A Phase I/II Study of Anti-CD3 x Anti-HER2/Neu (Her2Bi) Armed Activated T Cells (ATC) and Pembrolizumab Combination Therapy in Women With Metastatic Breast Cancer
Phase: PHASE1
Conditions: Metastatic Breast Cancer
Sponsor: University of Virginia

 
 
CONFIDENTIAL  
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Protocol number/short title: Breast-47:Her2-BATS and Pembrolizumab in metastatic breast cancer 
PI: Dillon, P 
Version/Date:11.1/ 12 April 2023 
 
 
 
Study Title 
A Phase I/II Study of Anti-CD3 x Anti-HER2/neu (Her2Bi) Armed 
Activated T Cells (ATC) and Pembrolizumab combination therapy in 
Women with metastatic breast cancer. 
 
 
Study Intervention 
MK-3475 (Pembrolizumab) with Her2Bi Armed Activated T Cells (ATC) 
 
 
Indication Studied 
Metastatic Breast Cancer 
 
 
Sponsor 
University of Virginia 
 
 
Principal Investigator 
 
Biostatistician 
 
Patrick Dillon, MD 
 
Qin Liu, PhD Wistar Institute, Philadelphia, PA 
 
 
Protocol Number 
Breast-47 
 
 
IND Number 
IND 9985 
 
 
Development Phase 
of Study 
Phase I/II 
 
 
GCP Statement 
This study is to be performed in full compliance with acceptable Current 
Good Clinical Practices (cGCP) and regulations. All required study 
documentation will be archived as required by regulatory authorities. 
 
 
Confidentiality 
This document is confidential and the property of the University of Virginia. 
No part of it may be transmitted, reproduced, published, or used by other 
persons without prior written authorization from the study Sponsor-
Investigator. 
 
 
 

Protocol number/short title: Breast-47: Her2-BATS and Pembrolizumab in metastatic breast cancer 
PI: Dillon, P 
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TABLE OF CONTENTS 
1.0 
SUMMARY ........................................................................................................ 5 
2.0 
OBJECTIVES .................................................................................................... 7 
2.1 
Primary objective ................................................................................. 7 
2.2 
Secondary objectives .......................................................................... 7 
3.0 
BACKGROUND & RATIONALE ....................................................................... 7 
3.1 
Background ......................................................................................... 7 
3.1.1 
Pharmaceutical and Therapeutic Background ....................................18 
3.1.2 
Preclinical and Clinical Trial Data .......................................................20 
3.1.3 
Rationale for Dose Selection/Regimen/Modification ...........................20 
3.1.4 
Phase II toxicity data for the combination of PBZ and HER2 BATs .....21 
4.0 
METHODOLOGY .............................................................................................22 
4.1 
Entry Criteria ......................................................................................22 
4.1.1 
Subject Inclusion Criteria ....................................................................22 
4.1.2 
Subject Exclusion Criteria ...................................................................23 
4.2 
Treatment Regimen ............................................................................25 
4.2.1 
Rationale for Staggered Enrollment Plan ............................................26 
4.2.2 
BATS ..................................................................................................26 
4.2.2.1 
BATS Preparation ..............................................................................26 
4.2.2.2 
BATS Infusions ...................................................................................29 
4.2.3 
Pembrolizumab ..................................................................................29 
4.2.3.1 
Investigational Product .......................................................................30 
4.2.3.2 
Packaging and Labeling Information ...................................................30 
4.2.3.3 
Clinical Supplies Disclosure ................................................................30 
4.2.3.4 
Storage and Handling Requirements ..................................................30 
4.2.3.5 
Returns and Reconciliation .................................................................30 
4.2.4 
Dose Modifications .............................................................................31 
4.2.4.1 
Dose Modification and Toxicity Management for Immune-Related 
AEs 
31 
4.2.4.2 
Other Dose Modification .....................................................................34 
4.2.5 
Trial Blinding/Masking ........................................................................34 
4.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ...........34 
4.3.1 
Acceptable Concomitant Medications .................................................35 
4.3.2 
Prohibited Concomitant Medications ..................................................35 
4.4 
Rescue Medications & Supportive Care .............................................36 
4.4.1 
Supportive Care Guidelines ................................................................36 
4.5 
Diet/Activity/Other Considerations ......................................................41 
4.5.1 
Diet .....................................................................................................41 
4.5.2 
Contraception .....................................................................................41 

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4.5.3 
Use in Pregnancy ...............................................................................43 
4.5.4 
Use in Nursing Women .......................................................................43 
4.5.5 
Duration of Treatment .........................................................................43 
4.5.6 
Discontinuation/Withdrawal from Study ..............................................44 
4.5.7 
Subject Status Definitions ...................................................................44 
4.6 
Clinical Criteria for Early Trial Termination ..........................................45 
5.0 
TRIAL FLOW CHART ......................................................................................46 
5.1 
Study Flow Chart ................................................................................46 
6.0 
TRIAL PROCEDURES .....................................................................................49 
6.1 
Trial Procedures .................................................................................49 
6.1.1 
Administrative Procedures ..................................................................49 
6.1.1.1 
Informed Consent ...............................................................................49 
6.1.1.2 
Inclusion/Exclusion Criteria .................................................................49 
6.2 
Registration ........................................................................................49 
6.2.1.1 
Medical History ...................................................................................49 
6.2.2 
Clinical Procedures/Assessments .......................................................50 
6.2.2.1 
Adverse Event (AE) Monitoring ..........................................................50 
6.2.2.2 
Full Physical Exam .............................................................................50 
6.2.2.3 
Performance Scale .............................................................................50 
6.2.2.4 
Tumor Imaging and Assessment of Disease.......................................50 
6.2.3 
Laboratory Procedures/Assessments .................................................52 
6.2.4 
Immune Evaluations ...........................................................................54 
6.2.5 
Visit Requirements .............................................................................54 
6.2.5.1 
Screening ...........................................................................................54 
6.2.5.2 
Treatment Period ................................................................................54 
6.2.5.3 
Post-Treatment Visits .........................................................................54 
6.3 
Assessing and Recording Adverse Events .........................................55 
6.3.1 
Assessment of Adverse Events ..........................................................56 
6.3.1.1 
Adverse Event Definition ....................................................................56 
6.3.1.2 
Secondary Adverse Events ................................................................57 
6.3.1.3 
Preexisting Medical Conditions ...........................................................57 
6.3.1.4 
Expectedness .....................................................................................57 
6.3.1.5 
Severity ..............................................................................................57 
6.3.1.6 
Attribution ...........................................................................................58 
6.3.1.7 
Seriousness........................................................................................58 
6.3.1.8 
Abnormal Laboratory Values / Clinical Assessments ..........................59 
6.3.1.9 
Death .................................................................................................60 
6.3.2 
Reporting of Adverse Events to Merck................................................60 
6.3.2.1 
Reporting of Serious Adverse Events to Merck ...................................60 

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6.3.2.2 
Reporting of Overdose to Merck .........................................................61 
6.3.2.3 
Reporting of Pregnancy and Lactation to Merck .................................61 
6.3.2.4 
Reporting of Events of Clinical Interest to Merck ................................62 
6.3.2.5 
Protocol-Specific Exceptions to Serious Adverse Event Reporting to 
Merck 
62 
6.3.3 
UVA Cancer Center DSMC Reporting Requirements .........................63 
6.3.4 
IRB Reporting Requirements ..............................................................63 
6.3.5 
Reporting to the FDA ..........................................................................65 
6.3.6 
Data Safety Monitoring Plan ...............................................................65 
6.3.6.1 
UVA Cancer Center Data Safety Monitoring Committee .....................65 
7.0 
EVALUATION CRITERIA ................................................................................68 
7.1 
Dose Limiting Toxicity .........................................................................68 
7.2 
Response Criteria ...............................................................................68 
7.3 
Other Measures of Effect ....................................................................69 
7.3.1 
Progression-free survival ....................................................................69 
7.3.2 
Overall survival ...................................................................................69 
7.3.3 
Objective response rate (ORR) ..........................................................69 
7.3.4 
Duration of response (DoR) ................................................................69 
7.3.5 
Disease control rate (DCR) .................................................................69 
7.3.6 
Immune Evaluations ...........................................................................69 
7.4 
Toxicity and Safety .............................................................................69 
8.0 
STATISTICAL ANALYSIS PLAN .....................................................................70 
8.1 
Design ................................................................................................70 
8.2 
Sample Size and Accrual....................................................................71 
8.3 
Populations and Analysis Plans ..........................................................71 
8.3.1 
Outcomes ...........................................................................................71 
9.0 
ADMINISTRATIVE AND REGULATORY DETAILS .........................................72 
9.1 
Institutional Review Board (IRB) Approval and Consent .....................72 
9.2 
Adherence to the Protocol ..................................................................72 
9.2.1 
Emergency Modifications....................................................................72 
9.2.2 
Other Protocol Deviations/Violations ..................................................73 
9.3 
Record Retention ...............................................................................73 
9.4 
Obligations of Investigators ................................................................74 
10.0 
REFERENCES. ................................................................................................74 
11.0 
APPENDICES ..................................................................................................79 
11.1 
Appendix 1: Suggested Supportive Care Guidelines for BATs 
Infusions and Example Discharge Instruction Document .....................................................79 
 
 
 
 

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1.0 SUMMARY 
Non-toxic approaches are needed to improve progression free survival (PFS) and overall 
survival (OS) in all patients (pts) who have metastatic breast cancer (MBC). In our previous 
clinical trials, anti-CD3 activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific 
antibody (HER2Bi) traffic to tumors, exhibit anti-HER2 cytotoxicity, proliferate, and secrete 
immunokines upon tumor engagement (1). 
This proposal uses HER2Bi armed ATCs (HER2 BATs) to target breast cancer in 
combination with pembrolizumab (PBZ) in women with MBC. Women with MBC who have 
failed two or more lines of therapy are eligible regardless of their HER2 or hormonal status. 
The strategy of this protocol is to increase functional T cell activity at the tumor site and 
increase local and systemic anti-tumor responses. Combining BATs with a checkpoint 
inhibitor by blocking PD-1 signaling is likely to enhance anti-breast cancer immune 
responses more than BATs or PBZ alone. We hypothesize that multiple IV infusions of 
HER2 BATs in combination with PBZ will be safe without producing intolerable toxicity, 
infiltrate metastatic lesions, lyse tumor, and induce a "vaccine" response and that 
immunotherapy (IT) mediated anti-tumor “immunization” will induce both functional and 
phenotypic immune changes detectable in the blood that translate into improved total 
toxicity profile (TTP) and overall survival (OS) for subjects with advanced MBC.  
The primary objective is to conduct a phase I/II clinical trial in women with MBC to estimate 
the safety and maximum tolerated dose (MTD) of BATs in combination with PBZ. The 
secondary objectives are to estimate the safety of the MTD, preliminarily estimate objective 
response rate (ORR), duration of response (DoR), and disease control rate (DCR), to 
assess OS and progression-free survival (PFS), to establish a dose-expansion cohort 
(DEC), and to evaluate immune responses. Immune responses will be tested to determine if 
phenotype and function of peripheral blood mononuclear cells (PBMC) and cytokine profiles 
are altered from baseline in various schedules for the combination of BATs and PBZ.  
The study design assesses safety and immune responses to PBZ administered in 
combination with BATS infusions (~1010/infusion ± 20%), as follows: 
 
 
 
 
 
 

Protocol number/short title: Breast-47: Her2-BATS and Pembrolizumab in metastatic breast cancer 
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Figure 1 
 

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2.0 OBJECTIVES 
2.1 
Primary objective 
[1]  To determine the MTD for BATs combined with PBZ in subjects with MBC. 
2.2 
Secondary objectives  
[1]  To estimate the safety of the MTD for BATs combined with PBZ in subjects with 
MBC. 
[2]  To evaluate immune responses in MBC subjects by sequential monitoring of 
phenotype, IFN-γ EliSpots, anti-breast cancer cytotoxicity of peripheral blood 
mononuclear cells (PBMC) directed at breast cancer cell lines, Th1/Th2 serum 
cytokine patterns, and anti-breast cancer antibodies in the serum during the 
“vaccinate and consolidate” process. 
[3]  To obtain a preliminary estimate of the objective response rate (ORR), duration 
of response (DoR), and disease control rate (DCR) in subjects treated at the MTD 
for BATs combined with PBZ. 
[4]  To establish a dose-expansion cohort (DEC) of an additional 12 subjects to further 
evaluate the safety and preliminary efficacy (PFS and OS). 
3.0 BACKGROUND & RATIONALE 
3.1 
Background 
Unmet Need for Treatment of Breast Cancer Metastases. Metastatic Breast Cancer 
represents a significant clinical challenge. About 20-85% of the patients who present with 
localized breast cancers will progress to MBC in 5 years and approximately 6-10% of the 
patients present with metastatic disease de novo.  Depending on the stage at which 
metastasis is detected the median survival is in the range of 18-24 months(2).   Both 
chemotherapy and hormonal therapy have been used to treat MBC with different levels of 
success.  Most patients experience objective responses associated with palliation of 
symptoms (3-5), but complete responses (CR) are uncommon and short-lived.  Initial 
responses may last between 8 and 14 months (6-8), however, progression of disease is 
inevitable, and durable responses to subsequent therapies are progressively fewer.  For the 
20-25% of women with MBC who are HER2/neu (HER2) overexpressed, Herceptin®, 
pertuzumab, lapatinib and ado-trastuzumab have become mainstays of treatment in 
combination with chemotherapy.  New treatment strategies, however, are needed to prolong 
progression-free and overall survival in the 75-80% of the MBC patients who are HER2 
normal (not over-expressed) and thus, not eligible for the FDA approved HER2 targeted 
therapies.  In our phase I clinical trial, we have administered anti-CD3 activated T cells 
(ATC) armed with anti-CD3 x anti-HER2/neu bispecific antibody (HER2Bi) to women with 

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both HER2-positive and HER2-negative MBC to determine their safety and the MTD.  
Arming ATC with HER2Bi makes every T cell into a HER2-specific cytotoxic T lymphocyte 
(CTL) with the potential to induce high levels of specific cytotoxicity that is independent of 
HER2 receptor-mediated mechanisms and thus, HER2 expression levels (9).  Indeed, 
evaluation of immune responses in our phase I clinical trial subjects suggests that infusions 
of HER2 BATs induce robust immune responses regardless of the subject’s HER2 status.  
Consistent with this observation, log rank analyses comparing Kaplan-Meier estimates of 
PFS and OS between HER2(3+) subjects (n =7) and HER2(0-2+) subjects (n = 7) enrolled 
in the phase I trial found no significant difference between the stratified groups. In the 
HER2(3+) group, median overall survival was 21 months, but did not differ significantly (p = 
0.98) from the OS curve of the HER2(0-2+) group for which median OS remained undefined 
(> 50% of subjects still survive) strongly suggesting that HER2 BATs may prolong survival 
independent of HER2 status.  From a mechanistic standpoint, this is not surprising.  For 
example, unlike monoclonal antibody therapy with Herceptin®, which induces cellular death 
through interference with receptor-mediated pathways and is thus, more effective in cells 
heavily reliant on those signaling pathways, low levels of receptors may be sufficient to 
redirect enough BATs to induce T cell mediated mechanisms of cellular death.  A subset of 
clinical situations thus exists where tumors of MBC subjects with low level HER2 
expression/amplification—a characteristic that would preclude therapy with Herceptin®—
may still possess enhanced susceptibility to the directed cytotoxicity of HER2 BATs. 
Additional clinical data is available from larger studies to further support the use of HER2 
targeted therapies in breast cancer patients deemed HER2 normal by ASCO CAP 
guidelines (10, 11).  In summary, Chumsri et al report mutations in breast cancer subjects 
responsive to trastuzumab in the absence of HER2 amplification.   Additionally, 
Koumarianou et al describe a study of 130 subjects deemed HER2 normal who achieve 
benefit from HER2 targeting with Herceptin®.  Recently, Brunello et al showed that subsets 
of triple negative breast cancer subjects derive benefit from HER2 targeted therapies(12). 
Intriguingly, even some subjects deemed HER2 negative by radiolabeled HER2 PET 
imaging, achieved responses to ado-trastuzumab in the Zephir study by Gephir et al (13).  
Older reports of trastuzumab responses in IHC intermediate subjects are well known in the 
breast cancer community (14). 
Role of Immune Checkpoint Inhibitors: Experimental and clinical evidence strongly 
suggests that cancer cannot develop or progress without escaping immune surveillance(15); 
the PD-1 immune checkpoint pathway is one mechanism tumors use to escape detection. 
PD-1 (programmed cell death protein-1) is a receptor expressed by T cells upon activation. 
PD-1 induction on activated T cells occurs in response to PD-L1 or L2 engagement and 
limits effector T-cell activity in peripheral tissues. Such interaction limits normal tissue 
damage (16), and can be hijacked by cancers to limit anti-tumor immune response (17). The 
relevance of the PD-1 signaling pathway in limiting anti-tumor immune responses is 
suggested by the observation of higher levels of PD-1 on tumor infiltrating lymphocytes 
(TILs) compared to circulating cells(18). In addition, animal studies show that tumors 

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expressing PD-L1 have increased resistance to T cell immune responses and are more 
invasive. Inhibiting the PD-1/PD-L1 interaction can reverse resistance to anti-tumor T cell 
response and shrink tumors (19). Both nivolumab and PBZ have been approved by the FDA 
for malignant melanoma. Recently, the data in previously untreated advanced NSCLC has 
also been encouraging(20). All enrolled subjects had to have PD-L1 (≥ 1% staining) positive 
cancers. Of the 73 pts screened for the trial, 78% had PD-L1 positive tumors. The overall 
response rate in these subjects was 26% and the disease control rate was 64%. The 
median duration of response was not reached and 100% of the responders continued to 
have disease response at the time of reporting. Data with PBZ suggests that tumor PD-L1 
expression may predict for higher probability of clinical benefit, though clinical benefits were 
also observed in subjects with PD-L1 negative tumors (20).  
MK-3475 (PBZ)] in Breast Cancer. Drugs targeting either PD-1 or PD-L1 have shown 
promising rates of clinical benefit. PBZ is a humanized high affinity IgG4 PD-1 blocking 
antibody designed to directly block the interaction between PD-1 and PD-L1 and PD-L2 
(21). Blockade enhances the functional activity of the target lymphocytes to facilitate tumor 
regression and ultimately immune rejection. In a recent phase Ib trial for metastatic triple 
negative breast cancer (TNBC) reported at the San Antonio Breast Cancer (SABCS) 
meeting on December 10, 2014 by Dr. Rita Nanda, safety, tolerability, and anti-tumor activity 
was evaluated in bi-weekly infusions of MK-3475 in 27 subjects (29-79 years old) who had 
relapsed after treatment of early stage breast cancer or had progressed with advanced 
disease (22). All subjects had tumors that expressed high levels of PD-L1.  There was 1 
clinical response, 4 partial responders, 6 with stable disease, and 12 with progressive 
disease. In those with measurable disease, 5 (18.5%) had encouraging results. Additional 
clinical evidence of PBZ activity in breast cancer was presented at SABCS 2015 (abstract 
S5-07) by Hope Rugo from the Keynote-28 trial.  That trial used PBZ in pretreated 
metastatic ER+ subjects with >1% PD-L1 positivity on tumor or stroma.  An overall response 
rate of 12% and a clinical benefit rate of 20% was observed in breast cancer subjects.   
Further proof of principle comes from positive responses observed with alternative PD-1 and 
PD-L1 agents. For example, Avelumab monotherapy in metastatic breast cancer yielded an 
8.6% partial response rate and a 31% disease control rate (abstract S1-07).  Likewise a trial 
of atezolizumab and nab-paclitaxel observed an overall response rate of 89% in nine first-
line metastatic subjects and an overall response rate of 42% in all 24 metastatic subjects 
(first through third line) (abstract 850477). Toxicities in all four of these highlighted 
checkpoint inhibitor studies have been tolerable and no treatment-related deaths in breast 
cancer subjects have been reported. 
There is strong interest in combining immune check point inhibitors with active 
immunotherapy strategies such as vaccines and T cell therapy. Our group has already 
developed HER2 BATs and conducted clinical trials showing that infusion of HER2 BATs is 
both safe and feasible. We propose to evaluate a novel strategy of combining immune 
checkpoint PD-1 inhibitor, PBZ with BATs (BATs+PBZ). This study will assess the 
feasibility and preliminary efficacy of this novel therapy in subjects with MBC. 

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MK-3475 (PBZ) in ER+ and HER2+ breast cancer.  In regard to the use of Pembrolizumab 
in ER+ and HER2+ patients, a goal of this project is to uncover a method to render 
immunologically silent tumors such as ER+ breast cancer, to be immunologically 
recognizable.  Employing armed T cells (BATS) and a checkpoint inhibitor seeks to address 
this highly valuable goal in breast cancer.  We have already shown an example of an ER 
positive/HER2 negative patient with a partial response to BATS alone (figure 5d).  Activity of 
PD-1 inhibitors in ER positive metastatic breast cancer was reported in the two following 
abstracts:     
a. Rugo HS, Delord J-P, Im S-A, et al. Preliminary efficacy and safety of 
pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-
positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. 
Presented at: 2015 San Antonio Breast Cancer Symposium; December 8-12, 2015; 
San Antonio, TX. Abstract S5-07.  
b. Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-
L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 
Ib JAVELIN solid tumor trial. Presented at: 2015 San Antonio Breast Cancer 
Symposium; December 8-12, 2015; San Antonio, TX. Abstract S1-04. 
In the Rugo KEYNOTE-28 study, there have been 3 PR’s and 4 SD subjects reported out of 
25 evaluable subjects to date, We propose and hypothesize that BATS may synergize with 
PD-1 inhibitors to improve response rates in ER positive and negative populations and in 
HER2 amplified populations. If preferential response is observed in a subset of subjects, 
then a future trial will focus on efficacy in that subpopulation. 
BATs.  HER2 BATs mediate high levels 
of cytotoxicity directed at both low and 
high HER2-expressing breast cancer cell 
lines (23). BATs showed repeated killing, 
proliferation, and release of Th1 
cytokines, RANTES and MIP-1, 
interferon-γ (IFN-γ), tumor necrosis 
factor-α (TNF-α),and granulocyte-
macrophage colony stimulating factor 
(GM-CSF) that induce DC maturation. 
Dying tumor cells release tumor 
associated antigens (TAA), and lead to 
increased cross-presentation of TAA by 
antigen presenting cells. This 
mechanism, illustrated in Fig 1, may 
vaccinate subjects against their own 
tumor antigens. In preclinical studies, we showed that intravenous infusions of HER2 BATs 
inhibited the growth of established HER2+ PC-3 tumors in SCID/Beige mice significantly 
more than ATC alone (p<0.001) and prevented tumor development in co-injection WINN 
assays (24, 25). Furthermore, arming ATC with HER2Bi makes every T cell into a non-MHC 
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 TAA. 

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restricted HER2-specific cytotoxic T lymphocyte (CTL)(23). Trastuzumab’s clinical effect 
requires high levels of HER2 expression whereas low levels or nil expression of HER2 
receptors is sufficient to allow targeting by potent granzyme/perforin non-MHC restricted 
killing mediated by BATs. This ability to target low level HER2 or negative expressing tumors 
provides a unique opportunity to target MBC in subjects with HER2 0-2+ disease. More 
recently, the expression of HER2 receptors on breast cancer stem cells provides another 
explanation of why targeting HER2 negative tumors could lead to extended median OS in 
HER2 negative subjects (26, 27).  
Phase I and II clinical trials(28-31); a total of 320 x 109 cells were infused in 4 to 8 
divided doses without finding a maximum tolerated dose (MTD). There were no dose 
limiting toxicities (DLTs). No one needed ICU care or blood pressure or ventilator support in 
contrast to those who received BiAb infusions alone for solid tumors.  Furthermore, we 
showed that ATC armed with CD20Bi are not only highly effective at lysing CD20 resistant 
targets but also secrete Th1 cytokines such as IFN-γ upon contact with CD20+ malignant B 
cells (32). In our phase I clinical trials in 12 non-Hodgkin's lymphoma subjects with high risk 
or resistant NHL, multiple infusions of CD20 BATs following high dose chemotherapy (HDC) 
and autologous stem cell transplant (SCT) induce significantly higher levels of anti-
lymphoma activity in the peripheral blood after multiple infusions of CD20 BATs following 
HDC and autologous SCT than subjects undergoing SCT alone (33). Multiple infusions of 
HER2 BATs in phase I clinical trials have been shown to be safe in subjects with breast 
cancer with some promising anti-tumor activity and OS (34). In addition, targeted T cells 
were detected in the blood of these subjects for at least 1 week after infusions, serum 
cytokine profile shifted to Th1, and immune monitoring studies demonstrated evidence of 
highly cytotoxic fresh endogenous peripheral blood mononuclear cells (PBMC) that killed 
breast cancer cells (34, 35). Chemical heteroconjugation of BiAbs was quick, inexpensive 
and straightforward, enabling rapid large scale current good manufacturing practice (cGMP) 
production of clinical grade BiAbs. Anti-HER2, anti-EGFR, anti-GD2, and anti-CD20 
strategies have been translated into clinical phase I studies (28, 30).  
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(36-39).The tumoricidal cytokines produced include 
interferon-γ(IFNγ), tumor necrosis factor-α(TNFα),and GM-CSF(40-42). In animals, infusions 
of ATC provide anti-tumor effects (43-46) and improve engraftment when limiting doses of 
stem cells were given after lethal total body irradiation (47). In humans, a phase I trial 
treating non-Hodgkin’s lymphoma subjects with cyclophosphamide before infusing activated 
CD4+ cells resulted in one complete, 2 partial and 8 minor responses in 31 subjects with 
advanced cancers (48, 49). Our earlier clinical trials showed that even unarmed ATC with 
low dose IL-2, and GM-CSF in subjects with MBC following HDC and SCT were well 
tolerated and clinically effective even without retargeting them to cancer cells (31). If 
nonspecific T cells have enhanced cancer-directed activity after chemotherapy, BATs may 
have even greater anti-tumor activity. 

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HER2 BATs target high (SK-BR-3) and low (SUM 1315) HER2 cell lines.  In our 
preclinical studies, we showed that HER2 
BATs were able to lyse breast cancer cell 
lines that expressed not only high 
amounts of HER2 (SK-BR-3, high 3+ 
expression) but more importantly target 
and lyse lines that express little (MCF-7, 
a negative control for 
immunohistochemistry)(50) or essentially 
no HER2 expression (SUM1315). SUM 
1315 is known to be negative for HER2 
by Western blotting (Fig. 2a) and flow 
cytometry (Fig. 2b). Fig. 2c shows 
specific cytotoxicity of HER2 BATs 
directed at SUM 1315 and SK-BR-3. 
Flow cytometry showed that SUM 1315 
cells had a very low mean fluorescent 
intensity (MFI) and only 6.7% were 
positive. These results are consistent 
with the Western blot (Fig. 2a).   Goat 
anti-HER2/neu was used to detect 
HER2/neu receptors on SUM 1315 and 
SK-BR-3 cells. Fig. 2c shows that BATs exhibit high levels of cytotoxicity directed at SUM 
1315 cells. It is clear that only a few molecules of HER2/neu on their surface are sufficient to 
allow binding and triggering of specific cytotoxicity.  This is consistent with the observation 
that as few as 10-30 TCR-ligand interactions are sufficient to mediate T cell killing (51). 
These data and our clinical and immunologic data on subjects treated with HER2 BATs who 
were HER2-negative in our phase I/II clinical trials provide the rationale to target tumors that 
may have low or variable antigen expression.  
Fig. 2: Cytotoxicity remains high in very low HER2/neu 
expressing SUM 1315 cells. a) Western blot shows very 
low (SUM 1315) and high (SK-BR-3) HER2/neu expression; 
b) Flow cytometry shows surface expression of HER2/neu 
on 6.7% of SUM 1315 with very low mean fluorescent 
intensity (MFI) and 95.1% of SK-BR-3 with a high MFI; and 
c) Cytotoxicity remained high in the very low expressing 
HER2/neu SUM 1315 cell line. 

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BATs inhibit differentiation of myeloid derived suppressor cells (MDSC) and Tregs. In a 
3D matrigel model, co-culture of PBMC with tumor 
spheres showed increased proportions of tumor induced 
MDSC (CD33+/CD11b+/HLA-DR-) and Treg 
(CD4+/CD25hi/CD127lo) populations. Comparison of 
tumor sphere killing and MDSC and Treg populations in 
culture conditions with or without BATs showed a 
significantly higher killing of tumor spheres (p<0.0001) 
and reduced percentage of MDSC (p<0.0005) and Treg 
(p<0.028) populations in BATs containing co-cultures 
compared to control culture conditions without BATs 
(Fig. 3). In addition to decreased proportions of MDSC, 
we have shown that BATs induced a shift in the 
STAT3/STAT1 ratio. In the presence of BATs, tumor 
derived immune suppressive STAT3 activation 
decreased significantly while immune activating STAT1 expression and activation increased 
significantly. These data suggest that targeted immunotherapy with BATs directed at tumor 
targets not only kills tumor spheres but also reduces MDSC and Treg populations as part of 
the targeting response.  
BATs induce cytokines and chemokines that inhibit MDSC differentiation and 
activation. We recently reported that in Th1 cytokine enriched microenvironment, IFN-γ 
induced chemokines, MIG/CXCL9 and IP-10/CXCL10, were upregulated while IL-1β and IL-
6 were down regulated with concomitant reduction in the percentage of MDSC (Fig. 4) in a 
3D co-culture model. Similarly, levels of 
IFN- γ, IL-2, IL-2R and IL-12p41/71 
were significantly higher in culture 
supernatants from BATs containing co-
cultures compared to control condition 
without BATs. High levels of IFN- γ, IL-
2, IL-12p41/71, CXCL9, CXCL10, 
upregulation of STAT1 and 
downregulation of STAT3 are likely to 
activate anergic immune cells in the 
tumor microenvironment and 
corroborate with reduced number of 
MDSC. These data suggest that BATs 
inhibited differentiation of MDSC and 
Tregs through cytokines/chemokines.  
Phase I study of HER2 BATs in subjects with metastatic breast cancer (MBC) 
Fig 3. Right panel shows the BATs 
mediated cytotoxicity against MB-231 
tumor spheres in 3D culture. Left panel 
shows significantly reduced granulocytic 
and monocytic MDSC populations in the 
presence of BATs. 
Fig 4. Cytokine profile of culture supernatants detected by 
multiplex luminex system show the increased levels of cytokines 
IL-12, TNF-α and IFN-γ inducible chemokines MIG/CXCL9 and 
IP-10/CXCL10 in the presence of BATs (aATC) compared to 
control condition (without BATs). While levels of immune 
suppressive cytokines IL-6 and IL-1β were reduced in the 
presence of BATs vs. control.  
 

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Targeting of MBC with HER2 BATs. In a phase I trial, 8 infusions of HER2 BATs were given 
twice per week for 4 weeks with low-dose IL-2 (300,000 IU/m2/day) and GM-CSF (250 
μg/m2/dose given twice weekly) in a standard 3+3 dose escalation schema with 5, 10, 20, and 
40 × 109 BATs per dose for total doses 
of 40, 80, 160, and 320 × 109 BATs. 
Up to 320 × 109 HER2 BATs were 
frozen and infused into women with 
MBC without DLTs(16). However, the 
dose of 320 × 109 was not consistently 
achievable due to technical feasibility. 
These women were heavily pretreated 
and all but one of the HER2 3+ 
subjects 
had 
received 
prior 
Herceptin®. PBMC exhibited high 
levels of cytotoxicity directed at a 
HER2+ MBC cell line (SK-BR-3) that 
persisted up to 4 months (35) and 
there were significant increases in 
serum Th1 cytokines (Fig. 5a) and IL-
12 (Fig. 5b)(31, 34) during and after 
infusions. The marked increases in 
serum IL-12 (not produced by T cells) 
show that endogenous monocytes 
activated by BATs infusions secreted 
high levels of IL-12. The Kaplan-Meier 
(K-M) showed that OS was 36.2 
months for the entire group, 57.4 
months for the HER2 3+ group, and 
27.4 months for the HER2-negative 
group (Fig. 5c). Of 22 evaluable 
subjects, one had very good partial response (Fig. 5d) with nearly all of the liver metastases 
responding, and 12 subjects had stable disease at 15 weeks after initiation of immunotherapy. 
There was a reduction in CEA (3 of 5), CA 27.29 (2 of 4), and HER2 serum receptor (2 of 5) 
levels. 
Very good partial response in HER2-negative subject. A partial responder in the HER2-
negative group had two well-defined liver metastases on a PET/CT (2.5 × 1.7 cm and 2.5 × 
1.3 cm) as shown in Fig. 5d (left panel). This subject was ER positive. Re-imaging after 
immunotherapy showed regression of the multiple lesions after 6 months (Fig. 5d, right 
panel). The sum of longest diameters was decreased by 30% at 4 weeks after 
immunotherapy and was decreased by >70% at 6 months. The subject was progressing on 
Femara and was restarted on Femara after immunotherapy. 
Fig. 5: 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 57.4 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-negative partial responder showing 2 liver mets pre-
immunotherapy  (left) PET/CT which disappeared post-immunotherapy  
(right).  
0
10
20
30
40
50
60
70
80
90 100
0
20
40
60
80
100
120
Her2 -ve
Her2 3+
All
Months
Percent survival
c 

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Clinical toxicities of BATs. The most frequent manageable clinical toxicities were fever, 
chills, transient hypotension, headaches, and fatigue. Fever, chills, and hypotension were 
preempted with pre-
hydration and pre-
medication with 
diphenhydramine and 
acetaminophen. No 
MBC subject required 
ICU admission for 
cardiorespiratory 
support. There was 
one death due to a 
toxic level of digoxin 
and one subject 
developed a subdural 
hematoma due to hypertension associated with GM-CSF and T cells. The subdural 
hematoma was successfully evacuated without any complications. 
Evidence for activation and immunization of endogenous immune cells in MBC 
subjects. PBMC exhibited high levels of cytotoxicity directed at SK-BR-3 that persisted up 
to 4 months. Fig 6 shows specific cytotoxicity mediated by endogenous lymphocytes 
(IgG2a-negative population) directed against SK-BR-3 in two representative subjects. PBMC 
from these subjects were depleted of IgG2a+ bearing cells (BATs) 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.  
No Human Anti-Mouse Antibody (HAMA) responses. Because anti-CD3 mAb moiety 
comprising the BiAb is a murine IgG2a mAb, we evaluated subjects’ sera before and after 
HER2 BATs infusions for the development of HAMA to IgG2a in an ELISA. Of the 10 
subjects evaluated, none developed clinically significant HAMA levels (>10 ng/ml) during or 
immediately after the treatment regimen.  
Pilot study: Vaccination with HER2 BATs infusions and boost after SCT with 
"immune" ATC. In 5 of 7 evaluable subjects 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 (see 
below), a second leukapheresis was performed to obtain "anti-breast cancer immune" 
PBMC. ATC were produced and cryopreserved for multiple infusions (4-15 infusions) after 
HDC and SCT to create immunologic space. A third leukapheresis was performed after G-
Fig 6: Pheresis, BATs, unarmed ATC and IgG2a- populations were tested for 
specific cytotoxicity directed at SK-BR-3. Specific cytotoxicity (E/T = 10:1) was 
performed in 51Cr assays. IgG2a+ were depleted using Miltenyl beads. The clear bars 
show cytotoxicity directed at SK-BR-3 targets and the solid bars show cytotoxicity 
directed at Raji targets. 
BATs 
BATs 

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CSF stimulation to obtain the stem cells for SCT. Two of 7 subjects 
had rapidly progressing disease and were not evaluable. Three 
subjects received 3 infusions of 5 × 109 twice per week for 3 weeks 
and 1 infusion of 5 × 109 per week for 6 weeks post-SCT. After 
moving the protocol to KCI, 2 subjects received 1 infusion up to 40 
× 109 cells per week for 4 weeks. Figure 7a shows that fresh 
PBMC mediated high levels of anti-breast cancer cytotoxicity in 5 
women pre-, during (mid-immunotherapy), post-immunotherapy , 
pre-SCT (post-immunotherapy), and at various time points after 
SCT (1 month, 2 months, 3 months, 6 months, 1-2 years). When 
fresh PBMC from 2 pts were stimulated with SK-BR-3 targeted T 
cells and using a new assay for inducing anti-breast cancer 
antibodies in vitro(52), the 14-day B cell cultures secreted anti-SK-
BR-3 antibodies. Figure 7b shows amounts of anti-SK-BR-3 
antibody produced in vitro detected by whole cell ELISA in four 
subjects at the same time points. The ability of PBMC to produce 
antibodies directed at SK-BR-3 in vitro is confirmed by the 
presence of IgG anti-SK-BR-3 antibodies (levels ranging from 10 
ng to 200 ng/ml) in all 5 subjects more than 1 year post-SCT (data 
not shown).These results show that the PBMC contained memory 
B cells that produce anti-breast cancer antibodies in vitro.  This 
proof-of-concept pilot study shows that both cellular and humoral 
anti-tumor immune responses can be easily detected during 
immunotherapy and these immune responses can be transferred 
via the "immune" ATC and detected after SCT. Two out of the 5 women remain alive at 
2,664 and 1,302 days from their original enrollment data prior to receiving BATs in the 
phase I trial. These results strongly suggest that BATs provided a survival benefit and may 
have induced a vaccination response.  
Phase I Clinical Trial in Stage II/III, HER2 0-3+ High 
Risk Breast Cancer Subjects (> 4+ Nodes): In our phase 
I clinical trial, women with locally advanced breast cancer 
were infused with HER2 BATs in combination with IL-2 
and GM-CSF after Texel, Adriamycin, and Cytoxan. Seven 
of 9 subjects were 0-2+ HER2 and 2 of 9 had 3+ HER2 
expression. The median OS remains undefined with 
survival ranging from 14.2 to 136.3 months (Fig 8).  Five of 
9 subjects are alive, 4 out of the 5 subjects have no 
evidence of disease and 1 subject relapsed at 91.8 
months. There were no DLTs. These clinical responses 
suggest that BATs infusions in the adjuvant setting may 
have been exceptionally efficacious.  
Fig 7: a) Multiple infusions of ATC after SCT 
promoted the development of cytotoxicity 
that 
could 
be 
detected 
during 
immunotherapy (Mid IT) and at 2-4 weeks 
post immunotherapy (Post IT), and 1 mo 
(1M), 2 mos (2M),  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 subjects had been 
immunized against her own tumor antigens 
by multiple infusions of BATs that can be 
transferred in ATC product after SCT. 
a 
b 
Fig 8 The K-M curve for phase I clinical trial 
in high risk subjects treated with adjuvant 
chemotherapy 
and 
HER2Bi-BATs 
infusions. 

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Summary of clinical trials using BiAb BATs (BATs). Our clinical trials show that: 1) large 
numbers of ATC can be expanded in vitro, armed with HER2Bi for breast cancer or CD20Bi 
for NHL and infused safely without DLTs(16, 33); 2) BATs can be detected by simple flow 
cytometry in vivo and are found to circulate up to 5 weeks (1-2%) after the last infusion 
without IL-2 infusions (data not shown)(31, 33); 3) most of the time, the targeted total 
infusion doses have been achieved without difficulty; no HAMA responses inhibited T cell 
infusions; 4) BATs can target and kill even low antigen-expressing tumors; and 5) BATs 
infusions induced the development of cytotoxic endogenous immune cells that could be 
detected in MBC subjects (34) as well as in subjects who received CD20 BATs after 
SCT(33); and 6) multiple infusions of BATs can induce robust cellular and humoral 
responses that can be collected, expanded, and used to boost anti-tumor responses after 
HDC and SCT. 
Immune Check Point Inhibitors enhance EGFR BATs function. Our group has 
demonstrated that combining ipilimumab, an immune checkpoint inhibitor, with BATs can 
enhance the anti-tumor activity of BATs. In PBMC from healthy individuals, the addition of 
ipilimumab at the initiation of culture significantly enhanced T cell proliferation (p = 0.0029). 
Fig 9a shows the dose titration effect 
on cytotoxicity in the presence or 
absence of EGFR BATs (Armed ATC- 
aATC in the figure) and Fig 9b shows 
increased killing by normal EGFR 
BATs in the presence or absence of 
ipilmumab at an E:T of 25:1 for 
COLO356/FG. Fig 9c shows the 
same experiments for 3 colorectal 
subjects. BATs infusions increased 
the secretion of chemokines CCL2, 
CCL3, CCL4, CCL5, CXCL9, and 
GM-CSF [data not shown]. Fig 10 
Fig 10 
Fig 9c 
Fig 9b 
Fig 9a 

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shows that higher doses of 
ipilimumab in the presence 
of EGFR BATs increase 
IFN-γ, IL-2R, IL-12, and IL-
10 secretion, while reducing 
IL-10 secretion.(53)  
Induction of Serum IL-2 
and GM-CSF Levels after 2 
Weeks or 4 Infusions of 
BATs.  
The serum concentration of 
IL-2 
and 
GM-CSF 
were 
determined 
for 
several 
reasons. First, we asked 
whether we could detect the 
IL-2 and GM-CSF that was 
being given 
to 
subjects.  
Second, 
we 
wanted 
to 
assess the levels of IL-2 and 
GM-CSF 
that 
would 
be 
induced by multiple infusions 
of BATs in subjects with MBC.  The mean levels of IL-2 (upper panels) and GM-CSF (lower 
panels) markedly increased by the 4th or 5th infusion (Fig 11).  Low levels of IL-2 (<100 pg/ml) 
were detected until the 5th infusion and low levels of GM-CSF were detected up until the 4th 
infusion.  The left panels show that a subset of Her2/neu 0-2+ subjects have similar response 
patterns to the entire group of subjects (0-3+ group in the right panels.  The IL-2 data show 
that there is no increase or accumulation of the injected IL-2 up until the 3rd infusion (nearly 2 
weeks of IL-2 injections).  Similarly, there is no increase in serum GM-CSF until after the 3rd 
infusion (2 weeks after the twice weekly GM-CSF shots began).  These data suggest that 
infusions of BATs in combination with low dose IL-2 and GM-CSF induce systemic immune 
responses.  But it remains unclear whether IL-2 and GM-CSF were required to induce the 
observed responses.  Our recent studies using anti-CD3 x anti-EGFR BiAb armed T cells 
(EGFR BATs) in 5 subjects with unresectable or metastatic pancreatic cancer showed that 
once weekly infusions of EGFR BATs was enough to induce a minor response that lasted 6.5 
months with the median overall survival of 29.4 months.  Furthermore, two subjects developed 
complete responses of their disease after they received subsequent chemotherapy after they 
were treated for progressive disease following their immunotherapy (SITC Abstract, Lum et 
al, 2016).  Based on this observation, we elected to not add low dose IL-2 and GM-CSF to the 
combination of BATS and Pembrolizumab (PBZ) (MK-3475). 
3.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
Fig 11: Serum IL-2 and GM-CSF Levels. The mean is indicated ± S.D. Serial serum 
samples collected at the indicated time points were quantitated with the BioPlex.  

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effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from, that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, 
most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed 
on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific 
T-cell expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the 
United States for the treatment of patients with unresectable or metastatic melanoma and 

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disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
3.1.2 Preclinical and Clinical Trial Data 
Refer to the most recent Investigator’s Brochure for PBZ for a review of the current 
preclinical and clinical data. In the phase Ib KEYNOTE-012 Study, MK-3475 was used to 
treat triple negative breast cancer (TNBC), gastric cancer, urothelial cancer, and head and 
neck cancer subjects IV at 10 mg/kg every 2 weeks in subjects with PD-L1+ tumors by 
immunohistochemistry.  The report focused on the TNBC subjects. There were 27 evaluable 
subjects for anti-tumor activity with an overall response rate of 18.5%.  The time to response 
was 17.9 weeks (range 7.3 -32.4 weeks) with a median duration of response ≥47.3 weeks 
(R. Nanda, JCO 34;2460). Rugo et al reported the preliminary efficacy and safety of MK-
3475 for PKD-L1-positive estrogen receptor-positive (ER+)/HER2-negative advanced breast 
cancer enrolled in KEYNOTE-028 (SABCS S5-07, 2015). 
3.1.3 Rationale for Dose Selection/Regimen/Modification  
The planned dose of pembrolizumab for this study is 200 mg every 3-4 weeks for Arm 3 
(less frequent for other arms).  As pembrolizumab is being combined with an investigational 
treatment (HER2 BATs) in this study, pembrolizumab will not be given at a fixed q3 week 
frequency. Initially (to the first group of patients), one dose of pembrolizumab will be given 
only after HER2 BATs is completed. Based on safety, an additional dose will be added 
about halfway through BATs treatment and, if that is deemed safe, a dose will also be given 
prior to starting BATs infusions.  Based on the totality of data generated in the Keytruda 
development program, 200 mg Q3W is the appropriate dose of pembrolizumab for adults 
across all indications and regardless of tumor type.  As outlined below, this dose is justified 
by: 
• 
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg  Q2W, representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2) 
• 
Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the distributions 
of exposures, supporting suitability of 200 mg Q3W 
• 
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg Q3W.  

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3.1.4 Phase II toxicity data for the combination of PBZ and HER2 BATs  
In a  phase II study in 
metastatic castrate-resistant 
prostate 
cancer 
(mCRPC) 
patients, 8 infusions of Her2 
BATs (up to 1010/infusion) are 
being given twice per week for 
4 weeks in combination with 
anti-PD-1 
therapy 
with 
pembrolizumab given once 
every 3 weeks starting 3 
weeks before the 1st BATs 
infusion. 
 
The 
primary 
objective is to assess the 
percentage of patients free of 
clinical 
progression 
at 
6 
months after registration. We 
hypothesized that infusions of 
Her2 
BATs 
will 
induce 
measurable 
immunologic 
changes and evidence of 
clinical efficacy, and that 
blocking PD-1 signaling will enhance the T cell mediated killing. The objective is to estimate 
the magnitude of change in anti-PC immune functions and markers, after infusions of Her2 
BATs in mCRPC and to evaluate the magnitude of increase in tumor infiltrating T cells, PD-1 
expression and the Th1/Th2 ratio in prostate cancer tumor tissue before and after 
immunotherapy.  The clinical toxicities in the first 9 patients is summarized in the table below.  
The toxicities observed were not different than reported in the phase I for hormone-refractory 
prostate cancer (HRPC) by Vaishampayan et al (54)and Lum et al (16).  
 
 
Number of 
Subjects 
(%) of 
Subjects 
Total 
Adverse 
Events 
Grade 
1 
Grade 
2 
Grade 
3 
Subjects with 
AEs 
55.6 
16 
 
 
 
Chills 
44.4 
2 
1 
1 
 
Fatigue 
22.2 
2 
2 
 
 
Fever 
22.2 
2 
2 
 
 
Infusion 
reaction 
22.2 
1 
1 
 
 
Headache 
44.4 
4 
4 
 
 
Nausea 
22.2 
2 
2 
 
 
Heartburn 
11.1 
1 
1 
 
 
Immune 
system other 
11.1 
1 
 
 
1 
Hypertension 
11.1 
1 
 
 
1 
Fig 12.  Schema for Treatment of mCRPC, phase II.   

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4.0 METHODOLOGY 
4.1 
Entry Criteria 
4.1.1 Subject Inclusion Criteria 
[1]  Histologically confirmed breast cancer (infiltrating ductal or lobular breast carcinoma) 
with evidence of measurable metastatic disease. Metastatic disease must be biopsy 
proven. 
a. Since histologic type, lymphatic permeation, blood vessel invasion, and 
degree of anaplasia may be prognostic variables, appropriate slides of the 
primary lesion will be requested for future review. HER2, estrogen, and 
progesterone receptor positivity will be recorded. 
[2]  Measurable lesion. Patients are required to have at least one measurable non-bone 
lesion ≥10 mm that has not been irradiated. 
a. Measurable metastatic disease documented by radiograph, CT scan, 
PET/CT, MRI, or physical exam is required. Each subject will be required to 
have at least one measurable lesion that has not been irradiated with a 
minimum size in at least one diameter of ≥ 10 mm for liver lesions, lung, skin, 
and ≥ 15 mm lymph node metastases. Biopsy of recurrent site(s) is not 
required.   
[3]  Patients must have HER2 status determined by CISH, FISH or IHC. HER2 status of 
positive or negative are both eligible for the study. 
In order to be eligible for participation in this trial, the patient must also: 
[4]  Be female ≥ 18 years of age  
[5]  Be willing and able to provide written informed consent for the trial. 
[6]  Have a performance status (PS) ECOG 0-1 
[7]  Have a life expectancy ≥ 3 months 
[8]  Demonstrate adequate organ function as defined in Table 1, all screening labs in the 
table should be performed within 10 days prior to on-study date.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute lymphocyte count  
≥ 500/mm3 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥ 100,000 / mcL 
Note: If there is an absence of other medical conditions 
related 
to 
thrombocytopenia 
that 
would 
preclude 
participation in the protocol as determined by the treating 
investigator, the platelet requirement is ≥ 75,000 / mcL 
 
Hemoglobin 
≥ 9 g/dL (or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment) 

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Renal 
 
Serum creatinine OR 
≤1.5 X upper limit of normal (ULN) OR 
Measured or calculated creatinine 
clearance1 
(GFR can also be used in place of 
creatinine or CrCl) 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR ≤ 5 X ULN for subjects with liver 
metastases  
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
 
 
1 Creatinine clearance should be calculated per institutional standard. 
 
[9]  Female patients of childbearing potential should have a negative pregnancy test 
within 10 days prior to on-study date.  If a urine or serum test is positive or cannot be 
confirmed as negative, the other (urine or serum pregnancy test, whichever was not 
performed first) will be required.   
[10]  Female patients of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Section 4.5.2, for the course of the study 
through 120 days after the last dose of study medication. 
[11]  Patients must have had two or more lines of prior therapy (chemo or hormonal) in 
the metastatic setting 
4.1.2 Subject Exclusion Criteria 
The patient must be excluded from participating in the trial if the subject: 
• 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to on-study date. 
• 
Has a known history of active TB   (Bacillus Tuberculosis) 
• 
Hypersensitivity to PBZ or any of its excipients. 
• 
Lack of recovery (i.e., ≤ Grade 1 or baseline prior to last line of cancer therapy) from 
non-laboratory adverse events except ≤ Grade 2 neuropathy  

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• 
Has history of another malignancy within the past 5 years.  Exceptions include basal 
cell carcinoma of the skin or squamous cell carcinoma of the skin that has 
undergone potentially curative therapy or in situ cervical cancer. 
• 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to on-study date and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to leukapheresis.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.   
• 
Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
• 
Has a known history of (non-infectious) pneumonitis/interstitial lung disease that 
required steroids or has current pneumonitis/interstitial lung disease. 
• 
Has an active infection requiring systemic therapy. 
• 
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
• 
Is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 
days after the last dose of trial treatment. 
• 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
• 
Has Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or known history of 
Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (HCV) antibody is detected. Note: 
Patients may be eligible if HCV antibody is detected as long as HCV viral load is 
undetectable following an FDA approved treatment regimen.  
• 
Has received a live vaccine or live-attenuated vaccine within 30 days prior to on-
study date. Administration of killed vaccines is allowed. 

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Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
• 
Has a history of significant cardiac disease, including: 
- 
History of a recent myocardial infarction (within one year), a past myocardial 
infarction (more than one year ago) along with current coronary symptoms 
requiring medications and/or evidence of depressed left ventricular function 
(LVEF < 45% by MUGA or ECHO).  
- 
Current history of angina/coronary symptoms requiring medications and/or 
evidence of depressed left ventricular function (LVEF < 45% by MUGA or 
ECHO) 
- 
Clinical evidence of congestive heart failure requiring medical management 
(irrespective of ECHO results). 
• 
Pt may be excluded if, in the opinion of the PI and investigator team, the pt is not 
capable of being compliant. 
 
4.2 
Treatment Regimen 
The administration of BATS and PBZ will be increased in a standard 3 + 3 dose 
escalation/dose de-escalation approach, starting with schedule #1. This approach combines 
8 infusions of BATs (~1010/infusion ± 20%) and one to three infusions of PBZ using a 
previously established schedule of BATs (1 x 1010 per infusion) and PBZ (200 mg). PBZ will 
be added to 8 infusions of BATs in 3 schedules: #1) after the 8th BATs infusion; #2) after the 
4th and 8th BATs infusions; and then, #3) before the 1st and after the 4th and 8th BATs 
infusions. Once the maximum tolerated dose is reached, there will be a dose expansion 
cohort (DEC) of 12 evaluable subjects using the MTD to confirm the toxicity profile and 
estimate TTP, PFS, and OS.  
According to standard 3 + 3 dose escalation/dose de-escalation rule, if there are 2 or more 
DLTs at Schedule #1, the study will be closed. If there are no dose limiting toxicities (DLTs) 
in the first 3 subjects (0/3) or at maximum 1 subject with DLT out of 6 subjects (1/6) with 
treatment of Schedule #1, we will advance to Schedule #2. If there are 0/3 or 1/6 DLTs at 
Schedule #2, we will advance to Schedule #3. If there are no more than 1/6 DLTs, Schedule 
#3 will be used as the MTD in this study. Otherwise, Schedule #2 will be used as the MTD if 
no more than 1 out of 6 patients at Schedule #2 have DLTs. This design will require a 
minimum of 3 and a maximum of 18 evaluable patients to identify the MTD. To take the 
eligible but not evaluable patients into account (estimated at 10%), the following plan is 
considered. Among 18 eligible patients, if the true unevaluable rate is 10%, 2 unevaluable 

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patients are expected. Since the probability of 4 unevaluable patients out of 18 eligible 
patients is 7% and the null hypothesis that the unevaluable rate is 10% can’t be rejected at a 
one-sided type I error rate of 2.5%, a maximum of 4 unevaluable patients will be accepted. 
Thus, a maximum of 22 eligible patients may be recruited and among them 4 unevaluable 
patients will be allowed. Note that patients that are enrolled but do not receive any BATs 
infusions will not be included in this maximum. Similar consideration is taken for a DEC of 12 
patients at the MTD. Among the 12 eligible patients in the DEC, a maximum of 3 
unevaluable patients will be accepted considering that the probability of 3 unevaluable 
patients out of 12 eligible patients is 8.5%, which cannot reject the null hypothesis that the 
unevaluable rate is 10% at a one-sided type I error rate of 2.5%. Thus, a total of 15 eligible 
patients may be recruited in the DEC. As in the dose escalation phase, these maximums do 
not include patients that enroll but do not receive any BATs infusions.   
This treatment regimen is illustrated in Figure 1. 
4.2.1 Rationale for Staggered Enrollment Plan 
In the original version of this protocol, a staggered enrollment was based on the historical 
information from the phase I studies using HER2 BATs wherein the acute toxicities are mostly 
resolved in 2-3 days and the side effects of PBZ are usually resolved before the next infusion 
3 weeks after the first PBZ dose.  In an ongoing phase II clinical trial in patients with hormone 
refractory prostate cancer (HRPC) [Personal communication Vaishampayan and Lum], PBZ 
and HER2 BATs with the same doses and schedule have been given to 9 patients on schedule 
#3 planned for this protocol without any dose limiting toxicities.  Therefore, staggered 
enrollment is no longer required for this protocol.    
 
4.2.2 BATS  
4.2.2.1 BATS Preparation 
Apheresis will be performed according to UVA standards.  The apheresis procedure may be 
repeated (once) if adequate and viable cells are not available or cannot be used for other 
reasons from the first apheresis procedure.  
Exclusions for apheresis related to past treatment prior to apheresis. Participants must not 
undergo apheresis if any of the following apply: 
• 
Current or recent (within 4 weeks prior to apheresis) use of an investigational agent or 
investigational device. 
• 
Current or recent (within 14 days prior to apheresis) use of an anti-cancer monoclonal 
antibody (mAb) except denosumab (Xgeva)  
• 
Current or recent (within 14 days prior to apheresis) chemotherapy, targeted small 
molecule therapy, hormonal therapy, radiation therapy to the axial skeleton, 
monoclonal antibody therapy, or radiation therapy  

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- 
Note: If the participant was receiving hormonal therapy prior to study therapy, 
it may be restarted after the restaging scan 1 month after the 8th BATs 
infusion. 
Leukapheresis Procedure.  Reported toxicity from leukapheresis is minimal. Subjects have 
a small potential for infection, bleeding, and bruising from the placement of peripheral or 
central catheters used for leukapheresis. Use of the anticoagulant citrate dextrose may cause 
symptoms of mild hypocalcemia, which are controlled with calcium replacement. Peripheral 
IV catheters will be used for leukapheresis. If the apheresis nurses cannot obtain adequate 
venous access by pre-assess, the subject will be scheduled to have a central venous catheter 
placed by interventional radiology. The risks for central venous catheter placement include 
pain, blood loss, infection, pneumo/hemothorax (rare), cardiac arrest (extremely rare), and 
death (extremely rare). A large bore groin catheter may be placed for apheresis instead of a 
central catheter. Unless AEs lead to failure of lymphocyte collection or meet the criteria for a 
serious adverse event, they will not be reported.   
 
Production of BATs.  BATs are prepared in the UVa cGMP facility.  Immediately after 
leukapheresis, the lymphocytes are activated with soluble monoclonal anti-CD3 antibody 
(OKT3), which cross-links the CD3 receptors on T cells and activates them.  The ATC are 
expanded in the presence of IL-2 for up to 14 days.  After culture, ATC are harvested, armed 
with OKT3 x Herceptin® (HER2Bi), washed to remove unbound HER2Bi,  and 
cryopreserved in 10% dimethyl sulfoxide (DMSO) and 20% protein (human albumin or 
serum) using rate controlled freezing and storage in liquid nitrogen.  No exogenous IL-2, 
OKT3, or other culture reagents (e.g. medium components) are present in the final 
cryopreserved product.  Armed product is released for clinical use after Quality Control 
testing for sterility (bacterial and fungal culture, endotoxin and mycoplasma), phenotype (% 
of CD3 cells), and activity (i.e. cytolytic activity against the SKBR-3 cell line or equivalent).  
OKT3. This is a murine IgG2a monoclonal antibody directed at human CD3 commercially 
available from Miltenyi Biotec, Auburn, CA.  It is purchased in vials containing 1 mg/1 ml of 
reconstituted bacteriostatic water.  OKT3 is used to activate T cells for growth and for 
heteroconjugation with Herceptin® to produce the HER2Bi bispecific antibody for arming 
subject ATC. 
Anti-HER2/neu monoclonal antibody (Herceptin®, Trastuzumab; Genentech, Inc., CA).  
Herceptin is a humanized murine monoclonal antibody directed at HER2/neu, and is 
commercially available in multi-dose vials containing 440 mg of drug.  For this study, 
Herceptin® is heteroconjugated to OKT3 to produce the HER2Bi bispecific antibody for 
arming subject ATC.  
Anti-CD3 (OKT3) x anti-HER2/neu heteroconjugated bispecific monoclonal antibody 
(HER2Bi).  Anti-CD3 x anti-HER2 is produced under GMP conditions. IND #9985 was 
cleared for clinical trials by the FDA that specifies the production of bispecific antibody, 
sterility testing, and the standard operation procedures for arming of activated T cells.  The 

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HER2Bi has been retested for targeting and cytotoxicity and shown to be stable for over 3 
years stored at 4oC. 
Facility.  Qualified personnel who are familiar with procedures which minimize undue 
exposure to themselves and to the environment will undertake the preparation, 
handling, and safe disposal of immunotherapeutic agents in a self-contained protective 
environment. Cells will be generated in the UVA cGMP Facility under FDA #BB-IND 
9985 with standard operating procedures (SOPs) for producing HER2Bi and growing, 
splitting, harvesting, arming of ATC, and cryopreservation of BATs. 
Activation, Culture, and Freezing of BATs.  Lymphocytes are obtained by 
leukapheresis and cultured at a density of 1-3 × 106 cells/ml in RPMI 1640 media 
(Lonza) containing 100 IU/ml of IL-2 (Novartis), 10-20 ng/ml of OKT3, and 2% human 
serum (Valley Biomedical or Hyclone).  Cells will be cultured for a maximum of 14 days 
in medium to which no additional OKT3 will be added during the expansion period. 
Preparation of anti-CD3 x anti-HER2 (HER2Bi) Bispecific Antibody.  The specific 
details for the production, purification, and quality control testing are part of IND #9985. 
Arming of ATC with HER2Bi.  The harvested ATC will be counted and a dose of 50 ng 
of HER2Bi per million ATC will be added to the solution and incubated for 1 hr at 4oC.  
The BATs will be washed, counted, and resuspended in the final solution that will be 
cryopreserved in aliquots specific for each infusion. 
Cytotoxicity Assay and IFNγ EliSpots.  Cytotoxicity is measured in a 20 hr 51Cr -
release assay to ensure activity (minimum ≥ 10% cytotoxicity) of BATs over their 
unarmed counterparts.  Tumor target 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.  These wells containing tumor cells will be washed and armed or unarmed ATC 
will be added at different E:T ratios for 20 hr incubation at 37oC.  The next day, the 
supernatants harvested from the microtiter wells will be counted and the percent 
specific lysis will be calculated.  IFNγ EliSpots will be performed by plating SK-BR-3 
targets. 
Quality Assurance of BATs 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. Several separate cryovials of HER2Bi armed ATC will be frozen 
at the time of harvesting and cryopreservation of the armed cells for the future QC testing. 
Release criteria for armed products for clinical use include: negative results for anaerobic and 
aerobic bacterial cultures, fungal cultures, negative mycoplasma and endotoxin assays 
(endotoxin < 2.5 EU/mL, otherwise a calculated infusion rate will be used to ensure the subject 
received no more than 5 EU/kg/hr), and ≥10% cytotoxicity directed at HER2 target cells (25:1 

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E/T). Phenotyping of the product will be recorded. The preferred criteria for ATC are >50% 
CD3+ cells, <10% for CD19, CD20, CD16, and CD56+ cells. The product can still be used at 
the discretion of the investigator if some of the phenotyping criteria are not met. 
4.2.2.2 BATS Infusions 
Toxicity associated with BATs has been minimal. The reported symptoms have been 
reversible with cessation of therapy. Most subjects treated with BATs experienced no major 
side effects during infusions. Fever and chills were the most common reported reactions 
Other rarely reported effects included mild gastrointestinal and neurologic symptoms. 
Toxicity associated with reinfusion of cryopreserved cells may be partially attributable to the 
DMSO preservative. The BATs have been documented to cause fever, chills, nausea, 
vomiting, headache, hypotension, hypertension, and fatigue. See section 4.2.4 for dose 
limiting toxicities and Appendix for Supportive Care Guidelines for BATs infusions  
4.2.2.2.1 Bispecific Antibody Armed Activated T-Cells (BATs) Infusion Instructions 
BATs infusions will be done in the outpatient clinic infusion center (infusions may be 
performed within the UVA hospital or within the clinical research unit as long as appropriate 
code cart is available). All appropriate assurances for identification of product, subject, 
sterility, etc., will be performed prior to infusion according to the SOPs for the BATs IND.  
Frozen BATs will be thawed at the bedside of the subject just prior to infusion. If there is 
evidence of infusion-related toxicities, subsequent BATs will be thawed, washed, and 
resuspended in medium prior to infusion. BATs will be infused intravenously (IV) at a rate 
based on the endotoxin content of the product through a central venous access catheter (to 
minimize the risk of clotting). All subjects will be observed for at least 6 hours after each 
infusion. If stable, subjects will be discharged home with detailed instructions regarding 
when and how to contact the study team (see Appendix for an example) under the care of 
his/her caregiver. If the subject’s home is more than 40 minutes away from UVA hospital, the 
subject will be instructed to stay locally with his/her caregiver for at least two nights following 
each BATs infusion. If the subject is asymptomatic after staying two nights within 40 minutes’ 
drive of UVA, the subject may resume travel as usual.  
Via connection to central venous access catheter, (CVC) infuse 500 ml of 0.9% NaCl over 1 
hour prior to BATs infusion.  Infusion rate for BATs will be subject specific.  Flush CVC line 
with 100ml 0.9% NaCl following BATs infusion then run 0.9% NaCl at 200 ml/hr x 4 hrs. 
Have emergency medications available for every BATs infusion (use institutional order set). 
Notify treating MD if systolic BP is ≥ 160 or if diastolic is ≥ 90 prior to starting infusion. Hold 
infusion and confirm with Dr. Lum's staff that the infusion will be delayed. 
4.2.3 Pembrolizumab 
PBZ 200 mg will be administered as a 30 minute IV infusion at the times indicated by their 
assigned schedule. Every effort should be made to target infusion timing to be as close to 30 

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minutes as possible.  However, given the variability of infusion pumps, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
4.2.3.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 4. 
Table 4  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
4.2.3.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
4.2.3.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-
Investigator and/or designee are not blinded to treatment. Drug identity (name, strength) is 
included in the label text; random code/disclosure envelopes or lists are not provided. 
4.2.3.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. The PBZ obtained from Merck will be stored in the 
investigational pharmacy at the University of Virginia Emily Couric Clinical Cancer Center.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
4.2.3.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 

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proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal 
are kept. 
4.2.4 Dose Modifications 
If there are delays for the administration of BATs or PBZ, the schedules for administration of 
both BATs and PBZ will be delayed. 
4.2.4.1 Dose Modification and Toxicity Management for Immune-Related AEs 
There is no dose reduction allowed on the protocol. Adverse events (both non-serious 
and serious) associated with PBZ or BATs exposure may represent an immunologic 
etiology.  These adverse events may occur shortly after the first dose or several months 
after the last dose of treatment. Study treatment must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per the table below. See section 4.4.1 for supportive 
care guidelines, including use of corticosteroids and stopping guidelines, monitoring and 
follow-up for infusion reactions. In addition, the drugs can be held for any grade of toxicity by 
the treating physician if it is felt that it is the best interest of the subject.  
Attribution of Toxicity: When study interventions are administered in combination, 
attribution of an adverse event to a single component is likely to be difficult.  Therefore, while 
the investigator may attribute a toxicity event to pembrolizumab alone, to BATs alone, or to 
the combination, for adverse events listed in the table below, both interventions must be held 
according to the criteria in the table. 
Holding Study Interventions: When study interventions are administered in combination, if 
the AE is considered immune-related, both interventions should be held according to 
recommended dose modifications. 
Restarting Study Interventions: 
Participants may or may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab or BATs in this study, as described in the table. 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions. 
If the toxicities do resolve and conditions are aligned with what is defined in the table, the 
combination of BATs and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to BATs 
alone, re-initiation of pembrolizumab as a monotherapy may be considered at the principal 
investigator’s discretion. 
General instructions: 
1. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 
weeks. This criterion may also be met if the toxicity resolves to pre-study baseline grade (if 
toxicity was present at baseline). 

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2. For situations where study intervention has been withheld, study intervention may resume 
after the irAE decreased to ≤ Grade 1 (or baseline, as described above) after corticosteroid 
taper.  
3. Study intervention must be permanently discontinued if the irAE does not resolve within 12 
weeks of last dose or corticosteroid dose is not ≤10 mg prednisone or equivalent per day 
within 12 weeks of the last study treatment.  
4. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral 
steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids. 
Table 5: Dose Modification Guidelines for Immune Related Adverse Events 
Immune-
related 
AEs 
Toxicity 
grade or 
conditions 
(CTCAE v4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumoni
tis  
Grade 2 
Withhold  
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
• Add prophylactic antibiotics 
for opportunistic infections 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
• 
Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis.  
• 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation 
or 
Increased 
bilirubin 
Grade 2a 
Withhold 
• Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
• 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable 
Grade 3b or 4c  
Permanently 
discontinue 
• Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 

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Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyc
emia 
 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of β-cell failure 
Withholdd 
• Initiate insulin replacement 
therapy for participants 
with T1DM  
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
• 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysi
tis 
Grade 2 
Withhold 
• 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.   
 
• 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinued  
Hyperthyr
oidism  
Grade 2 
Continue  
• Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate  
• 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinued 
Hypothyro
idism 
Grade 2-4 
Continue  
• 
Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per standard 
of care 
• 
Monitor for signs and symptoms 
of thyroid disorders.  
 
Nephritis  
grading 
according 
to 
increased 
creatinine 
or acute 
kidney 
injury 
Grade 2 
Withhold  
• 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurologi
cal 
toxicities 
Grade 2 
Withhold  
• 
Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditi
s 
Grade 1  
Withhold 
• 
Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 2, 3 or 
4 
Permanently 
discontinue 
Exfoliative 
Dermatolo
gic 
Condition
s 
Suspected 
SJS, TEN or 
DRESS 
Withhold 
• 
Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
• 
 
Confirmed 
SJS, TEN or 
DRESS 
Permanently 
discontinue 
All other 
immune-
related 
AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• 
Based on type and 
severity of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of evente.   

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Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
AE=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a. 
AST/ALT >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin >1.5 to 3.0 x ULN 
if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b. 
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x 
ULN if baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c. 
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
e. 
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs. (eg. 
vasculitis and sclerosing cholangitis). 
  
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
subject vacation, and/or holidays). Subjects should be placed back on study therapy within 3 
weeks of the scheduled interruption, unless otherwise discussed with the Sponsor-
Investigator. The reason for interruption should be documented in the subject's study record. 
With investigator and Principal Investigator agreement, subjects with a laboratory adverse 
event still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic 
and controlled. Subjects who experience a recurrence of the same severe or life-threatening 
event at the same grade or greater with re-challenge of PBZ should be discontinued from 
trial treatment. 
4.2.4.2 Other Dose Modification 
If there is grade 3 toxicity at any time, HER2BATs treatment will be held until toxicity 
improves to grade 0 or baseline. The treating physician may decide not to proceed with the 
next infusion for any grade of toxicity if it is deemed appropriate for the subject’s overall 
clinical care. 
4.2.5 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor-Investigator, investigator and subject will 
know the treatment administered. 
4.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in section 4.3.2 are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.   The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. However, the decision to 

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continue the subject on trial therapy requires the mutual agreement of the Investigator and 
the subject.  
4.3.1 Acceptable Concomitant Medications 
Subjects 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.  Subjects will receive calcium replacement during the 
pheresis procedure, if needed for symptoms of hypocalcemia. 
Subjects will be routinely pre-medicated before BATs infusion with diphenhydramine 50 mg 
IV or PO or per MD discretion and acetaminophen, 650 mg PO 20-60 minutes prior to 
infusion of cryopreserved BATS, to prevent fever, chills, and pain. The subject will alternate 
ibuprofen 600 mg every 8 hours with acetaminophen 650 mg every 8 hours for 24 hours 
after the BATs infusion.  
If the participant was receiving hormonal therapy prior to study therapy, it may be restarted 
after the restaging scan 1 month after the 8th BATs infusion. 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  This includes antineoplastic systemic chemotherapy or biological therapy 
(except immunotherapy) after apheresis through 1 week prior to first study treatment (BATs 
infusion or pembrolizumab). All concomitant medication including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids should be noted in the 
medical record. 
Concomitant medications should be monitored regularly during the study according to 
standard clinical care and to confirm that no prohibited concomitant medications are used. 
Concomitant medications do not need to be recorded or reported for research unless they 
relate to reporting for an SAE or an ECI.  
4.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy may not be administered 
prior to apheresis and from 1 week prior to first study treatment (BATs infusion or 
pembrolizumab) through 1 week following last BATs infusion 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents not specified in this protocol 
• 
Radiation therapy  

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o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are 
live attenuated vaccines, and are not allowed. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids (e.g. equivalent to or less than oral prednisone 10 mg daily) 
is allowed. 
• 
Subjects CAN continue on bone modifying agents such as zolendronic acid or 
densumomab if deemed necessary by the treating physician.  
• 
Subjects with HER2+ breast cancer should not be receiving an anti-HER2 drug while 
receiving combination treatment with BATS and PBZ. Anti-HER2 treatment should 
be discontinued at least 14 days prior to the first BATS infusion.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.4 
Rescue Medications & Supportive Care 
4.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Guidelines for supportive care for BATs infusions are included in the 
Appendix. 
• 
Ancillary therapy:   
Subjects 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 subjects will stop hormonal 

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therapy 2 weeks prior to on-study date.  Hydrocortisone (50-100 mg IV every 6 hours +/- 
30 minutes) for severe adverse reactions related to BATs infusions is allowed. 
Suggested supportive care measures for the management of immune-related adverse 
events at least possibly related to study treatment are outlined below. Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to PBZ. 
Supportive care guidelines for events determined to be related to HER2 BATs may be found 
in the Appendix. 
Note: if after the evaluation the event is determined not to be immune-related, the 
investigator does not need to follow the treatment guidance (as outlined below). Refer to 
section 4.2.4 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
• 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids (1-2 mg/kg/day of 
prednisone or equivalent).  Higher doses of steroids may be used if deemed 
clinically indicated.  
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Evaluate participants with suspected pneumonitis with radiographic imaging 
and initiate corticosteroid treatment. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 

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electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis:  In subjects with moderate enterocolitis (Grade 
2), BATs infusion or PBZ should be withheld and anti-diarrheal treatment 
should be started.  If symptoms are persistent for more than one week, 
systemic corticosteroids should be initiated (0.5 mg/kg/day of prednisone or 
equivalent).   
o For Grade 3 or 4 diarrhea/colitis:  In subjects with severe enterocolitis 
(Grade 3 or greater), BATS infusion or PBZ will be permanently discontinued 
and treatment with systemic corticosteroids should be initiated at a dose of 1 
to 2 mg/kg/day of prednisone or equivalent.  If the treating physician believes 
that the subject is deriving clinical benefit from the study drug, then the 
treating physician after consultation with the Principal Investigator may 
discuss with the subject regarding continuing protocol related therapy.  
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) 
or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) or evidence of β-cell failure 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 
Administer anti-hyperglycemic in participants with hyperglycemia 
 
Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less (or 
baseline if existing prior to study entry), steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  

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Thyroid disorders can occur at any time during treatment. Consider monitoring 
subjects for changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less (or 
baseline if existing prior to study entry), steroid taper should be 
started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly or more frequently) or baseline, if existing 
prior to study entry. 
o Treat with IV or oral corticosteroids (0.5-1 mg/kg/day of prednisone or 
equivalent).   
o For Grade 3-4 events, treat with intravenous corticosteroids (1-2 mg/kg for 24 
to 48 hours.  
o When symptoms improve to Grade 1 or less (or baseline, if existing prior to 
study entry), a steroid taper should be started and continued over no less 
than 4 weeks. 
• 
Renal Failure or Nephritis: 
o For Grade 2-4 events, treat with corticosteroids (1-2 mg/kg/day of prednisone 
or equivalent).   
o When symptoms improve to Grade 1 or less (or baseline, if existing prior to 
study entry), steroid taper should be started and continued over no less than 
4 weeks.  
o Monitor changes in renal function 
• 
Nausea/vomiting:  
Nausea and vomiting should be treated aggressively, and consideration should be 
given in subsequent cycles to the administration of prophylactic antiemetic therapy 

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according to standard institutional practice.  Subjects should be strongly encouraged 
to maintain liberal oral fluid intake. 
• 
Infection:  
Subjects with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional 
practice. 
• 
Management of Infusion Reactions:  
Acute infusion reactions (which can include cytokine release syndrome, angioedema, 
or anaphylaxis) are different from allergic/hypersensitive reactions, although some of 
the manifestations are common to both AEs.  Signs and symptoms usually develop 
during or shortly after drug infusion and generally resolve completely within 24 hours 
of completion of infusion. Signs/symptoms may include: Allergic 
reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); Bronchospasm; 
Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, 
malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); Nausea; 
Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); 
Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
Table 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of PBZ (MK-3475). 
Table 6: Infusion Reaction Treatment Guidelines for PBZ 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of PBZ (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 

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Table 6: Infusion Reaction Treatment Guidelines for PBZ 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment that led to this 
toxicity.  
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
4.5 
Diet/Activity/Other Considerations 
4.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.5.2 Contraception 
PBZ and/or BATs may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if PBZ and/or BATs have transient adverse effects on the composition of sperm.   
Female subjects will be considered of non-reproductive potential if meets one of the below 
criteria:  
(1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 

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replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female subjects of reproductive potential must agree to avoid becoming pregnant while 
receiving study drug and for 120 days after the last dose of study drug by complying with 
one of the following:   
(1) practice abstinence† from heterosexual activity;  
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are**: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.  
**If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites 
in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 

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days after the last dose of PBZ.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
4.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study treatment, the subject will 
immediately discontinue the study treatment.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor-Investigator and 
to Merck without delay and within 24 hours to the Sponsor-Investigator and within 2 working 
days to Merck if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to Merck.    
4.5.4 Use in Nursing Women 
It is unknown whether PBZ is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible. 
4.5.5 Duration of Treatment 
Subjects will continue to receive study treatment (defined as BATS in combination with PBZ) 
until: 
• 
Subject has completed all protocol specific treatments  
• 
Confirmed disease progression (per irRECIST)** 
• 
Unacceptable adverse event(s)  
• 
Subject withdraws consent for further treatment 
• 
Female subject has a confirmed positive serum pregnancy test 
• 
Subject is determined to not be eligible for apheresis as required by the study, as 
determined by the Stem Cell Transplant Team  
• 
Subject’s cells do not grow adequately (to the assigned dose level) during activation 
and arming process or cannot be used for other reasons (e.g., viability, 
contamination or bag breakage in the freezer). As indicated in section 4.2.2.1, 
apheresis may be repeated (once) if adequate and viable cells are not available from 
the first apheresis procedure. 
• 
Subject receives a non-study treatment (not protocol-specified) for their cancer 
• 
Subject non-compliance 
• 
General or specific changes in the subject’s condition render the subject 
unacceptable for further treatment in the judgment of the investigator 

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** Subjects do not have to be discontinued from treatment for pseudoprogression (flare). 
Progression occurring within the first 12 weeks of treatment must be confirmed by repeat 
cross sectional imaging within 4 weeks as per irRECIST. 
If any of the above events occurs, the subject will be considered off treatment and in follow-
up. Subjects that do not receive any doses of BATs will not be in follow-up, but will only be 
followed for safety as described in section 6.3. Subjects that discontinue prior to receiving all 
scheduled doses of BATs and/or PBZ may continue to participate in the remaining aspects 
of the study (tissue samples, immune studies, follow-up, etc.) and will be included in the 
intent to treat analysis. A subject who is withdrawn or discontinues from the study after 
receiving at least 2 BATs infusions is considered a discontinuation and will not be replaced.     
4.5.6 Discontinuation/Withdrawal from Study 
Subjects may withdraw or be discontinued from the study at any time for any of the following 
reasons: 
• 
Subject decides to withdraw from the study 
• 
Subject is unable or unwilling to complete the follow-up procedures 
• 
The subject is lost to follow-up 
• 
Death 
All subjects that discontinue or withdraw from the study will continue to receive standard of 
care treatment. Subjects who have withdrawn consent for the study will not be followed for 
any reason.   
4.5.7 Subject Status Definitions 
Enrolled: All subjects who sign an informed consent will be considered enrolled on the 
study. All subjects consented to the study must be entered into OnCore. 
Screen Failure: A subject who is withdrawn or discontinues from study screening prior to 
being determined eligible is considered a screen failure. Screen failures are not considered 
a study accrual and will be replaced. Note: The UVa IRB-HSR defines any individual that 
has signed an informed consent as an enrollment in this study and so screen failures should 
be reported to the IRB with enrollment numbers. 
On-Study: A subject is considered on-study on the date when the study team has confirmed 
the subject has met all of the inclusion and none of the exclusion criteria, and the treating 
physician/surgeon or study PI has signed off on the confirmation. 
On-Treatment: A subject is considered on-treatment on the date that they receive the first 
treatment of either BATS or PBZ. 

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Off-Treatment: A subject is considered off-treatment on the date that they have met any of 
the criteria listed in Section 4.5.5. 
On Follow-up: A subject is considered on follow-up on the date that they have met any of 
the criteria listed in Section 4.5.5.    
Off-Study: A subject is considered off-study if they are removed from the study for any of the 
reasons listed in Section 4.5.6, or if they have completed the follow-up interval. 
4.6 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of an adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of a Merck decision to no longer supply Pembrolizumab, ample notification will 
be provided so that appropriate adjustments to subject treatment can be made. 
 

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5.0 TRIAL FLOW CHART 
5.1 
Study Flow Chart 
Trial Period:
Pre-
Treatment 
Study Treatments 
Post-Treatment Follow-Up1 
Visit:
Prior to On--
Study10 
Pheresis 
Pembro 
#1 
BATS 
#1 
BATS 
#2 
BATS 
#3 
BATS 
#4 
Pembro 
#2 
BATS 
#5 
BATS 
#6 
BATS 
#7 
BATS 
#8 
Pembro 
#3 
Visit 1 Visit 2 Visit 3 Visit 4 
Timing:
 
-30d- 
-21d 
-7d 
Week 1 
Week 2 
Week 
3-4 
Week 5 
Week 6 
Week 7 
14 d 
30 d 
90 d 
6m 
Scheduling Window (Days):
 
 
± 2d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 5d 
+ 10d 
+ 20d 
± 10d 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Treatments/Procedures 
Pheresis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BATS infusion2 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
PBZ 
 
 
X3 
 
 
 
 
X4 
 
 
 
 
X 
 
 
 
 
                                               
1 Follow-up visit timing listed is based on the date of the last study treatment. See section 6.2.5.3. 
2 Subject should receive BAT #1-8 infusions twice per week (+/- 3 days).  
 
3 Initiate PBZ infusion 7 ± 2 days prior to BATS infusion for Schedule 3 only. 
4 Schedules 2 and 3 only. 

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Trial Period:
Pre-
Treatment 
Study Treatments 
Post-Treatment Follow-Up1 
Visit:
Prior to On--
Study10 
Pheresis 
Pembro 
#1 
BATS 
#1 
BATS 
#2 
BATS 
#3 
BATS 
#4 
Pembro 
#2 
BATS 
#5 
BATS 
#6 
BATS 
#7 
BATS 
#8 
Pembro 
#3 
Visit 1 Visit 2 Visit 3 Visit 4 
Timing:
 
-30d- 
-21d 
-7d 
Week 1 
Week 2 
Week 
3-4 
Week 5 
Week 6 
Week 7 
14 d 
30 d 
90 d 
6m 
Scheduling Window (Days):
 
 
± 2d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 5d 
+ 10d 
+ 20d 
± 10d 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(SAEs 
only) 
 
Physical Examination/Performance 
status 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Disease Status, Additional Treatment1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Laboratory Procedures6 
β-HCG (for WOCBP) 
X 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                               
5 If clinically indicated, additional evaluation studies (one 10 mL red top tube) may be drawn at any or all of the following time points: pre-infusion, 1, 2, and 4 hours (+/- 15 minutes), 8 
and 16 hours (+/- 1 hour), 24, 48, and/or 72 hours (+/- 2 hours) after each infusion, to study cytokine release. “Clinically indicated” is based on the clinical judgment of the investigator. 
6 Labs required prior to treatments do not need to be repeated if labs have been performed within 72 hours prior to dose 
7 A total of 60 mL of blood will be drawn at each of the designated time-points. One 10 mL red top tube and five 10 mL green or lavender top tubes containing anti-coagulant. Immune 
evaluation blood drawn on the same day as BATs #1 and #5 should be drawn prior to BATs infusion. Blood for immune evaluation does not need to be collected after first disease 
progression following participation. 
8 Tumor imaging should be performed at intervals consistent with routine clinical care as close to recommended times as possible. Alterations to the usual schedule are not considered 
protocol deviations as long as the reason for the alteration is documented. 
9 Please refer to Table 8 for full list of lab requirements 
10 As described in the eligibility criteria, hematological, renal, hepatic, and coagulation labs should be completed within 10 days of on-study. The screening MUGA scan or ECHO may 
be done within 60 days of on study date. All other screening procedures must be done within 4 weeks of on-study date.  
11 β-HCG (for WOCBP) prior to apheresis may be completed within 7 days prior to apheresis. It does not need to be repeated if the screening test was completed within 7 days prior to 
apheresis. This may be completed at a non-UVA laboratory at the convenience of the participant. 
12 TSH, T3 and T4 testing at the time of PBZ treatment following all BATs infusions is only required for participants on Schedule #3 

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Trial Period:
Pre-
Treatment 
Study Treatments 
Post-Treatment Follow-Up1 
Visit:
Prior to On--
Study10 
Pheresis 
Pembro 
#1 
BATS 
#1 
BATS 
#2 
BATS 
#3 
BATS 
#4 
Pembro 
#2 
BATS 
#5 
BATS 
#6 
BATS 
#7 
BATS 
#8 
Pembro 
#3 
Visit 1 Visit 2 Visit 3 Visit 4 
Timing:
 
-30d- 
-21d 
-7d 
Week 1 
Week 2 
Week 
3-4 
Week 5 
Week 6 
Week 7 
14 d 
30 d 
90 d 
6m 
Scheduling Window (Days):
 
 
± 2d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 3d 
± 5d 
+ 10d 
+ 20d 
± 10d 
HBsAg B & C and HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
 
Serum Chemistry Panel9 
X 
X 
X 
X 
 
 
 
X 
X 
 
 
 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, T3, T4 
X 
 
 
 
 
 
 
 
 
 
 
 
X12 
X 
 
 
 
Immune Evaluations7 
 
X 
 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Cytokine assays5 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 

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6.0 TRIAL PROCEDURES 
6.1 
Trial Procedures 
The Trial Flow Chart summarizes the trial procedures to be performed at each visit.  
Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
6.1.1 Administrative Procedures 
6.1.1.1 Informed Consent 
An investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. Consent must be documented by the subject’s dated signature 
on a consent form along with the dated signature of the person conducting the consent 
discussion. A copy of the signed and dated consent form should be given to the subject 
before participation in the trial. 
6.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
6.2 
Registration  
Subject must meet all of the eligibility requirements listed in section 4.1 prior to registration.  
Subjects who are consented to the study must be registered in OnCore in accordance with 
the University of Virginia Cancer Center OnCore SOP, which can be found on the OnCore 
Resources page (see the Oncore Help tab). General guidelines are provided below for 
reference, but the procedure should follow the OnCore SOP in case of any discrepancy. 
All subjects who have signed an informed consent should have the following information 
entered into OnCore: 
• 
demographics 
• 
date of signed informed consent 
 
6.2.1.1 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, past conditions that affect eligibility and history of all past 
cancers and cancer treatment.  Details regarding the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as medical history.   

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6.2.2 Clinical Procedures/Assessments 
6.2.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Please refer to section 6.3 for detailed information regarding the assessment and 
recording of AEs.   
6.2.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period and prior to the first PBZ (for schedule #3) or HER2 BATs infusion 
(schedules #1 and #2) (for baseline conditions) only.  Clinically significant abnormal findings 
should be recorded as medical history.   
At subsequent visits specified in the Trial Flow Chart, the investigator or qualified designee 
will perform a directed physical exam as clinically indicated.   
6.2.2.3 Performance Scale 
The investigator or qualified designee will assess ECOG performance status at time points 
specified in the Trial Flow Chart.   
6.2.2.4 Tumor Imaging and Assessment of Disease 
Tumor measurements should be done clinically by physical exam and by CT, MRI or 
PET/CT prior to initiation of treatment.     
Imaging should be repeated throughout the study at intervals consistent with routine clinical 
care. The images should be evaluated using immune related RECIST criteria (irRECIST) 
(55, 56) (see Section 6.2.2.4.1) and RECIST. If progression is noted on radiographic 
imaging, confirmation by a second scan in the absence of rapid clinical deterioration is 
required.  Data will be collected for post-hoc analysis by RECIST criteria, but RECIST will 
not be used for any decisions related to study treatment. 
6.2.2.4.1 Response Definitions Immune-Related RECIST Criteria (irRECIST)  
Measurable lesions must be accurately measured in at least one dimension with a minimum 
10 mm in the longest diameter for non-nodal lesions, and a minimum 15 mm in short axis for 
lymph nodes. At baseline, the sum of the longest diameter (SumD) of all target lesions will 
be measured. At each subsequent tumor assessment, the longest diameters of non-nodal 
target and new non-nodal measurable lesions, and short axes of nodal target and new nodal 
measurable lesions should be added together to provide the total measurable tumor burden 
(TMTB): 
Total Measurable Tumor Burden = SumD index lesions + SumD new, measurable lesions 

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Response categories are defined as immune-related complete response (irCR), immune-
related partial response (irPR), immune-related stable disease (irSD), immune-related 
progressive disease (irPD) and confirmed progressive disease. Decreases in total 
measurable tumor burden are compared to the baseline tumor burden. New measurable 
lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per time point) must meet the same criteria 
as defined for baseline target lesion selection (i.e., at least 10 mm in the longest diameter). 
These new patterns are considered clinically meaningful because they appear to be 
associated with favorable survival. 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 subject 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 20% 
(minimum of 5 mm) compared with baseline or nadir 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 subject’s tumor type, disease stage, and clinical status 
because awaiting a response after tumor burden increase may not be appropriate for 
subjects with rapid symptomatic progression accompanied by a decline in performance 
status.  
Table 7.  Derivation of irRECIST overall responses 
Complete Response (irCR) Complete disappearance of all measurable and non-
measurable lesions.  
Lymph nodes must decrease to < 10 mm in short axis. 
No new lesions 
Confirmation of response as indicated.  
Partial Response (irPR) 
Decrease of ≥ 30% in TMTB relative to baseline  
No unequivocal progression of non-target lesions  
No new lesions.  
Confirmation of response as indicated. 
Stable Disease (irSD) 
Failure to meet criteria for irCR or irPR in the absence of 
irPD. 
Progressive Disease 
(irPD) 
Increase of >20% (minimum of 5 mm) in TMTB compared 
to baseline or nadir  
OR 
Progression of non-target lesions 
OR 
New lesion 

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Confirmation of progression is recommended minimum 4 
weeks after the first irPD assessment.  
Confirmed Progressive 
Disease  
New unequivocal progression or worsened progression 
from initial PD visit 
OR 
Appearance of another new lesion 
Other 
irNE, used in exceptional cases where insufficient data 
exists. 
irND, in adjuvant setting when no disease is detected. 
  
6.2.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below in Table 8.   
 

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Table 8.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
(β-hCG)† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
aPTT 
WBC 
Aspartate aminotransferase (AST) Specific gravity  
Total triiodothyronine (T3) 
Red Blood Cell Count 
Carbon Dioxide ‡ 
Microscopic exam (If abnormal)  
Free thyroxine (T4) 
Absolute Neutrophil Count 
  (CO2 or biocarbonate) 
β-hCG † 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Total protein 
 
  
 
Blood Urea Nitrogen 
 
 
† WOCBP only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
 
 
 

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6.2.4 Immune Evaluations 
To measure functional changes in immune cell populations as a consequence of 
immunotherapy, anti-tumor cytotoxicity will be examined.  Samples of serum will be stored 
for future evaluations such as cytokine and anti-tumor antibody immune responses.  The 
specific procedures are well-described in the literature. Blood drawing studies will be 
performed as outlined in the Trial Flow Chart. The subsequent paragraphs summarize the 
tests and procedures. 
Serum cytokine/chemokine levels:  Serum will be stored for subsequent cytokine analysis 
at the indicated time points, if clinically indicated.  
PBMC subsets and phenotype analysis:  Peripheral blood mononuclear cell (PBMC) and 
tumor-infiltrating lymphocyte (TIL) samples using immunohistochemistry to determine T cells 
and T cell subpopulations. 
Cytotoxic activity and IFNγ production in PBMC populations:  PBMC will be tested in 
specific cytotoxicity and IFNγ EliSpot assays after exposure to SK-BR-3 (HER2+ breast 
cancer), or Daudi and/or Raji (Burkitt's lymphoma) at the indicated time points. Specific 
activity of pre-IT samples will be compared to those obtained during and post-IT.  
6.2.5 Visit Requirements 
6.2.5.1 Screening 
Prior to the performance of any study-specific procedures, the subject will have the nature of 
the study explained to them, and will be asked to give written informed consent. Informed 
consent must be obtained prior to any study-specific procedures that do not form a part of 
the subject’s normal care. However, assessments performed according to standard of care 
prior to receipt of informed consent may be utilized to fulfill the screening requirement, if 
completed within the required window for screening.  
Eligibility criteria will be assessed as stated in section 4.1. Eligible subjects will be 
leukapheresed after being determined eligible to obtain lymphocytes for expansion or 
when the lymphocyte population has recovered to ≥ 500 lymphocytes/mm3. 
6.2.5.2 Treatment Period 
The treatment period will consist of the duration of intervention with any of the 
treatments listed in the Treatment Regimen section. Subject should receive study 
assessments as defined in the Trial Flow Chart. 
6.2.5.3 Post-Treatment Visits 
Follow-up visits should be scheduled within 14 (±5) days, 1 month (±5 days), 3 months (±10 
days) and 6 months (±10 days) following administration of the last study treatment in all 
subjects to perform the assessments defined in the Trial Flow Chart. As described in the Trial 

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Flowchart, IEs will be done if there continue to be immune responses at 6 month ((± 2 weeks) 
intervals until the responses have disappeared (e.g. if there is a positive response at 6 months 
post study treatment, then an IE will be collected approximately 6 months later. If that test is 
positive, then she would be tested again 6 months later). 
 
Following the 6 month post-treatment visit, study staff will contact subjects (by phone or 
email, or passively via medical record) every 3 months for survival, disease status, and 
information on cancer treatment until death, withdrawal of consent, or the end of the study, 
whichever occurs first. If this information is in the medical record, no contact is necessary. 
Subjects who discontinue trial treatment for a reason other than disease progression should 
continue to have imaging performed and tumor measurements by irRECIST until first 
progression following study treatment.   
6.3 
Assessing and Recording Adverse Events 
After informed consent has been obtained, and prior to initiation of investigational 
treatment, only serious adverse events caused by a protocol-mandated intervention should 
be reported (e.g., serious adverse events related to procedures such as leukapheresis). AEs 
reported between the time the subject signed the informed consent and the administration of 
the first dose of any study medication will be captured as concurrent medical history unless 
due to a protocol-related procedure. 
After initiation of study treatment, all adverse events will be reported according to the 
guidelines in the following sections. Throughout the study, investigators should report any 
deaths, serious adverse events, or other adverse events of concern that are believed to be 
related to the investigational intervention. 
An adverse event is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product or 
protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of an investigational agent, is also an adverse event. 
Adverse events may occur during the course of clinical trials or within the follow-up period 
specified by the protocol, or prescribed in clinical practice, from overdose (whether 
accidental or intentional), from abuse and from withdrawal. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  

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Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Progression of the cancer under study is not considered an adverse event.  
6.3.1 Assessment of Adverse Events 
After initiation of investigational intervention (BATs or PBZ), all adverse events, whether 
reported by the subject or noted by study personnel, should be reported according to the 
guidelines in the following sections. After this period, investigators should report any deaths, 
serious adverse events, or other adverse events of concern that are believed to be related 
to the investigational intervention.  
Adverse events clearly related to prior chemotherapy (e.g. neuropathies that have not 
changed with treatment or symptoms such as pre-existing nausea, fatigue) will be recorded 
as baseline.  
Adverse events should be assessed for seriousness, severity, attribution and expectedness, 
in relation to PBZ treatment and BATs treatment, by the Principal Investigator or designee. 
The following sections provide definitions for adverse event characteristics and reporting 
requirements.   
AEs should be followed to resolution or stabilization, and reported as SAEs if they become 
serious. This also applies to subjects experiencing AEs that cause interruption or 
discontinuation of study intervention, or those experiencing AEs that are present at the end of 
their participation in the study. Such subjects should receive post-treatment follow-up as 
appropriate.  
If an ongoing AE changes in its severity or in its perceived relationship to study drug, a new 
AE entry for the event should be completed with the following exception. During the time 
between one infusion and the next, or in the 72 hours following the 4th and 8th BATs infusions, 
events should only be recorded once with the maximum severity grade that the participant 
experienced. 
AE and SAE recording will continue until 30 days after the last dose of study drug. SAE 
recording for all events (regardless of relation to study treatment) will continue through at 
least 90 days following the last dose of study treatment. SAEs considered related to study 
drug may be recorded and reported at any time, even after the patient’s final visit. 
6.3.1.1 Adverse Event Definition 
An adverse event is any untoward medical occurrence in a subject who has received an 
investigational intervention, whether or not related to the investigational intervention(s). 
Medical conditions present before starting the investigational intervention will be considered 
adverse events only if they worsen after starting study treatment. Adverse events include 
unfavorable, harmful or pathological changes in the general condition of a subject; subjective 

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or objective symptoms (spontaneously offered by the subject and/or observed by the 
Investigator or the study nurse); intercurrent events or exacerbation of pre-existing diseases 
which occurred after the administration of the study drug; clinically significant changes in 
laboratory abnormalities; or any undesirable and unintended effect of research occurring in 
human subjects as a result of the collection of identifiable private information under the 
research. Progression of the cancer under study is not considered an adverse event. 
6.3.1.2 Secondary Adverse Events 
In general, events occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be considered a single event identified by the primary cause. However, a 
secondary event should be listed as an independent event if it meets one of the following 
criteria: 
o severe  
o serious  
o separated in time from the primary event 
If it is not clear as to whether events are dependent, then record as separate adverse events. 
6.3.1.3 Preexisting Medical Conditions 
A preexisting medical condition is one that is present during the pre-study screening 
assessments. These conditions should be noted on the Medical History form. Preexisting 
medical conditions are not considered adverse events unless any of the following 
characteristics worsen following initiation of any study-related procedure: 
• 
frequency 
• 
severity 
• 
character  
If any of the above conditions apply, then this should be recorded as an adverse event. 
Remember to convey that this is a change in a preexisting condition when describing the event 
(e.g., “increased frequency of kidney stones”). 
 
6.3.1.4 Expectedness 
The expectedness of the adverse event will be determined by the Investigator based on 
current literature, the Investigator’s Brochure or package insert and the Investigator’s 
experience. See Appendix for more details on expected risks. 
6.3.1.5 Severity 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the 
CTCAE version 4.03 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 

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To assess severity of adverse events not included in the CTCAE version 4.03, use the table 
below.  
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADLa 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADLb 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
a. 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b. 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. 
 
6.3.1.6 Attribution  
The Principal Investigator will evaluate all AEs and assess their toxicity and attribution, if any, 
to PBZ or BATs treatment.  See Table  for further guidance on evaluation of attribution. The 
following criteria will define the attribution: 
Definite:  The AE is clearly related to the investigational intervention. 
Probable: The AE is likely related to the investigational intervention. 
Possible: The AE may be related to the investigational intervention. 
Unlikely: The AE is doubtfully related to the investigational intervention. 
Unrelated: The AE is NOT related to the investigational intervention. 
6.3.1.7 Seriousness  
A serious adverse event (SAE) or serious adverse drug reaction (ADR) is any adverse event 
temporally associated with the subject’s participation in research that meets any of the 
following criteria: 
• 
Results in death; 
• 
Is life threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• 
Results in a persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose; 
• 
Other important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 

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based upon appropriate medical judgment, they may jeopardize the subject or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition. For reporting purposes, also consider the 
occurrences of pregnancy as an event which must be reported as an important 
medical event. 
*Hospitalization or prolonged hospitalization should be documented and reported as a serious 
adverse event, except if the hospitalization meets at least one of the following criteria: 
• 
The hospitalization is less than 24 hours without an admission 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for anticipated or 
protocol specified procedures such as administration of Intravenous fluids, 
central line insertion, biopsy procedures ) 
• 
Hospitalization for a preexisting condition, provided that all of the following 
criteria are met: 
o The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of 
the expected normal progression of the disease.  
o The subject has not suffered an adverse event. 
If the hospitalization meets any of these criteria, then it is not considered a serious adverse 
event. In addition, hospitalization related to convenience (e.g. transportation issues etc.) will 
not be considered a SAE. 
Refer to Table 10 for additional details regarding each of the above criteria. 
6.3.1.8 Abnormal Laboratory Values / Clinical Assessments 
It is the responsibility of the investigator, or designee, to review and document all laboratory 
findings and clinical assessments, which may include vital signs, physical exams and ECGs. 
Medical and scientific judgment should be exercised in deciding whether a laboratory 
abnormality or clinical finding should be classified as an adverse event. In general, an 
abnormal laboratory test result or clinical finding should be considered as an adverse event if 
it meets at least one of the following criteria: 
- 
Is associated with clinical symptoms 
- 
Results in a change in study treatment (e.g., treatment modification, 
interruption or discontinuation) 
- 
Requires a medical intervention or change in concomitant therapy  
- 
Clinically significant in the investigator’s judgment  
 
Note that if a clinically significant laboratory abnormality or clinical finding is a sign of a disease 
or syndrome (e.g. elevated ALT) then this should be recorded as a single event identified by 
the diagnosis (hepatic failure).  

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If a clinically significant laboratory abnormality is not a sign/symptom of another primary event, 
the abnormality itself should be recorded as an adverse event. The event should be described 
using a specific clinical term (“hyperkalemia”), if possible, or as test result above or below the 
normal range (e.g., "elevated Vitamin D," as opposed to "abnormal Vitamin D"). 
6.3.1.9 Death 
Death should be considered an outcome of an adverse event and not an independent adverse 
event. The event or condition that caused the death should be recorded as the adverse event 
with the outcome of death. If the cause of death is unknown and cannot be ascertained at the 
time of reporting, then the event should be reported as an “unexplained death”. If the cause 
of death later becomes available (e.g., after autopsy), “unexplained death” should be updated 
by the established cause of death.  
6.3.2 Reporting of Adverse Events to Merck 
6.3.2.1 Reporting of Serious Adverse Events to Merck 
SAE reports and any other relevant safety information related to PBZ are to be forwarded to the 
Merck Global Safety facsimile number: +1-215 664-6229.  A copy of all 15 Day Reports and 
Annual Progress Reports is submitted as required by FDA, European Union (EU), 
Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators 
will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide 
Product Safety; FAX 215 664-6229) at the time of submission to FDA. 
For the time period beginning when the consent form is signed until treatment assignment, 
any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study (reference section 6.3.1.9 for 
additional details) that occurs to any subject must be reported within 24 hours to the 
Sponsor-Investigator and within 2 working days to Merck Global Safety if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at study treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause other than progression of the cancer under study 
(reference section 6.3.1.9 for additional details) whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor-Investigator and within 2 working days to 
Merck Global Safety. Note that SAE reporting to UVA DSMC, UVA IRB, and FDA differs and 
is described in other sections.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 

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in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor-Investigator and to Merck 
Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
6.3.2.2 Reporting of Overdose to Merck 
For the purposes of this trial, an overdose of PBZ will be defined as any dose of 1,000 mg or 
greater (≥5 times the indicated dose).  No specific information is available on the treatment 
of overdose of PBZ. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor-Investigator and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 661-6229) 
6.3.2.3 Reporting of Pregnancy and Lactation to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 

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Such events must be reported within 24 hours to the Sponsor-Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-6229). 
6.3.2.4 Reporting of Events of Clinical Interest to Merck 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 24 hours to the Sponsor-Investigator and within 2 
working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-6229). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor-Investigator and within 2 working days to Merck 
Global Safety if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor-
Investigator and within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in section 6.3.2.2, that is not associated with 
clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
6.3.2.5 Protocol-Specific Exceptions to Serious Adverse Event Reporting to Merck 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 6.3.2.3, unless there is evidence suggesting a causal relationship between the drug 
and the event. Any such event will be submitted to the Sponsor-Investigator within 24 hours 
and to Merck Global Safety within 2 working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 

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The Sponsor-Investigator will monitor unblinded aggregated efficacy endpoint events and 
safety data to ensure the safety of the subjects in the trial. Any suspected endpoint which 
upon review is not progression of the cancer under study will be forwarded to Merck Global 
Safety as a SAE within 2 working days of determination that the event is not progression of 
the cancer under study. 
6.3.3 UVA Cancer Center DSMC Reporting Requirements 
All adverse events must be reported into the University of Virginia Cancer Center OnCore 
database within the time frames specified below: 
Table A: High Risk Studies 
Reporting requirements for AEs that occur within 30 days of the last dose of protocol specified treatment 
 
Grade 1 
Grade 2 
Grade 3 
Grade 
4 & 5 
Expected 
and 
unexpected 
 
Expected 
 
Unexpected 
Expected 
Unexpected 
Expected 
and 
Unexpected 
Without 
hospitalization 
With 
hospitalization 
Without 
hospitalization 
With 
hospitalization 
Unrelated 
Unlikely 
OnCore 
30 daysa 
OnCore 
30 days 
OnCore 
30 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
7 days 
Possible 
Probable 
Definite 
OnCore 
30 daysa 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
30 days 
OnCore 
15 days 
OnCore 
7 days 
OnCore 
7 days 
OnCore 
(24-hrs)* 
7 days 
 
*Enter into Cancer Center database within 24 hours if unexpected and definitely related to protocol specified treatment 
Hospitalization defined as an inpatient hospital stay or prolongation of a hospital stay equal to or greater than 24 hours 
a Grade 1 unexpected or expected hematologic/metabolic events will be recorded in the Cancer Center Database; however, regardless of attribution, 
these events do not have to be reported as adverse events.  
 
 
6.3.4 IRB Reporting Requirements 
Serious, unexpected adverse events considered at least possibly related to study treatment 
must be submitted to the site Institutional Review Board according to the participating site 
institutional policies. 
For the University of Virginia clinical site, the Principal Investigator (PI) or designee is 
responsible for reporting AEs and unanticipated problems to the UVA HSR-IRB according to 
the following guidelines. 
Type of Event 
To whom will it be 
reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting in 
death 
that 
is 
deemed 
DEFINITELY related to (caused 
by) study participation 
An internal event is one that 
occurs in a subject enrolled in a 
UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected, 
Related adverse event  
IRB-HSR 
Within 7 calendar days 
from the time the study 
IRB Online 

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See Oncore reporting requiremen
 
team 
received 
knowledge of the event. 
 
Timeline 
includes 
submission 
of 
signed 
hardcopy of AE form. 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that 
are not adverse events or 
protocol violations  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team 
received 
knowledge of the event.  
Unanticipated Problem report form.  
 
http://www.virginia.edu/vprgs/irb/HSR
_docs/Forms/Reporting_Requiremen
ts-Unanticipated_Problems.doc ) 
 
  
Protocol Violations 
 (The IRB-HSR only requires 
that 
MAJOR 
violation 
be 
reported, 
unless 
otherwise 
required by your sponsor, if 
applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team 
received 
knowledge of the event.  
 
Protocol Violation and Enrollment 
Exception Reporting Form 
 
 
http://www.virginia.edu/vprgs/irb/hsr_
forms.html 
 
Go to 3rd bullet from the bottom.  
Data Breach  
The UVa Corporate 
Compliance 
and 
Privacy Office, a 
 
 
ITC: 
 
if 
breach 
involves  electronic 
data-  
 
 
UVa 
Police 
if 
breach 
includes 
such 
things 
as 
stolen computers.  
As soon as possible and 
no later than 24 hours 
from the time the incident 
is identified. 
 
As soon as possible and 
no later than 24 hours 
from the time the incident 
is identified. 
IMMEDIATELY.  
 
 
UVa 
Corporate 
Compliance 
and 
Privacy Office- Phone 924-9741 
 
 
 
ITC:  Information Security Incident 
Reporting 
procedure,  
http://www.itc.virginia.edu/security/re
porting.html 
 
Phone- (434) 924-7166 
 

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6.3.5 Reporting to the FDA 
The Sponsor-Investigator for the study (the UVA PI or designee) is responsible for providing 
safety updates to the FDA per the following guidelines. The reporting times refer to the time 
the Sponsor-Investigator received knowledge of the AE. 
Table 9. FDA Reporting Requirements 
UVa PI HELD IND 
Type of Event 
To whom will it 
be reported: 
Time Frame for 
Reporting 
How reported? 
Life-threatening and/or fatal 
unexpected events related or 
possibly related to the use of 
the investigational agent. 
FDA 
Within 7 calendar days 
of the study team 
learning of the event 
Form FDA 3500A (MedWatch) or 
narrative 
Serious, unexpected and 
related or possibly related 
adverse events 
FDA 
Within 15 calendar days 
after the study team 
receives knowledge of 
the event 
Form FDA 3500A (MedWatch) or 
narrative 
All adverse events 
FDA 
Annually 
IND annual report 
 
 
6.3.6 Data Safety Monitoring Plan 
The Data and Safety Monitoring Board for this study is the UVA Data Safety Monitoring 
Committee (DSMC). 
6.3.6.1 UVA Cancer Center Data Safety Monitoring Committee 
The University of Virginia Cancer Center Data and Safety Monitoring Committee (DSMC) 
will provide oversight of the conduct of this study. The CC DSMC will report to the UVA 
Protocol Review Committee (PRC). The DSMC will review the following: 
• 
All adverse events 
• 
Audit results 
• 
Application of study designed stopping/decision rules 
• 
Whether the study accrual pattern warrants continuation/action 
• 
Protocol violations 
The CC DSMC will meet every month for aggregate review of AE data. Tracking reports of 
the meetings are available to the PI for review.  Issues of immediate concern by the DSMC 
are brought to the attention of the PI (and if appropriate to the PRC and IRB) and a formal 
response from the PI is requested. Per the Cancer Center NIH approved institutional plan 
this study will be audited approximately every 6 or 12 months.  
 

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Table 10.  Evaluating Adverse Events 
4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization 
indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during study treatment that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not 
include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing 
condition that has not worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a 
study treatment and is documented in the subject’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor-Investigator within 24 hours 
and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection 
purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 
24 hours to the Sponsor-Investigator and to Merck within 2 working days. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse 
event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause study treatment to be discontinued? 
Relationship 
to study 
treatment  
Did study treatment cause the adverse event? The determination of the likelihood that study treatment caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted 
on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory 
time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the 
test drug and the adverse event based upon the available information. 
The following components are to be used to assess the relationship between study treatment and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more likely study treatment caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to study treatment such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
study 
treatment?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or 
environmental factors 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to study 
treatment 
(continued)  
Dechallenge 
Was study treatment discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of treatment; or (3) the trial is a single-dose drug trial); or (4) Product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to study treatment in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug 
trial); or (3) Product(s) is/are used only one time). 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding study treatment or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of study treatment relationship). 
Yes, there is a reasonable 
possibility of study treatment 
relationship. 
There is evidence of exposure to study treatment.  The temporal sequence of the AE onset relative to the administration of study 
treatment is reasonable.  The AE is more likely explained by study treatment than by another cause. 
No, there is not a reasonable 
possibility of study treatment 
relationship 
Subject did not receive study treatment OR temporal sequence of the AE onset relative to administration of study treatment is not 
reasonable OR the AE is more likely explained by another cause than the study treatment.  (Also entered for a subject with overdose 
without an associated AE.) 
 
 
 
 
 

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7.0 EVALUATION CRITERIA 
7.1 
Dose Limiting Toxicity 
The incidence of dose limiting toxicity (DLT) in subjects will be monitored. A DLT is defined 
as any treatment related event (at least possibly related to treatment) following the start of 
any study mandated treatment which meets one of the below criteria per CTCAE v4.03: 
• 
Grade 3 nausea, vomiting or diarrhea persisting for >48 hours with optimal 
medical management 
• 
Grade ≥ 3 hypophysitis, or hyperthyroidism lasting > 7 days 
• 
Grade 3 fatigue, flu-like symptoms, BATs infusion reaction, and rash or other 
skin infections lasting greater than 72 hours 
• 
Grade ≥ 3 dyspnea that persists for more than 6 hours 
• 
Grade ≥ 3 hypotension requiring IV pressors > 72 hours or hospitalization > 
72 hours 
• 
Grade ≥ 4 cytokine release syndrome (CRS) EXCEPT that IV pressors may 
be used for up to 72 hours without being determined as a DLT 
• 
Any other non-hematological toxicity Grade ≥ 3 not resolving within 72 hours 
(except for those described above)  
• 
Grade 4 BATS infusion related reaction 
• 
Grade 3 or higher PBZ infusion related reaction 
• 
Grade 4 neutropenia lasting more than 5 days 
• 
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding, or 
any requirement for platelet transfusion 
• 
Grade 4 anemia 
• 
The study chair reserves the right to declare other AEs as DLT’s if they are 
clearly treatment related and are causing substantial morbidity for subjects. 
 
Subjects experiencing autoimmune DLTs will be removed from all study treatment (PBZ and 
HER2 BATs). Subjects experiencing DLTs other than autoimmune complications may 
continue on either HER2 BATs or PBZ treatment (e.g. if the patient has a Grade > 3 BATs 
infusion related reaction lasting more than 72 hours, she may continue on PBZ as long as 
the treating physician feels it is in her best interest).  Likewise, patients with prolonged high 
grade hypotension due to meperidine/dehydration/anti-emetics or any other cause not solely 
due to the BATS infusion may continue on study.   
 
All subjects with DLTs should also participate in the remaining aspects of the study (immune 
studies, follow-up, etc.) 
7.2 
Response Criteria  

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The primary method of evaluation of response to treatment will be irRECIST criteria as 
described in section 6.2.2.4. Response based on RECIST 1.1 criteria will also be collected for 
secondary analyses.   
7.3 
Other Measures of Effect   
All irRECIST and RECIST assessments of CR, PR or PD must be independently confirmed 
by the UVA DSMC prior to publication of study results as per the UVA DSMP charter. 
7.3.1 Progression-free survival  
Progression-free survival (PFS) is defined as the duration of time from start of treatment to 
time of progression or death from any cause, whichever occurs first. 
7.3.2 Overall survival  
Overall survival (OS) is defined as the duration of time from start of treatment to time of death 
from any cause. 
7.3.3 Objective response rate (ORR) 
Objective Response Rate (ORR) is defined as the percentage of subjects with a response of 
irCR or irPR per irRECIST (ORR = irCR + irPR). 
7.3.4 Duration of response (DoR) 
Duration of response is defined as the time from documentation of tumor response to disease 
progression.  
7.3.5 Disease control rate (DCR) 
Disease control rate (DCR) is defined as the percentage of subjects who achieve complete 
response, partial response and stable disease following treatment. 
7.3.6 Immune Evaluations  
All subjects receiving any dose of study treatment should continue assessment of immune 
markers.  
An immune response will be defined as a 30 IFNγ Elispots per million cells plated above the 
background of unstimulated spontaneous IFNγ Elispots per million cells plated.  
7.4 
Toxicity and Safety 
All subjects receiving any dose of study treatment will be evaluated for safety. Safety 
assessments will include: 
i. Incidence and severity of adverse events 
ii. Incidence of Dose-Limiting Toxicities (DLTs) 
 

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8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Design 
For Aim 1: According to standard 3 + 3 dose escalation/dose de-escalation rule, if there are 2 
or more DLTs at Schedule #1, the study will be closed. If there are no dose limiting toxicities 
(DLTs) in the first 3 subjects (0/3) or at maximum 1 subject with DLT out of 6 subjects (1/6) 
with treatment of Schedule #1, we will advance to Schedule #2. If there are 0/3 or 1/6 DLTs 
at Schedule #2, we will advance to Schedule #3. If there are no more than 1/6 DLTs, Schedule 
#3 will be used as the MTD in this study. Otherwise, Schedule #2 will be used as MTD if no 
more than 1 out of 6 patients at Schedule #2 have DLTs. This design will require a minimum 
of 3 and a maximum of 18 evaluable patients to identify the MTD. To take the eligible but not 
evaluable patients into account (estimated at 10%), the following plan is considered. Among 
18 eligible patients, if the true unevaluable rate is 10%, 2 unevaluable patients is expected. 
Since the probability of 4 unevaluable patients out of 18 eligible patients is 7% and the null 
hypothesis that the unevaluable rate is 10% can’t be rejected at one-sided type I error rate of 
2.5%, a maximum of 4 unevaluable patients will be accepted. Thus, a maximum of 22 eligible 
patients may be recruited and among of them 4 unevaluable patients will be allowed.  
 Once the MTD is identified, 12 evaluable subjects in the dose expansion cohort (DEC) will 
be enrolled at the MTD level to further evaluate the safety and explore the preliminary efficacy. 
Assuming an unevaluable rate of 10%, as above, similar considerations is taken for a DEC of 
12 evaluable subjects at the MTD. A maximum of 3 unevaluable patients in the DEC will be 
allowed (the probability of 3 unevaluable patients out of 12 eligible patients is 8.5%>2.5%) 
and a total of 15 eligible patients may be recruited in the DEC.   
In brief, the table below lists the dose-escalation decision rules for this study.  
Number of subjects with DLT/ 
cohort  
at a given dose schedule level 
Escalation decision rule 
0/3  
Accrue 3 new subjects for next advanced schedule level 
1/3 
Accrue additional 3 subjects at current schedule level 
1/6 
Accrue 3 new subjects for next advanced schedule level 
>=2/3  
or >=2/6 
Stop dose escalation. Enter 3 more subjects to previous 
schedule/dose level if only 3 subjects were enrolled to 
that cohort. If 6 subjects had been enrolled to that cohort 
already, then declare that previous dose / schedule as 
MTD. 
 
Aim 2 is exploratory, only summary and descriptive statistics will be performed on the immune 
evaluations.  

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Immune evaluations (IE) will be done at the time points indicated on the schema to define the 
pattern of immune responses. 
We will calculate the mean, median, and standard deviation for each studied immune variable 
at each studied time point and explore potential patterns of immune responses. The product-
limit method of Kaplan-Meier will be used to obtain preliminary estimates of PFS and OS, and 
survival curves will be plotted. With all subjects treated at the MTD, the objective response 
rate (ORR), duration of response (DoR), and disease control rate (DCR) will be calculated 
and corresponding 90% confidence intervals will be estimated using the Clopper-Pearson 
method. 
 
Justification for the expansion cohort size of 12 patients. The expansion cohort size of 
12 patients is used to get further assessment of the safety at the chosen MTD. This sample 
size will have the width of 90% confidence intervals (Clopper-Pearson method) of DLT rate 
within 50%. With an expected maximum DLT rate of 15% at the chosen MTD, a maximum of 
4 patients with DLTs will be acceptable (since the probability of 4 DLTs out of 12 patients is 
6.8%, the null hypothesis that the maximum DLT rate is 15% can’t be rejected at a one-sided 
type I error rate of 2.5%). In the expansion of this cohort, if one more DLT occurrs after 4 
patients have had DLTs, the expansion will be stopped. The table below shows the Clopper-
Pearson’s 90% confidence intervals for various number of DLTs. 
 
 
Number of DLTs 
Total N in the expansion cohort 
DLT rate (90% confidence interval) 
0 
12 
0% (0% - 22.1%) 
1 
12 
8.3% (0.4% -33.9%) 
2 
12 
16.7% (3.0% - 43.8%) 
3 
12 
25% (7.2% - 52.7%) 
4 
12 
33.3% (12.3% - 60.9%) 
8.2 
Sample Size and Accrual 
This study requires a maximum of 37 subjects (MTD identified at Schedule #3 with 6 
subjects at each Schedule/Dose level plus the 12 in the DEC and a maximum of 7 
unevaluable patients). Accrual is estimated at between 3-10 subjects per year. 
8.3 
Populations and Analysis Plans 
All subjects who are put on-study will be assessed for inclusion in the final report. Eligible 
subjects who do not complete the scheduled course of treatment due to reasons other than 
toxicity will not be used to guide decisions about dose/schedule selection. 
8.3.1 Outcomes 
All eligible subjects who receive any protocol treatment will be evaluated for safety 
endpoints. Only eligible subjects that receive at least two BATs infusions will be evaluated 
for efficacy endpoints. Subjects that discontinue or withdraw for a reason other than a DLT 
prior to receiving two BATs infusions within 20% of the target dose will be replaced.  

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Immunologic: 
All eligible subjects who receive any protocol treatment (BATs infusion or pembrolizumab) 
will be evaluated for immunologic response if at least one post treatment sample is 
evaluable for IFN-γ EliSpots analysis. 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations.  The IRB should approve the consent form and 
protocol. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to all ICH E6 principles and Good 
Clinical Practice (GCP), to ethical principles that have their origin in the Declaration of 
Helsinki. 
Before recruitment and enrollment onto this study, the subject will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local 
or state regulations. Once this essential information has been provided to the subject and 
the investigator is assured that the subject understands the implications of participating in 
the study, the subject will be asked to give consent to participate in the study by signing an 
IRB-approved consent form. 
Prior to a subject’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject and by the person who conducted the informed 
consent discussion. 
9.2 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.   
9.2.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard(s) to trial subjects without prior IRB-HSR approval/favorable opinion.   
For any such emergency modification implemented, a UVA IRB modification form must be 
completed by study Personnel within five (5) business days of making the change.   

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9.2.2 Other Protocol Deviations/Violations 
Protocol Deviations: A protocol deviation is any unplanned variance from an IRB approved 
protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or 
the value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
Study personnel will record the deviation, and report to any sponsor or data and safety 
monitoring committee in accordance with their policies.  Deviations should be summarized 
and reported to the IRB at the time of continuing review. 
Protocol Violations: An unplanned protocol variance is considered a violation if the 
variance: 
• 
Has harmed or increased the risk of harm to one or more research 
participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the 
investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
Violations should be reported by study personnel to the IRB within one (1) week of the 
investigator becoming aware of the event.  
9.3 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study investigator.  In the 
case of a study with a drug seeking regulatory approval and marketing, these documents 
shall be retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region.  In all other cases, study 

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documents should be kept on file until six years after the completion and final study report of 
this investigational study. 
9.4 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations, all applicable local regulatory 
laws and regulations and/or the Declaration of Helsinki.  The Principal Investigator is 
responsible for personally overseeing the treatment of all study subjects.  The Principal 
Investigator must assure that all study site personnel, including sub-investigators and other 
study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. It is the 
responsibility of the Principal Investigator to ensure that all study site personnel are aware 
that the study protocol and all data generated is confidential and should not be disclosed to 
third parties (with the exception of local and national regulatory bodies which require access 
for oversight purposes).  
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits will be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of the 
study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 
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Thakur, A., Littrup, P., Paul, E. N., Adam, B., Heilbrun, L. K., and Lum, L. G. (2011) Induction of 
specific cellular and humoral responses against renal cell carcinoma after combination therapy with 
cryoablation and granulocyte-macrophage colony stimulating factor: a pilot study. J Immunother 34, 
457-467 
53. 
Yano, H., Thakur, A., Tomaszewski, E. N., Choi, M., Deol, A., and Lum, L. G. (2014) Ipilimumab 
augments antitumor activity of bispecific antibody-armed T cells. Journal of translational medicine 12, 
191 
54. 
Vaishampayan, U. N., Thakur, A., Rathore, R., Kouttab, N., and Lum, L. G. (2015) Phase I Study of 
Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistance Prostate Cancer patients. 
Prostate Cancer  
55. 
Tazdait, M., Mezquita, L., Lahmar, J., Ferrara, R., Bidault, F., Ammari, S., Balleyguier, C., Planchard, 
D., Gazzah, A., Soria, J. C., Marabelle, A., Besse, B., and Caramella, C. (2018) Patterns of responses in 
metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and 
iRECIST criteria. Eur J Cancer 88, 38-47 

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56. 
Nishino, M., Giobbie-Hurder, A., Gargano, M., Suda, M., Ramaiya, N. H., and Hodi, F. S. (2013) 
Developing a common language for tumor response to immunotherapy: immune-related response criteria 
using unidimensional measurements. Clin Cancer Res 19, 3936-3943 
 
 
 

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11.0 APPENDICES 
11.1 
Appendix 1: Suggested Supportive Care Guidelines for BATs Infusions and 
Example Discharge Instruction Document 
Suggested Supportive Care Guidelines for BATs Infusions 
Note: These are suggested and not required per protocol. 
Medical Issue 
Grade 
Actions 
Allergic 
reactions 
 
 
 
 
 
 
Severe cytokine 
storm 
Grade 3 of true allergic 
reaction. 
 
 
 
 
 
 
 
For next infusion: Diphenhydramine hydrochloride 50 
mg IV, Hydrocortisone sodium succinate 100 mg IV q 
12 hrs (or equivalent) and acetaminophen 650 mg q 8 
hrs 
Appropriate antibiotics, blood products, antiemetics, 
fluids, electrolytes and general supportive care are to 
be used as necessary.  
Subjects with severe or life-threatening reactions will 
be given hydrocortisone sodium succinate 100 mg IV 
q 12 hrs, diphenhydramine 50 mg IV every 6 hours.  No 
one out of 130 subjects has developed CRS or 
required high dose steroids.  Call treating MD and the 
study PI immediately for any suspicion of developing 
CRS. The subject will receive fluid support, pressor 
support, ventilatory support, dialysis, or plasma 
exchange support in the intensive care unit as clinically 
indicated. 
Workup 
for 
macrophage 
activation 
syndrome (MAS) and disseminated intravascular 
coagulation as clinically indicated. Anti-coagulation 
can be administered based on the clinical situation. 
MAS and CRS have not been observed in subjects 
receiving BATs. In the rare occasion that treatment is 
needed for CRS beyond steroids or pressors, 
tocilizumab (ACTEMRA®), which is a humanized 
monoclonal antibody against the interleukin 6 receptor 
(IL-6R), will be given to target and block IL-6 receptors 
in treatment of CRS. The dose will be 8 mg/kg IV given 
as a single 60 min infusion. Serum will be drawn for 
testing as clinically indicated to assess levels of IL-6 
pretreatment and other relevant cytokines post-
treatment as clinically indicated.  IL-6 cannot be tested 
due to complexing between IL-6 and the anti-IL-6 
antibody.  Other cytokines such as IFNγ, TNFα, GM-
CSF, IL-2, IL-7, IL-8, IL-10, IL-12, and RANTES will be 
measured.  

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Infusional 
Reactions for IV 
HER2 
BATs 
(distinct 
from 
allergic 
or 
hypersensitivity 
reactions), 
generally 
develop during 
or shortly after 
infusion 
All grades 
 
 
Grade 
1 
(Transient 
flushing or rash, fever < 
38 oC (<100.4 oF)) 
Grade 2 (Rash, flushing, 
urticaria, dyspnea, drug 
fever ≥ 38 oC (≥100.4 oF)) 
 
Grade 3 (Symptomatic 
bronchospasm with or 
without urticaria, allergy-
related 
edema/ 
angioedema, 
hypotension (except as 
described 
in 
section 
below) 
 
Grade 4 (Anaphylaxis)  
 
Acetaminophen, diphenhydramine, steroids or other 
medications may be given for symptom control as 
needed. Anaphylactic precautions should be observed 
during HER2 BATs administration.  
Slow infusion rate by 50% and monitor subject for 
worsening of condition 
 
Stop infusion; symptom control (diphenhydramine 
hydrochloride) IV, acetaminophen for fever, and 
oxygen if needed) Cells from this infusion must be 
discarded but subjects may receive future infusions 
once symptoms have resolved (cells for this infusion 
must be discarded). 
Stop infusion immediately and remove the infusion 
tube. Cells for this infusion must be discarded.  
Administer diphenhydramine hydrochloride 50 mg IV, 
hydrocortisone 
100 
mg 
IV 
every 
6 
hours. 
Bronchodilators 
for 
bronchospasms, 
and 
other 
medications 
as 
medically 
indicated. 
Hospital 
admission should be considered.  
Stop infusion immediately. Cells for this infusion must 
be discarded. 
Administer diphenhydramine hydrochloride 50 mg IV, 
hydrocortisone 100 mg IV every 6 hours and 
epinephrine as indicated. 
Hypotension: 
usually delayed 
several 
hours 
after infusion 
SBP <90 mm/Hg  
 
SBP<70 mm/Hg 
Call treating MD and the study PI 
 
500 mL normal saline (NS) bolus. If unresponsive, stop 
the HER2 BATs infusion and repeat NS 500 mL. Fluid 
bolus may be repeated as needed or the increased IV 
rate may be maintained. If unresponsive, call treating 
MD and the study PI; subject may require IV pressors  
Hypertension 
 
SBP >160 mm/Hg or DBP 
>90 
Call treating MD and the study PI: 
Subject may require anti-hypertensive medication 
Capillary 
Leak 
Syndrome 
Grade 
3 
(respiratory 
compromise 
or 
fluid 
a. Stop HER2 BATs infusion (once stopped, cells 
should be discarded and infusion may not be restarted)  

Protocol number/short title: Breast-47: Her2-BATS and Pembrolizumab in metastatic breast cancer 
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support 
required 
for 
hypotension) 
 
 
 
 
 
 
 
Grade 4 (pressor support 
or mechanical ventilation 
is required) 
b. Provide appropriate supportive care depending on 
manifestations (e.g. oxygen, IV fluids) 
c. Furosemide 0.5-1 mg/kg (max 40 mg) IV every 6-12 
hours as needed for symptomatic pulmonary vascular 
congestion, tense ascites or significant weight gain (ie, 
10% of baseline), if blood pressure allows. If poor 
response to furosemide alone, add metolazone 0.2-0.4 
mg/kg/day (maximum: 10 mg/dose/day) PO prior to IV 
furosemide. Albumin may be required prior to 
furosemide if albumin < 3.0. If albumin and furosemide 
are given together, close attention to volume status to 
prevent hypotension and prerenal azotemia is 
important. 
Stop HER2 BATs infusion 
Dyspnea 
Oxygen saturation is less 
than 90% 
Brief oxygen supplementation 
If the subject is fluid overloaded, hypoxic and 
hypotensive, treatment should be stopped (cells for this 
infusion should be discarded) and vasopressor support 
initiated, as needed. If hypoxia continues to worsen, 
does not respond to the above measures, and is 
considered 
to 
be 
life 
threatening, 
mechanical 
ventilation should be initiated.  
Arrythmia 
Any 
evidence 
of 
arrhythmia not present at 
baseline 
Asymptomatic 
atrial 
irregularities related to an 
elevated temperature, but 
without 
evidence 
of 
ischemia 
or 
clinically 
significant hypotension 
Ischemia or Grade 3 or 
worse cardiac toxicity 
Immediate ECG evaluation 
 
Monitor but continue therapy 
 
 
 
Stop HER2 BATs infusion 
Neurotoxicity 
Grade 3 or 4, except 
confusion  
 
If there are persistent neurologic signs and symptoms 
of possible CNS infection and/or cytokine storm, the 
attending team will proceed with appropriate diagnostic 
measures (e.g. spinal tap, MRI, or CT evaluations). 

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Grade 3 or 4 confusion 
(not fever related) 
 
 
Headaches 
Persistent confusion beginning after the start of an 
HER2 BATs infusion which is clearly not temperature 
related or related to supportive care medicines 
(diphenhydramine, 
morphine, 
etc.) 
will 
require 
immediate treatment stoppage.  
Imitrex 
50 
mg 
dose 
or 
ibuprofen, 
and/or 
acetaminophen. If the patient experienced headaches 
at a previous infusion, pre-medicate with 50 mg Imitrex 
Fever 
Persistent 
temperature 
elevations (>6 hours) of 
40oC 
or 
greater 
not 
responding to antipyretics 
 
 
 
 
 
Grade 2 chills, which may 
accompany temperature 
changes 
Grade 3 Confusion 
Hold HER2 BATs 
Continue acetaminophen (650 mg/dose), maximum 
dose of 3000 mg/day) every 8 hours alternating with 
ibuprofen 600 mg every 8 hours as needed  
Subjects developing fever following their first HER2 
BATs treatment through 30 days following their last 
HER2 BATs treatment should have blood cultures 
obtained if infection is suspected. If there is a high level 
of suspicion, the subject should be placed on a broad-
spectrum antibiotic, such as cefepime until afebrile and 
blood cultures have remained negative for 48 hours. 
 
Can be treated with meperidine 25 to 75 mg IV 
(maximum dose of 75 mg). 
Confusion related to fever will be managed by 
aggressive use of antipyretics and will not require dose 
reduction or drug stoppage, if the confusion normalizes 
with initiation of aggressive antipyretic measures 
 
 
 

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Example Discharge Instruction Document 
Discharge Instructions Following T-cell Infusions 
IRB-HSR # ______ 
Name: _________________________ 
 
Subject ID#: _________________ 
In the 24 - 48 hours following infusion of armed activated T Cells, you may experience any of 
the following side effects. Although these are usually minimal and will go away, it is important 
to your well-being that you report any of the following: 
• 
Difficulty breathing 
• 
Shaking chills 
• 
Fever – take your temperature every 4 hours while awake. Notify Dr. _________ if 
you experience fever higher than 100.5oF. 
• 
Nausea and vomiting 
• 
Headache (unrelieved by acetaminophen (Tylenol) and ibuprofen (Motrin) or 
caffeinated beverages such as Coke)  
Please stay locally (within about 40 minutes’ drive) to UVA with a caregiver for two nights. If 
after 2 nights you feel well and do not have any symptoms, you may travel outside of this 
area.  
Please continue to take acetaminophen (Tylenol) and ibuprofen (Motrin) as directed for 24 
hours following your discharge. If you experience shaking chills, you may take 25-50 mg of 
diphenhydramine (Benadryl). It is also very important to drink plenty of fluids during this 
time. If you develop fever over 100.5 after stopping the medications, restart the combination 
for another 12 hours (3 doses).  Notify the Doctor if your fever persists beyond 36 hours. 
Please also complete the table on the following page with the time you take each medication, 
your temperature and blood pressure and any comments you may have. Please continue 
filling out the table for as long as you are taking medications for side effects of the infusion. 
Add rows for any additional medications you are asked to take for these side effects (for 
example, diphenhydramine (Benadryl)).  
If you have any of the above side effects or have anything else that concerns you within the 
week following your T cell infusion, please notify us at one of the following numbers: 
During office hours (Monday – Friday 8am-4:30pm): _________ 
Outside of office hours: call 434 924-0000 and ask to page the on call Heme-Onc team doctor  
Subject signature ______________________________ 
 
Date ________________ 
Nurse signature ______________________________ 
 
Date ________________

Protocol number/short title: Breast-47: Her2-BATS and Pembrolizumab in metastatic breast cancer 
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Version/Date: Version 11.1/12 April 2023 
 
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Name _________________________ 
 
Subject ID# _______________ 
Date/Time 
Medication 
– 
protocol 
prescribed 
Other 
medications 
Temperature 
Blood 
Pressure 
Heart rate 
Symptoms/Comments* 
*Please include start and stop times for symptoms 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol number/short title: Breast-47: Her2-BATS and Pembrolizumab in metastatic breast cancer 
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Version/Date: Version 11.1/12 April 2023 
 
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Date/Time Medication – 
protocol 
prescribed 
Other 
medications 
Temperature Blood 
Pressure 
Heart 
rate 
Symptoms/Comments* 
*Please include start and stop times for symptoms 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 

Protocol number/short title: Breast-47: Her2-BATS and Pembrolizumab in metastatic breast cancer 
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Version/Date: Version 11.1/12 April 2023 
 
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Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
Acetaminophen 
650 mg every 8 hrs 
 
 
 
 
 
 
Ibuprofen 
600 mg every 8 hrs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject signature ______________________________ 
 
Date ________________