of toxicity.  Re-entry criteria are the same criteria required for initial treatment. 


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16
5.0 TOXICITIES, DOSE MODIFICATIONS AND MANAGEMENT 
 
5.1  Leukapheresis Procedure   
 
 Reported toxicity from leukopheresis is minimal. Patients have a small potential for infection from 
the placement of central catheters used for pheresis. Use of the anticoagulant citrate dextrose may 
cause symptoms of mild hypocalcemia, which are controlled with calcium replacement. 
 
5.2 Granulocyte-Macrophage-Colony Stimulating Factor (GM-CSF). 
 
Therapeutic Classification:  Colony stimulating factor. 
Known Side Effects and Toxicities:  Patients receiving GM-CSF (Leukine-Sagramostim) have 
experienced fever 60-90 min after administration (duration 1-4 hrs); chills; nausea; vomiting; 
diarrhea; fatigue; weakness; headache; decreased appetite; thrombosis; rapid or irregular heartbeat 
or other heart problems; feeling of faintness; facial flushing; pain in the bones, muscles, chest, 
abdomen, or joints; local reaction at the site of injection; rashes; and kidney and liver dysfunction. 
Eosinophilia or other blood component abnormalities may occur.  There have been infrequent 
reports of fluid accumulation or worsening of preexisting fluid accumulation in the extremities, in the 
lungs, and around the heart which may result in breathing problems or heart failure.  Rarely, 
patients have developed acute allergic reactions.  There have also been reports of low blood 
pressure, hypoxia, transient loss of consciousness, and difficulty in breathing after the first injection 
of Sargramostim. These signs may or may not recur with additional injections of Sargramostim.  
Patients with prior heart, lung, kidney, or liver problems may have worsening of their symptoms 
following administration of Sargramostim. There may be other side effects that could occur. 
 
5.3 Toxicity of Low-Dose Subcutanous (SQ) Interleukin 2 (IL-2). Therapeutic classification:  
Lymphokine Known Side Effects and Toxicities:  Administration of low dose SQ IL-2 (2 × 105 
IU/m2/day) for 90 days resulted in no grade III toxicities.  None of the patients experienced 
pulmonary capillary leak syndrome, severe hypotension, oliguria, azotemia, or hyperbilirubinemia.  
The most frequent toxicities included fatigue, fever, and nausea. None of the patients had to stop 
their SQ IL-2 therapy due to side effects.  Therefore, it is unlikely that major toxicities associated 
with the low dose SQ IL-2 will occur although death due to high dose IL-2 toxicity has been 
reported.60. 
 
 
 
 
5.4  EGFR BATs 
Toxicity associated with BATs has been minimal. The reported symptoms have been reversible with 
cessation of therapy.  Most patients treated with BATs some experienced chills, headaches, fatigue, and 
hypotension after infusions.  Fever, chills, fatigue, and headache were the most common reactions.  
Other rarely reported effects included mild gastrointestinal and neurologic symptoms.  
 
5.4.1 Dose Modification for EGFRBi-armed ATC-related Toxicities   
     All patients with treatment related, grade 4 non-hematologic toxicity will be removed. If the left 
ventricular ejection fraction (LVEF by MUGA) falls by more than 10% from the previous value after 
EGFRBi BATs, therapy will be withheld and the pt removed from the protocol (no one has been removed 
for cardiac-related toxicities in our phase I study).  If there is persistent grade-3 toxicity at any time, 
treatment will be held until toxicity improves to grade 0 or 1. If grade 3 toxicities recur, the BATs infusions 
will be stopped (this would be considered a DLT).  Toxicity will be assessed daily for 7 days after each 
reinfusion and then weekly for unresolved toxicities. 
 
   It is anticipated that in some cases, maximal T-cell expansion will not achieve the desired dose per 
infusion. In this case, the available T-cells will still be infused in 8 divided doses. Patients who receive 
less than this dose will be evaluable for clinical efficacy and immune responses. 


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17
 
5.5 Monitoring of patients getting chemotherapy   
 
The major toxicities expected with chemotherapy are myelosuppression, nausea, vomiting, diarrhea, 
neuropathy and loss of appetite. No dose modification is planned since patients are receiving only one 
course of treatment.  No prophylactic antibiotics are planned. The patients will receive prophylactic anti-
emetics and will be monitored for signs of acute toxicity.  
 
 
5.5.1. Cetuximab toxicity 
   Acne-like Rash: The most common adverse event associated with cetuximab administration is acne-
like rash. Acne-like rash usually occurs on the face, upper chest, and back, but occasionally extends to 
the extremities and is characterized by multiple follicular or pustular appearing lesions characterized 
histologically as a lymphocytic perifolliculitis or suppurative superficial folliculitis. The onset of rash is 
generally within the first 2 weeks of therapy. 
   A number of therapeutic interventions have been attempted, including oral and topical antibiotics, 
topical steroids, and rarely, oral steroids. The value of these measures is unknown since definitive clinical 
trials have not bee performed. The etiology of the acne-like skin rash is believed to be the result of 
cetuximab binding to EGFR in the epidermis. When cetuximab was chemically heteroconjugated to OKT3 
in the bispecific antibody format and infused on activated T cells in the phase I clinical trials, there were 
no nail disorders, allergic reactions, acute infusional reactions, cardiac toxicities, or skin rashes (Choi 
2015, GI ASCO abstract). 
 
Nail Disorder: Nail disorders were reported in 6.4% of patients receiving cetuximab as a single agent. The 
nail disorder is characterized as paronychial inflammation with associated swelling of the lateral nail folds 
of the toes and fingers. The most commonly affected digits are the great toes and thumbs. According to 
investigators, the nail disorder persists for up to 3 months after discontinuation of cetuximab.  Soaks in 
aluminum acetate (Burow’s) solution BID-QID will prevent secondary infection. Symptom relief may be 
achieved with standard bandages or with the application of liquid bandages (cyanoacrylate preparations). 
Preliminary analysis in patients treated at usual doses (400 mg/m2 initial dose, followed by 250 mg/m2 
weekly), revealed that the incidence of nail disorders is greater in patients who received more than 6 
infusions (approximately10%) compared to patients treated with 6 or less infusion of cetuximab 
(approximately 3%). 
 
Allergic Reactions: The majority of the allergic/hypersensitivity reactions described have been grade 1 to 
2 toxicities with less occurrences of grade 3-4. All reactions responded promptly to appropriate medical 
intervention. 
 
Infusion Reaction: Infusion reactions are distinct from allergic or hypersensitivity reactions, although 
some of the manifestation are overlapping. Infusion reactions generally develop during or shortly after the 
infusion. Mild infusion reactions (chills, fever, dyspnea) have been reported in 23% of patients receiving 
cetuximab as a single agent. Severe infusion reactions (airway obstruction [bronchospasm, stridor, 
hoarseness], urticaria, hypotension) were reported in 2% of patients receiving single agent cetuximab. 
Infusion reactions occur most often with the first dose. 
 
Pulmonary Toxicity: Interstitial lung disease has been reported in less than 1% of patients who have 
received cetuximab for advanced colorectal cancer, and in one pt with head and neck cancer. 
 
Cardiac Toxicity: Recent reports described the occurrence of cardiac dysfunction, chest pain, and/or 
cardiac ischemia/infarction. These events occurred in patients who were receiving cetuximab in addition 
to 5-FU-containing therapy. Cardiac ischemia/infarction and acute cariomyopathy are known side effects 


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18
of 5-fluorouracil-based chemotherapy. It is presently unclear if the addition of cetuximab may increase the 
risk of 5-FU-related cardiac events. 
 
Other Toxicities: Other reported or potential toxicities associated with cetuximab include: 
 
Skin—Pruritis (10%), alopecia 
Gastrointestinal—Diarrhea (28%, 2% grade 3/4), nausea/vomiting (29%), 
stomatitis/mucositis (11%), anorexia, constipation 
Metabolites—Hypomagnesemia (rarely grade 4 requiring aggressive IV repletion) 
Pulmonary—Interstitial pneumonitis was reported in 3 of 633 (<0.5%) patients; 
one pt died as a consequence. 
EENT—Conjunctivitis (7%) 
Constitutional—Fatigue/malaise, asthenia, infection 
Musculoskeletal—Back pain 
Hematologic—Anemia, leukopenia 
CNS—Headache (25%, 3% grade 3/4) 
 
5.6 Unexpected or Life-Threatening Toxicity   
   Reporting requirements and procedures depend upon: (1) whether agents are suspected of causing 
toxicity, (2) whether possibility of such atoxicity was reported in the consent form, or manufacturer’s 
literature, (3) the severity or grade of the toxicity. 
 
Expected toxicities:  
Grade 4 myelosuppression: Report only as part of regular data submission.  All other toxicities, 
Grades 4 and 5: Written report to principal and co-investigators within 10 working days.  All other 
toxicities, Grades 1 to 3: Report only as part of regular data submission. 
 
Unexpected Toxicities: 
Unexpected toxicities are toxicities that are not listed in the toxicity management section of the 
protocol, the consent form, or the manufacturer’s package insert.   
• 
REPORTING ADVERSE REACTIONS: 
 All serious and unexpected adverse drug reactions will be reported to the IRB and FDA within 5 
days of the event. 
 
5.7 Toxicity Grading   
   The NCI CTEP CTCAE v4.0 Toxicity Tables and 0-4 Grading Scale will be used. 
 
5.8 Study Stopping Criteria:   
• 
Death due to toxicity (not from disease progression) 
• 
Occurrence of 2 patients with grade 4 adverse events attributable to study treatment 
 
6.0 DRUG FORMULATION 
 
6.1  
Murmonab OKT3 : This is a murine IgG2a monoclonal antibody directed at human CD3 and is 
commercially available from Miltenyl, Auburn, CA). It is purchased in vials containing 5 mg/5 ml of 
reconstituted bacteriostatic water. OKT3 is used to activate T cells for growth and for 
heteroconjugation with Cetuximab to produce anti-CD3 x anti-EGFR bispecific antibody. 
 
6.2  
Anti-EGFR monoclonal antibody Cetuximab (Bristol-Myers Squibb, New York, NY):  
Cetuximab is a humanized murine monoclonal antibody directed at EGFR, and is commercially 
available as single-use, 50 ml vials containing 100 mg of drug as a sterile, preservative-free, 
injectable liquid. The binding characteristics and its ability to mediate cytotoxicity towards non-
small cell lung cancer cells (A-549) and other lung cancer cell types (Calu-6) have been well 


Protocol version: 06/22/201508/25/2015 
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19
documented in our preclinical studies. 
 
6.3 
Anti-CD3 (OKT3) x anti-EGFR (cetuximab, Erbitux®) heteroconjugated bispecific antibody 
(EGFRBi): See section 7.3 on the production of anti-CD3 x anti-EGFR per GMP conditions. 
Investigational New Drug (IND) application BB-IND #13091: Product Name: Autologous T Cells 
Activated with OKT3 and Expanded with Interleukin-2 (Prometheus) armed with OKT3 (anti-CD3) 
x Cetuximab (anti-EGFR) given with Granulocyte Macrophage Colony-Stimulating Factor and 
Interleukin 2. Sponsor:  L.G. Lum. Approved 8/06 to date. BB-IND #13091 has SOPS that 
specifies the production of bispecific antibody, sterility testing, and the standard operation 
procedures for arming of activated T cells. 
 
6.4 
Leucovorin: Leucovorin is commercially available in parenteral formulations (3- and 5-mg 
ampules; 50-,100- and 350-mg vials). In situations where leucovorin (folinic acid) is not available 
because of shortage, then the pure l-stereioisomer, levoleucovorin (levo-folinic acid) may be 
administered as a substitute, at one-half of the protocol-stipulated leucovorin dose (200 mg/m2 of 
levoleucovorin in most situations) in order to facilitate continuity of pt care. 
 
6.4.1   Leucovorin Storage and Preparation: All dosage forms are stored at room temperature. 
The reconstituted parenteral solution,10 mg/mL, is stable for at least 7 days at room temperature. 
At concentrations of 0.5 to 0.9 mg/mL the drug is chemically stable for at least 24 hours at room 
temperature under normal laboratory light. The 50- and 100-mg vials for injection are 
reconstituted with 5 and 10 mL of sterile water or bacteriostatic water, respectively, resulting in a 
10-mg/mL solution. The 350-mg vial is reconstituted with 17 mL of sterile water resulting in a 20-
mg/mL solution. Leucovorin (0.5–0.9 mg/mL) is chemically stable for at least 24 hours in normal 
saline, 5% dextrose, 10% dextrose, Ringer's injection, or lactated Ringer's injection. Leucovorin 
(0.03, 0.24, and 0.96 mg/mL) is stable for 48 hours at room and refrigeration temperatures when 
admixed with floxuridine (FUDR, 1, 2, and 4 mg/mL) in normal saline. Leucovorin is also 
compatible with fluorouracil. 
 
6.5 
Fluorouracil: Fluorouracil is a fluorinated Pyrimidine Antimetabolite that inhibits thymidylate 
synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, interfering with DNA, 
and to a lesser degree, RNA synthesis. Fluorouracil appears to be phase specific for the G1 and 
S phases of the cell cycle. Pharmacies or clinics shall obtain supplies from normal commercial 
supply chain or wholesaler for injection 50 mg/mL (10 mL, 20 mL, 50 mL, and 100 mL). 
Fluorouracil may be given IV push or IV infusion. 
 
6.5.1  Fluorouracil Drug Product Storage and Preparation 
Store intact vials at room temperature and protect from light. A slight discoloration may occur with 
storage but usually does not denote decomposition. Dilute in 50 to 1000 mL of 0.9% NaCl or 
D5W. If exposed to cold, a precipitate may form; gentle heating to 60ºC will dissolve the 
precipitate without impairing the potency. Solutions in 50 to 1000 mL 0.9% NaCl or D5W or 
undiluted solutions in syringes are stable for 72 hours at room temperature. Fluorouracil and 
leucovorin are compatible for 14 days at room temperature.  
 
6.6  
Oxaliplatin 
Oxaliplatin is used in combination with infusional 5-fluorouracil/leucovorin for the treatment of 
cancer. Oxaliplatin is commercially available as a 50-mg or 100-mg vial. Refer to the label for 
additional information regarding treatment with oxaliplatin. 
 
6.6.1  Oxaliplatin Storage and Preparation 


Protocol version: 06/22/201508/25/2015 
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20
Oxaliplatin is provided as a sterile, preservative-free, lyophilized powder for reconstitution in vials 
containing 50 mg and 100 mg of oxaliplatin. The lyophilized powder is reconstituted by adding 10 
mL (for the 50-mg vials) or 20 mL (for the 100-mg vials) of Water for Injection or 5% dextrose 
solution and then by diluting in an infusion solution of 250 mL of 5% dextrose solution. Oxaliplatin 
should be stored at 25ºC (77ºF) in the light-proof packaging provided. Temperature excursions to 
15ºC to 30ºC (59ºF to 86ºF) are permitted. DO NOT mix with solutions containing normal 
saline or other chloride-containing fluids/diluents. DO NOT combine with alkaline 
medications or media (such as basic solutions of 5-FU, trometamol) which cause OXAL to 
degrade. Do not use needles or intravenous infusion sets containing aluminum items for the 
preparation or administration (risk of degradation of OXAL on contact with aluminum).  
  
6.7       Proleukin  
Proleukin (IL-2; Prometheus, San Diego, CA) is purchased as a preservative-free lyophilized 
powder in vials containing 22 million International Units (IU) for expanding T cells.  Patients will 
not receive IL-2 infusions. 
 
6.8 
Granulocyte-macrophage colony stimulating factor (GM-CSF, Leukine)  
GM-CSF (rhu -GM-CSF, sargramostim) is a 127 amino acid glycoprotein produced in a yeast (S. 
cerevisiae) expression system by Immunex, which differs from the native GM-CSF by substitution 
of leucine for arginine at position 23.  GM-CSF is a hematopoietic growth factor that stimulates the 
proliferation and differentiation of hematopoietic progenitor cells.  GM-CSF is provided as a 
lyophilized powder in glass vials, and is suitable for parenteral administration following 
reconstitution with 1 ml sterile water for injection, USP without preservative.  Active Ingredient: rhu 
GM-CSF 250 µg or 500 µg with a specific activity of approximately 5 × 107 U/mg in a normal 
human bone marrow colony assay.  Inactive Ingredients: Mannitol, USP 40 mg, Sucrose, USP 10 
mg, and tromethamine, USP 1.2 mg. Syringe: 14 day stability refrigerated.  Minibag: (50cc 
NS/D5W) 48 hour stability refrigerated. 
 
7.0 PREPARATION OF EGFRBi-ARMED ACTIVATED T-CELLS  
 
7.1 
Facility:  
Qualified personnel who are familiar with procedures which minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe disposal 
of immunotherapeutic agents in a self-contained protective environment. Cells will be generated in 
the Cancer Immunotherapy Laboratory (GMP facility in Karmanos Cancer Center) under a FDA 
approved IND #BB-13091 with standard operating procedures (SOPs) for growing, splitting, 
harvesting, arming of ATC, cryopreservation, and infusion of BATs. 
 
7.2 
Activation, Culture, and Freezing of Armed ATC: 
Lymphocytes are obtained by pheresis and cultured at a density of 1-3 x 106 cells/ml in RPMI 
1640 media (Lonza), containing 100 IU/ml of IL-2, 10-20 ng/ml of OKT3 (Janssen Biotech, Inc or 
Miltenyi Biotech), and 2% human serum (Valley Biomedical). Cells will be cultured for a maximum 
of 14 days in media. 
 
7.3 
Preparation of anti-CD3 x anti-EGFR Bispecific Antibody:  
BB-IND #13091 entitled “Autologous T Cells Activated with OKT3 and Expanded with Interleukin-
2 armed with OKT3 (anti-CD3) x Cetuximab (anti-EGFR) given with Granulocyte Macrophage 
Colony-Stimulating Factor and Interleukin 2” specifies details for the production, purification, and 
quality control testing are part of the new IND that was submitted to the FDA on 3/29/2011.  
Lawrence G. Lum, MD, DSc is the sponsor.  (Phone number 313-576-8326 and e-mail: 
luml@karmanos.org). 


Protocol version: 06/22/201508/25/2015 
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21
 
7.4 
Arming of ATC with EGFRBi: 
The harvested ATC will be counted and a dose of 50 ng of EGFRBi per million ATC will be added 
to the solution and incubated for 1 hr at 4oC. The BATs will be washed, counted, and re-
suspended in the final solution that will be cryopreserved in aliquots specific for each infusion. 
 
7.5 
Cytotoxicity Assay:  
Cytotoxicity is measured in a 20 hr 51Cr -release assay.  The EGFR+ cell line, will be used as a 
positive control and an EGFR- cell line will be used as a negative control. Tumor cells are plated 
in a flat-bottomed microtiter plate and incubated at 37oC. The targets are washed and labeled the 
next day with 51Cr at 37oC. The wells containing tumor cells will be washed and armed or 
unarmed ATC will be plated at different E:T ratios and incubated for 20 hrs at 37oC. The next day, 
the supernatants harvested from the microtiter wells will be counted and the percent specific lysis 
will be calculated47. 
 
7.6 
Quality Assurance of ATC Cell Product: 
 Lists of suppliers of monoclonal antibodies, heteroconjugation reagents, and culture reagents will 
be maintained as well as lot numbers used and supplier provided documentation of sterility and 
documentation that all reagents are free of endotoxin and mycoplasma. The final bag of cells to 
be administered will be tested for sterility, mycoplasma, and endotoxin level. Records of all quality 
control measures will be maintained by the laboratory. 
 
8.0 REGISTRATION AND REQUIRED DATA 
 
8.1 
Pre-Study.  
    All patients enrolled will be evaluated and staged prior to initiation of therapy.  Baseline studies will be 
completed within ≤4 weeks prior to study registration. 
 
8.2      Protocol Registration 
    The attending physicians in the gastrointestinal oncology service will consider the pt for the study.  All 
pt information will be forwarded to Data Manager at (313-576-8506 or Stephanie Bower at 313-576-9276) 
at the Karmanos Cancer Institute Clinical Trial Office for determination of eligibility.  Upon informed 
consent and eligibility confirmation, the pt will be registered to the study.  
 
8.3 Tests and Observations 
Immune evaluations will be conducted as delineated in Table 1. Baseline serum and cell will be aliquoted 
from the pheresis. Blood draws (4 green top tubes containing approximately 40 mls of anti-coagulated 
blood and 1 red top tube containing 8 mls of serum) will be pre-BAT infusion, after the 4th infusion, and 
then approximately 2 weeks (14±4 days), 2 months (60 days±7 days, optional), 4 months (120 days±7 
days) and optionally every 6 months (180 days±7 days) after the last infusion.  Optional IEs will be 
done if there continue to be immune responses at 6 month (± 2 weeks) intervals until the responses 
have disappeared. 
 


Protocol version: 6/22/2015, 8/25/201505/27/2016 
 
 
8.3 Table 1: Tests and 
Observations 
 
Pre –Registration1 
Pheresis 
Chemotherapy 
Pre - BAT 
Week 1 
Week 2 
Post BAT #4 
Week 3 
Week 4 
1-2 wks Post #8 
2 mos after last 
infusion 
4 mos after last 
infusion  
6 mos after last 
infusion 
BAT #12 
BAT #2 
BAT #3 
BAT #4 
BAT #5 
BAT #6 
BAT #7 
BAT #8 
History and Physical3 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Performance Status3 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
CBC  
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Metabolic Panel 
w/ Mg + Phosphorus 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
CEA or CA 19-9 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg B & C and HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis & CrCl4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immune Studies5 
 
X 
 
X9 
 
 
 
 
X 
 
 
 
 
X 
(X) 
X 
(X) 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
CTor PET/CT6  
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Tumor Measurements7 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Pheresis8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bridging chemo 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BAT Infusion 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Safety Assessment 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
Table Legend  
1. All tests performed ≤4 Weeks prior to study registration. 
2. Pt should receive BAT #1-8 infusions twice per week for 4 weeks (+/- 2 days). 
3. H&P and Performance: To be performed by one of the protocol investigators or their designee. 
4. Creatinine clearance may be calculated. 
5. Optional (X) immune evaluation assessment (± 1 week). Immune function testing samples will be delivered to Dr. Lum’s laboratory (HWCRC RM 723).  
Please call Dana Schalk at 313-576-8320 for specimen pickup.  Do not leave the blood overnight.  A total of 60 48 mls of blood will be drawn at each of the 
designated points.  One 10 ml red top tube and five 10 ml green or lavender top tubes containing anti-coagulant.  
6. CT or PET/CT: To be repeated approximately every 8-12 weeks to until progression of disease 
7. Tumor evaluation will be done with the discretion of the PI according to the schema figure above 


Protocol version: 06/22/201508/25/2015 
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23 
8. T-cells will be collected using pheresis and transported by Dr. Lum;s staff at Karmanos Cancer Institute to the cGMP facility.  Collected cells will be cultured 
and armed in Dr. Lum’s laboratory according to established protocols. 
9. Prior to BAT infusion. (-3 days to day of infusion) 


Protocol version: 06/22/2015 
9.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE 
9.1 Tumor Measurements 
All tumor measurements will be measured in centimeters prior to initiation of therapy.  These 
measurements should be done according to Wolchok criteria.  An estimate of overall objective and 
subjective response will be made and recorded at the end of treatment, 2 months after the first 
infusion. Since it is expected that immune activity would lead to tumor flare, the restaging CT’s may 
be repeated 2 months later based on immune-related response criteria (irRC).61,62  and the 
designation of CR, PR, SD, or PD will be made at that time.  
 
9.2 Response Definitions: Response will be defined by using the irRC criteria with the allowance of an 
initial mild PD due to the nature of immunologic therapies as above. 
 
“Only measurable lesions are taken into consideration. Measures are taken bidimensionally for 
each lesion. Measurability is defined as 5 × 5 mm or more on helical computer tomography scans. 
The sum of the perpendicular diameters (SPD) of index lesions at baseline is added to that of 
new lesions to calculate total tumor burden according to the following formula: 
 
Tumor Burden = SPD index lesions +SPD new, measurable lesions 
 
Response categories are defined as immune-related complete response (irCR), immune-related 
partial response (irPR), immune-related stable disease (irSD), and immune-related progressive 
disease (irPD) using the same thresholds defined by standard WHO criteria”. Decreases in total 
measurable tumor burden compared to the baseline tumor burden (SPD of all index lesions at 
baseline). irPD should be confirmed at 2 consecutive times mandated for irPR or irCR. New lesions 
are allowed when the overall tumor burden decreases qualifying for partial response (≥50% 
decrease) or stable disease (<50% decrease to >25% increase) as described inTable 2. These new 
patterns are considered clinically meaningful because they appear to be associated with favorable 
survival.61,63 Importantly, early increases in the size of lesions may be due to infiltration of 
lymphocytes and does not preclude an irCR, irPR, or irSD at the next consecutive time point. If a pt 
is classified as having irPD, confirmation by a second scan in the absence of rapid clinical 
deterioration is required. Thus, the definition of confirmation of progression represents an 
increase in tumor burden of at least 25% compared with baseline at two consecutive time 
points at least 4 weeks apart. It is recommended that this confirmation be done at the 
discretion of the investigator in the context of the patient’s tumor type, disease stage, and 


Protocol version: 06/22/2015, 05/27/2016 
 
 
25
clinical status because awaiting a response after tumor burden increase may not be 
appropriate for patients with rapid symptomatic progression accompanied by a decline in 
performance status.” 
 
9.2.1 Complete Response (irCR): Disappearance of all clinical evidence of active tumor for a 
minimum of eight (8) weeks.  The pt must be free of all symptoms.  All measurable, evaluable 
and non-evaluable lesions and sites must be assessed. 
 
9.2.2 Partial Response (irPR): a decrease ≥ 50% decrease in SPD compared to the baseline SPD. 
This category includes changes in non-index lesions and new, nonmeasurable lesions under 
“non measurable response” in Table 2.  Unequivocal progression of non-index lesions if there 
is a decrease ≥ 50% in SPD is an irPR.  
 
9.2.3 Stable Disease (irSD): a decrease <50% to <25% of index and new, and measurable lesions 
with absent/stable non-index lesions or any new, non measurable lesions. 
 
9.2.4 Progressive Disease (irPD): ≥ 25% increase with any non-index lesions and any new, 
nonmeasurable lesions. 
 
9.3 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 PD the smallest 
measurements recorded since the treatment started). In general, the patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria.  
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time will be classified as having “symptomatic 
deterioration”. Every effort will 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, the residual lesion may be investigated 
(fine needle aspirate/biopsy), if possible, to confirm the complete response status. 
 
9.4 Duration of overall response.  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that 
recurrence or PD is objectively documented, taking as reference for PD the smallest measurements 
recorded since the treatment started.  
 
9.5  Duration of stable disease.  SD is measured from the start of the treatment until the criteria for 
disease progression are met, taking as reference the smallest measurements recorded since the 
treatment started.  
 
9.6  Reporting of results.  All patients included in the study will be assessed for response to treatment, 
even if there are major protocol treatment deviations. Each pt will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 8) 
unknown (not assessable, insufficient data). Patients with no measurable disease at the start of treatment 
will be evaluated based on recurrence-free survival. 
 
9.7  Additional Assessments.  All patients will have a baseline tumor marker assessment and testing of 
tumor markers at the designated follow-up time points. Changes in serial tumor marker measurements, in 


Protocol version: 06/22/2015, 05/27/2016 
 
 
26
those patients who have baseline elevations, will be utilized as a surrogate marker of clinical response, 
stable disease or disease progression and reported as such. 
 
9.8  Patients without residual disease:  Patients whose primary tumor or metastatic disease has been 
removed or successfully treated, respectively, prior to entry into the phase I trial will be evaluated based 
on duration of relapse-free survival. 
 
9.9. Progression free survival: length of time from enrollment in the study until disease progression or 
death.  
 
10.0 CRITERIA FOR REMOVAL OF PATIENTS FROM STUDY 
 
10.1  Disease Progression: Patients with progressive disease following BATs infusions will be removed 
from treatment, their disease pathologically documented, and the pt will be followed for survival and the 
immunologic endpoints. 
 
10.2  Extraordinary Medical Circumstances: If at any time the constraints of this protocol are 
detrimental to the patient’s health, the pt shall be withdrawn from treatment. In this event: 
 
10.2.1  Document reasons for withdrawal and record whether this action was pt or physician directed. 
 
10.2.2  The pt will remain technically on-study although treatment has been discontinued. The patients 
will be followed for relapse and survival. 
 
10.3 
Unexpected or Life-Threatening Toxicity (CTCAE v4.0 Table): 
 
10.3.1 Direct questions regarding drug therapy to the Principal Investigator. 
 
10.3.2  Reporting requirements and procedures depend upon: (1) whether agents are suspected of 
causing toxicity, (2) whether possibility of such a toxicity was reported in the consent form, or 
manufacturer’s literature (Published Toxicity), (3) the severity or grade of the toxicity. 
 
10.3.3 Expected toxicities include:  
 
10.3.3.1 Grade 4 myelosuppression: Report only as part of regular data submission. 
 
10.3.3.2 All other toxicities, Grades 4: Written Report to Principal and Co-Investigators, within 10 working 
days.  
 
10.3.3.3 All other toxicities, Grades 1 to 3: Report only as part of regular data submission. 
 
10.3.4 Unexpected Toxicities: Unexpected toxicities are toxicities that are not listed in the toxicity 
management section of the protocol, the consent form, or the manufacturer’s package insert. All 
unexpected toxicities will be reported to Principal and Co-Investigators, within 10 working days. 
 
10.4   Patient noncompliance with the protocol requirements 
 
10.5   Patient request to withdraw 
 
10.6   Development of serious intercurrent illness during the course of treatment 
 


Protocol version: 06/22/2015, 05/27/2016 
 
 
27
10.7   Patient removed at the discretion of the PI 
 
10.8 
Patient cells do not grow during activation and arming process or cannot be used for other 
reasons (e.g., viability, contamination or bag breakage in the freezer). 
 
11.0 ADVERSE EVENT (AE) REPORTING 
WSU IRB Adverse Event reporting 
Adverse Event reporting to begin after initiation of any immunotherapy drugs (IL-2 and GM-CSF).   
Adverse event reporting will be done in compliance with the Wayne State University Institutional 
Review Board (IRB) as follows: 
 
A.  Death or Life Threatening Adverse Reaction or Unexpected Event:  
If a death or immediately life-threatening Adverse Reaction/Unexpected Event occurs, it must be 
reported to the IRB office within five (5) business days of the PI becoming aware, even if the 
information in the report is incomplete. As more information is forthcoming, one or more additional 
reports should be filed with the WSU IRB Administration Office. The initial report of the Adverse 
Reaction or Unexpected Event and follow-up reports should be filed using the IRB Unexpected 
Problem Report Form.  
 
B. Serious Adverse Reaction or Unexpected Event:  
If a Serious Adverse Reaction/Unexpected Event occurs (one that necessitates or prolongs 
hospitalization, results in a permanent or significant disability or congenital anomaly, or is judged 
to be serious by the principal investigator), and is unexpected, (not listed in the consent form) it 
must be reported to the IRB within five (5) business days of the PI becoming aware. If the Serious 
Adverse Event is listed in the consent form but a relationship to the study intervention/activity 
cannot be ruled out by the PI, it must be reported to the IRB within five (5) business days. If the 
information is incomplete on the initial filing, follow-up reporting is required. The IRB Unexpected 
Problem Report Form should be used in all reports pertaining to these reactions/events.  
 
C. Non-Serious (Moderate or Minor) Adverse Reaction or Unexpected Event:  
If a non-serious Adverse Reaction occurs that is unexpected (not listed in the informed consent), 
it must be reported to the IRB within five (5) business days of awareness, unless the Principal 
Investigator can rule out the relationship to the study agent or intervention. If a non-serious 
Adverse Reaction occurs that is expected (listed in the informed consent), but is more frequent, 
more intense or longer lasting that expected, or requires medical treatment, it must be reported to 
the IRB within five (5) business days. If the reaction that is listed in the consent form occurs as 
described in the informed consent, it does not need to be reported to the IRB.  
If an Unexpected Event occurs, it must be reported to the IRB within five (5) business days of the 
awareness by the Principal Investigator. The Adverse Reaction/ Unexpected Event Form should 
be used for these submissions.  
 
D. Possibly-Related Adverse Reactions/ Unexpected Events 
In the rare case where a sponsor requires that a non-reportable (i.e., possibly related) Adverse 
Reaction/ Unexpected Event be reported to the IRB, an amendment should be submitted by the 
PI requesting that the non-reportable safety report be appended to the IRB file. It remains the 
primary responsibility of the WSU PI, the study sponsor, and any associated DSMC to identify 
trends that might require the event to be elevated to definitely or probably related status.  
If a trend is identified that elevates the Adverse Reaction to definitely or probably related status, 
an Unexpected Problem Report Form should be completed, along with an amendment for consent 
form changes, if needed, and submitted to the IRB. 
 


Protocol version: 06/22/2015, 05/27/2016 
 
 
28
Safety Reporting Requirements for IND Holders 
In accordance with 21 CFR 212.32, sponsor-investigators of studies conducted under an IND must 
comply with following safety reporting requirements:  
 
a. Expedited IND Safety Reports: 
 
7 Calendar-Day Telephone or Fax Report:   
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of 
investigational agent. An unexpected adverse event is one that is not already described in the 
Investigator Brochure.  Such reports are to be telephoned or faxed to the FDA within 7 calendar 
days of first learning of the event.  Each telephone call or fax transmission (see fax number 
below) should be directed to the FDA new drug review division in the Center for Drug Evaluation 
and Research or in the product review division for the Center for Biologics Evaluation and 
Research, whichever is responsible for the review of the IND. All telephone conversations will be 
log as note to file in the IND BB-#13091. 
 
15 Calendar-Day Written Report:  
The Sponsor-Investigator is also required to notify the FDA and all participating 
investigators, in a written IND Safety Report, of any serious, unexpected AE that is considered 
possibly related to the use of the investigational agent.  An unexpected adverse event is one that 
is not already described in the Investigator Brochure. 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed.  The new report should contain comments on the significance 
of the new event in light of the previous, similar reports.   
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech Drug Safety, and all participating investigators within 15 calendar days of first learning 
of the event.  The FDA prefers these reports on a MedWatch 3500a Form but alternative formats 
are acceptable (e.g. summary letter). 
 
FDA fax number for IND Safety Reports: 
 
1 – The reviewers for the FDA are at: 
 
 
  
Dr. TBD 
 
 
 
 
  
U.S. Food and Drug Administration 
 
  
Center for Biologic Evaluation and Research 
 
  
10903 New Hampshire Avenue 
 
  
Silver Spring, MD 20993-0002 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator must also be 
faxed to CBER at:  
 
Jean F. Gildner, MSHS, MT (ASCP), CQA (ASQ) 
Regulatory Project Manager 
FDA/CBER/OCTGT 
10903 New Hampshire Avenue 
Bldg. 71, RM. 5222 
Silver Spring, MD 20993-0002 
Phone: (240) 402-8296 


Protocol version: 06/22/2015, 05/27/2016 
 
 
29
Fax: (301) 595-1303 
jean.gildner@fda.hhs.gov 
 
 
 
 
 
                          AND: 
 
BB-IND #13091 Sponsor Contact Information 
Lawrence G. Lum MD, DSc 
Rm 740.1, 7HWCRC, 4100 John R 
Detroit,  MI 48201  
Tel# 313-576-8326 and fax # 313-576-8939 
 
12.0 STATISTICAL CONSIDERATIONS 
 
12.1 Study Design/Endpoints 
The objectives of this single arm phase II clinical trial are to evaluate the clinical efficacy and to confirm 
the safety of anti-CD3 x anti-EGFR-Bispecific Antibody Armed Activated T-Cells (BATs) therapy for 
locally advanced or metastatic pancreatic cancer who have received at least first line chemotherapy. The 
primary endpoint will test whether the treatment improves overall survival (OS) as compared to an 
historical standard. The secondary objectives include evaluating PFS after the last BATs infusion. Events 
that are considered progression events are detailed in section 9. 
 
12.2 Sample Size 
Previous studies indicated that the median survival of 2nd line pancreatic cancer patients receiving 
chemotherapy is 7 months21,64. The hypothesis in this trial is that the BAT therapy as described in this 
protocol will increase the median overall survival to 10.5 months (a 50% increase). A sample size of 39 
yields 0.80 power to detect an increase in median survival of 3.5 months assuming exponentially 
distributed death times, 48 months of accrual and 18 months minimum follow up with a one-sided Type I 
error of 0.05. We plan on enrolling 10% more patients, 43 total to ensure that we obtain 39 evaluable 
patients (patients who complete all BAT infusions) at the conclusion of the trial. The 3-6 six patients in the 
phase I portion, assuming no dose limiting toxicities, will be analyzed as part of the phase II. No 
additional patients would be needed (section 4.1 Treatment Plan). 
 
12.3 Analysis 
 
Descriptive statistics (point and exact 90% confidence interval estimates from the resultant Kaplan-Meier 
curve) will be generated for the primary objective as well for the PFS endpoint in the secondary 
objectives. The median OS and PFS will be estimated on an intention-to-treat basis (using all registered 
patients), and on a response-evaluable basis (using all patients who completed all BAT infusions) using 
the Kaplan-Meier method. Toxicity rates will be estimated using all treated patients. Point and 90% 
Wilson’s confidence intervals will be estimated to describe binary endpoints including toxicity rate and 
response rates. Patients who did not have an event 18 months after the last pt was enrolled will be 
censored for the survival endpoints (date of last contact for OS and date of last evaluation for progression 
for PFS). Exploratory Cox regression analyses will be undertaken to determine if any of the clinical 
covariates measured at the beginning of the trial (e.g., age, race, group assignment) are associated with 
OS and/or PFS. 
 
12.4 Evaluation of toxicity 
All registered patients will be evaluated for toxicity probably related to the treatment. Toxicity data will be 


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30
collected at least weekly during the course of treatment. Specific toxic outcomes are detailed in section 5 
of this protocol.  
 
12.5 Other toxic outcomes 
Data on other toxic side effects (excluding those detailed in section 5.0) that patients may experience will 
also be collected. We have chosen a safety threshold of 0.25 to monitor other toxic side effects. We 
would recommend reconsidering the phase II portion of the study for safety reasons if there were X many 
occurrences of grade 3 or higher toxicity (using the CTCAE guidelines) among the first N (or fewer) 
patients treated, as it would result in an upper confidence limit greater than 0.25: 
 
N 
X 
p 
UCL 
8 
1 
0.125 
0.255 
13 
2 
0.154 
0.256 
18 
3 
0.167 
0.253 
22 
4 
0.181 
0.261 
27 
5 
0.185 
0.256 
32 
6 
0.188 
0.252 
36 
7 
0.194 
0.256 
41 
8 
0.195 
0.252 
 
In the above table, N = the number of patients treated; X = the cumulative number of patients with a 
grade 3 or higher toxicity currently observed; p = the observed toxicity rate; and UCL = the exact 1-sided 
upper 80% confidence limit for p, using Wilson's method without a continuity correction. After treating 41 
patients, the potential toxicity risk of this regimen should be well defined, and thereafter the possible need 
for termination of the study based on toxicity should be minimal. 
 
12.6 Expected accrual rate, accrual duration, and study duration 
Our anticipated accrual rate is 11 patients per year. Thus, it should take approximately 4 years to accrue 
the 43 patients needed for the trial. Allowing for 18 months of follow-up to obtain the primary endpoint on 
the last pt enrolled and 6 months to assemble, analyze and interpret the data the total study duration is 
projected to be at most 6 years.  
 
12.7 Secondary Objectives 
12.7.1: Immune Evaluations: For the quantitative immune response variables measured in this 
objective, we will produce summary statistics (including means, medians, and standard deviations) pre- 
and post-BATs treatment. Subsequent analyses will compare the immune response variables (after a 
suitable transformation, if necessary) pre- and post-treatment using a paired t-test (or Wilcoxon sign 
ranked test if the data are not approximately normally distributed).   To explore whether immune 
responses associate with clinical responses, the association between the baseline of each biomarker and 
clinical endpoints (such as response, or OS) will be analyzed using logistic regression for binary 
endpoints and Cox regression for time to event endpoints. Analyses will adjust for other covariates such 
as age and tumor stage.  No multiplicity adjustment is planned due to the nature of being exploratory. A 
two-sided p-value of < 0.05 will be considered significant. Power calculation: Given the anticipated 39 
pts enrolled on this trial. We have 80% power to detect a difference in paired mean of an immune 
response variable pre- and post- treatment of 0.46 standard deviation units using a two-sided Type I error 
rate of 0.05. The minimum detectable effect size for the logistic and Cox regression analyses will be a 
function of the response and event rates. For example, assuming an event rate of 20%, we have 80% 
power to detect a hazard ratio of 2.7 with a two-sided Type error rate of 0.05. 
 


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31
12.7.2 Paraffin Block Staining: Each biomarker and computed biomarker (e.g., Th1/Th2) will be 
evaluated for normality and transformed (including non-parametric) if necessary to achieve normality. We 
will produce summary statistics (including means, medians, and standard deviations) for each variable 
and subsequently associate each variable with OS using Cox regression. In addition, a threshold for each 
variable associating with OS will be defined using classification and regression trees.65 Power 
calculation: Assuming an event rate of 20%, we have 80% power to detect a hazard ratio of 2.7 with a 
two-sided Type error rate of 0.05 with 39 patients. 
 
 
13. HUMAN SUBJECTS 
 
13.1  Recruitment   
In address concerns related to decreased minority recruitment in local and national protocols, we 
will take specific steps to enhance the awareness in the Detroit Metro Region and the State of Michigan 
to recruit minority groups for these studies. The location of the KCI provides a unique opportunity to 
recruit African Americans to the protocol. Our previous accrual record also indicated that we have been 
successful in recruitment to this pt population and with enrollment of African Americans. 
 
 
13.2  Informed Consent  
Patients will be enrolled only after informed consent is obtained after a full explanation and 
discussion of all alternatives with the investigator/s in a consultation visit of approximately 1 hr with a 
follow up and reinforcement of the risks and benefits with the nurse coordinator. The Consent forms are 
signed in the presence of one of the investigators and/or the Immunotherapy Nurse Coordinator. No links 
to pt names will be presented. The patients are given consent forms after the consult and asked to write 
down any questions after reading the consent forms and to bring the questions to the signing meeting.  
 
13.3  Data and  Safety and Monitoring Plan 
Pt safety will be monitored by the PI and protocol data manager(s) on a monthly basis. The safety 
of protocol participants will be reviewed and adherence to stopping rules will be monitored. Adherence to 
the protocol, i.e., protocol violations, and data completeness and integrity will also be reviewed. Overall 
assessment of accrual, toxicities and responses will be done at this time to determine whether significant 
benefits or risks are occurring that would warrant study closure.  A monthly summary will be provided to 
the Karmanos Cancer Institute Data and Safety Monitoring Committee and will be reviewed quarterly. 
One month prior to anniversary date of the IRB original approval, a yearly summary report of trial 
activities will be made to all participating co-investigators and the Karmanos Cancer Institute Protocol 
Review and Monitoring Committee (PRMC). This report will include the number of patients, the number of 
patients treated, a summary of all adverse events reported to date, a specific list of serious adverse 
events requiring immediate reporting and any significant developments that may affect the safety of the 
participants or ethics of the study. 
 
13.3.1  Meetings   
Scheduled meetings will be held monthly on the activity of the protocol.  These meetings will 
include the protocol investigators, data managers, and key personnel involved with the conduct of the 
protocol. 
 
13.3.2  Evaluation   
During these meetings the investigators will discuss matters related to: 
 
• 
Safety of protocol participants (Adverse Event reporting) 
• 
Validity and integrity of the data 


Protocol version: 06/22/2015, 05/27/2016 
 
 
32
• 
Enrollment rate relative to expectation of target accrual, characteristics of the  
 
participants 
• 
Retention of participants, adherence to the protocol (potential or real protocol violations) 
• 
Data completeness on case report forms and complete source documentation 
 
13.3.3  Completed Data and Safety Monitoring  
Reports of these regular investigator meetings will be kept on file in the office of the Clinical Trials 
Core. The data manager assigned to the clinical trial will be responsible for completing the report form.  
The completed reports will be reviewed and signed off by the Principal Investigator (PI) or by one of the 
Co-PI’s in the absence of the PI.  The signed off forms will then be forwarded to the Quality Manager, 
Clinical Trials Office for review of completeness and processing with the Karmanos Cancer Institute Data 
and Safety Monitoring Committee. 
 
13.3.4  Data Safety Monitoring Committee  
The Barbara Ann KARMANOS Cancer Institute, Data and Safety Monitoring Committee will meet 
on a monthly basis to review the prior months Serious Adverse Event forms and Data and Safety 
Monitoring study specific reports that have been filed. 
 
13.3.5  Retention Of Records  
All documentation of adverse events, records of study drug receipt and dispensation, and all IRB 
correspondence will be retained for a minimum of 2 years after the investigation is completed. 
 
13.3.6 Protocol Activation   
This protocol will not be activated until the Karmanos Cancer Institute Protocol Review 
Committee, the Wayne State University IRB, and the US Food and Drug Administration have approved 
the initiation of this protocol. 
 
 


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33
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