A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-Associated Cancers
Phase: PHASE1
Conditions: Papillomavirus Infections, Cervical Intraepithelial Neoplasia, Carcinoma In Situ, Vulvar Neoplasms, Vulvar Diseases
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: HPV-16 E7 TCR
Version Date:  12/5/2024
1
Abbreviated Title: HPV-16 E7 TCR
NIH Protocol #: 16C0154
NCT #: NCT02858310
OSP Number: 1604-1517
IBC Number: RD-16-V-04
Version Date: 12/5/2024
A Phase I/II Trial of T Cell Receptor Gene Therapy Targeting HPV-16 E7 for HPV-
Associated Cancers
NIH Principal Investigator:
Scott Norberg, DO
Center for Immuno-Oncology (CIO)
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
10 Center Drive, Room 3-3132
Bethesda, MD 20892
Phone: 301-275-9668
Email: scott.norberg@nih.gov  
Drug Name:
E7 TCR 
Transduced PBL
Fludarabine
Cyclophosphamide
Aldesleukin
IND Number:
16959
16959
16959
16959
Sponsor:
CCR, NCI
CCR, NCI
CCR, NCI
CCR, NCI
Manufacturer:
CC DTM
Generic
Generic
Generic
Supplier:
CC DTM
CC Pharmacy
CC Pharmacy
CC Pharmacy
Coordinating Center: NIH NCI Center for Cancer Research (CCR)
Participating Sites:  See Appendix A for role of participating sites
Safety Monitoring Committee (SMC):  NCI Intramural CCR SMC

Abbreviated Title: HPV-16 E7 TCR
Version Date:  12/5/2024
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PRÉCIS
Background:
•
Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical, 
vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly 
palliated by standard therapies.
•
HPV-16+ cancers constitutively express the HPV-16 E7 oncoprotein, which is absent 
from healthy human tissues.
•
Administration of T cell receptor (TCR) gene engineered T cells can induce objective 
tumor responses in certain malignancies including HPV-16+ cancers.
•
T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) display 
specific reactivity against HLA-A2+, HPV-16+ target cells.
Objectives:
Phase I Primary Objective
•
To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of 
metastatic HPV-16+ cancers.
Phase II Primary Objective
•
To determine safety and efficacy of E7 TCR cells plus aldesleukin for the treatment of 
metastatic HPV-16+ cancers.
Eligibility:
•
Patients greater than or equal to 18 years old with metastatic or refractory/recurrent HPV-
16+ cancer.
•
Prior first line systemic therapy is required unless the patient declines standard treatment.
•
Patients must be HLA-A*02:01-positive.
Design: 
•
This is a phase I/II clinical trial that will test the safety and efficacy of E7 TCR cells. 
•
All patients will receive a non-myeloablative lymphocyte-depleting preparative regimen 
of cyclophosphamide and fludarabine followed by a single infusion of E7 TCR cells. Cell 
infusion will be followed by high-dose aldesleukin.
•
Re-enrollment will be allowed for a small number of subjects.

Abbreviated Title: HPV-16 E7 TCR
Version Date:  12/5/2024
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TABLE OF CONTENTS
PRÉCIS...........................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION....................................................................................................................6
1.1
Study Objectives............................................................................................................6
1.2
Background and Rationale.............................................................................................6
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT........................................................16
2.1
Eligibility Criteria........................................................................................................16
2.2
Screening Evaluation...................................................................................................18
2.3
Participant Registration and Status Update Procedures...............................................20
2.4
Baseline Evaluations....................................................................................................21
3
STUDY IMPLEMENTATION..............................................................................................21
3.1
Study Design................................................................................................................21
3.2
Drug Administration....................................................................................................25
3.3
Aldesleukin: Intravenous Administration....................................................................28
3.4
Potential Repeat Treatment..........................................................................................28
3.5
On Study Evaluation....................................................................................................29
3.6
Post treatment Evaluation (Follow-Up).......................................................................30
3.7
Cost and Compensation ...............................................................................................31
3.8
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................31
3.9
Schedule of Evaluations ..............................................................................................33
4
CONCOMITANT MEDICATIONS/MEASURES ...............................................................35
4.1
Prohibited Medications................................................................................................35
4.2
Infection Prophylaxis...................................................................................................35
4.3
Other Concomitant medications to control Aldesleukin side effects ..........................36
5
CORRELATIVE STUDIES FOR RESEARCH....................................................................36
5.1
Biospecimen Collection...............................................................................................36
5.2
Gene-therapy-specific follow-up.................................................................................38
5.3
Sample Storage, Tracking and Disposition .................................................................39
6
DATA COLLECTION AND EVALUATION......................................................................40

Abbreviated Title: HPV-16 E7 TCR
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6.1
Data Collection ............................................................................................................40
6.2
Data Sharing Plans.......................................................................................................41
6.3
Response Criteria.........................................................................................................42
6.4
Toxicity Criteria...........................................................................................................47
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .....47
7.1
Definitions ...................................................................................................................47
7.2
OHSRP Office of Compliance and Training/IRB Reporting ......................................47
7.3
NCI Clinical Director Reporting .................................................................................47
7.4
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ......48
7.5
Institutional Biosafety Committee (IBC) Reporting Criteria ......................................48
7.6
NIH Required Data and Safety Monitoring Plan.........................................................49
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................50
8.1
Definitions ...................................................................................................................50
8.2
Assessment of Safety Events.......................................................................................51
8.3
Reporting of Serious Adverse Events..........................................................................51
8.4
Waiver of expedited reporting to CCR........................................................................52
8.5
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................53
8.6
Reporting Pregnancy ...................................................................................................53
8.7
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ...............54
8.8
Sponsor Protocol Deviation Reporting........................................................................54
9
CLINICAL MONITORING ..................................................................................................54
10
STATISTICAL CONSIDERATIONS...................................................................................55
11
COLLABORATIVE AGREEMENTS ..................................................................................56
11.1
Multi-Institutional Guidelines .....................................................................................56
12
HUMAN SUBJECTS PROTECTIONS ................................................................................57
12.1
Rationale for Subject Selection ...................................................................................57
12.2
Participation of Children..............................................................................................57
12.3
Participation of Subjects Unable to Give Consent ......................................................57
12.4
Evaluation of Benefits and Risks/Discomforts............................................................57
12.5
Risks/Benefits Analysis...............................................................................................62
12.6
Consent Process and Documentation...........................................................................62

Abbreviated Title: HPV-16 E7 TCR
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13
REGULATORY AND OPERATIONAL CONSIDERATIONS ..........................................63
13.1
Study Discontinuation and Closure .............................................................................63
13.2
Quality Assurance and Quality Control.......................................................................63
13.3
Conflict of Interest Policy............................................................................................64
13.4
Confidentiality and Privacy .........................................................................................64
14
PHARMACEUTICAL INFORMATION..............................................................................65
14.1
Interleukin-2 ...............................................................................................................65
14.2
Fludarabine ..................................................................................................................66
14.3
Cyclophosphamide ......................................................................................................67
14.4
Cell Preparation (E7 TCR Transduced PBL) ..............................................................68
14.5
Mesna...........................................................................................................................69
14.6
Filgrastim.....................................................................................................................70
14.7
Trimethoprim and Sulfamethoxazole Double Strength (TMP/SMX DS) ...................70
14.8
Aerosolized Pentamidine in Place of TMP/SMX DS..................................................70
14.9
Herpes Virus Prophylaxis............................................................................................71
14.10 Fungal Prophylaxis ......................................................................................................71
14.11 Support Medications....................................................................................................72
15
REFERENCES.......................................................................................................................73
16
APPENDICES........................................................................................................................75
16.1
Appendix A:  Participating Site Roles and Oversight Plan .........................................75
16.2
Appendix B: Adverse Events Occurring In ≥10% Of Patients Treated With 
Aldesleukin (N=525)1..................................................................................................76
16.3
Appendix C: Expected IL-2 Toxicities And Their Management ................................77
16.4
Appendix D: Interleukin-2 Toxicities Observed In Patients Treated At The NIH 
Clinical Center.............................................................................................................80
16.5
Appendix E: ECOG Performance Status Scale ...........................................................81

Abbreviated Title: HPV-16 E7 TCR
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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Phase I Primary Objective
•
To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of 
metastatic HPV-16+ cancers.
1.1.2
Phase II Primary Objective
•
To determine the safety and efficacy of E7 TCR cells plus aldesleukin for the treatment 
of metastatic HPV-16+ cancers.
1.1.3
Secondary Objective
•
To assess progression-free survival. 
1.1.4
Exploratory Objective
•
To conduct exploratory immunologic studies to understand and improve the administered 
treatment.
1.2
BACKGROUND AND RATIONALE
Adoptive T cell therapy (ACT), the administration of autologous tumor-specific T cells, can 
mediate durable, complete regression of certain advanced-stage malignancies. (1) T cells for 
ACT can be directed against diverse tumors through T cell receptor (TCR) gene therapy in which 
peripheral blood T cells are transduced to express a TCR targeting a tumor antigen. This clinical 
protocol is for a treatment that targets HPV-16+ cancers with TCR gene therapy directed against 
HPV-16 E7.  HPV-16 E7 is an ideal immunotherapeutic target that is constitutively expressed by 
and important for the survival of HPV-16+ cancers, and it is not expressed by healthy human 
tissues.(2)  The rationale for this protocol is based on the application of the potent 

Abbreviated Title: HPV-16 E7 TCR
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immunotherapy of ACT to the attractive therapeutic target of HPV-16 E7 in advanced-stage 
HPV-16+ cancers including cervical, oropharyngeal, anal, vulvar, vaginal, and penile 
malignancies. HPV-Associated Malignancies
In the United States, there are more than 11,000 deaths from cancer at HPV-associated sites 
annually (Table 1). (3-6)   Metastatic or recurrent/refractory malignancies from these sites are 
incurable and difficult to palliate.  Responses to chemotherapy are variable but generally short-
lived. (7-9) In a Gynecologic Oncology Group randomized trial comparing four cisplatin-based 
doublets as first line therapy for cervical cancer the response rates were 22 to 29 percent and 
median PFS was 4 to 6 months and median overall survival (OS) was 10 to 13 months. (10)  The 
addition of bevacizumab to combination chemotherapy has been reported to increase overall 
survival by 3.7 months, but the vast majority of patients die of their disease within 2 years. (11) 
Randomized trials of second line therapy are lacking, but response rates for single agents are 
generally reported to be less than 20 percent. (12) For oropharyngeal cancer, estimates of the 
chemotherapy responsiveness can be inferred from data on the oropharyngeal site in subset 
analyses from clinical trials for head and neck cancers.  In a pivotal clinical trial that established 
platinum, 5-flurouracil, plus cetuximab as first line therapy in head and neck cancer, patients 
with oropharyngeal tumors experienced PFS of 4 to 6 months and OS of 8 to 11 months. (8)  As 
with cervical cancer, randomized trials of second line therapy following platinum treatment 
failure are lacking.  A phase II trial of cetuximab, a monoclonal antibody targeting epidermal 
growth factor receptor (EGFR) reported a response rate of 13 percent with time to progression of 
70 days; cetuximab now represents the most promising second line therapy for this disease. (13) 
Thus, second line therapies for HPV-associated tumors have low response rates and poor 
response duration, and novel therapies are needed.
Table 1:  Estimated deaths from cancers at HPV-associated sites in the United States in 
2014.
Adapted from: American Cancer Society.  Cancer Facts & Figures 2014.  Atlanta: American 
Cancer Society; 2014.
Site
Deaths
Oral cavity & pharynx (not tongue or mouth)
4,170
Cervix
4,020
Vulva
1030
Female genital
880
Penis
320
Anus
950
Total
11,370

Abbreviated Title: HPV-16 E7 TCR
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1.2.1
Tumor-Infiltrating T Cells Targeting HPV Oncoproteins for HPV+ Cancers 
We are conducting a clinical trial of autologous HPV-targeted tumor-infiltrating T cells for 
metastatic HPV+ cancers in which objective tumor responses have been observed in cervical, 
oropharyngeal, and anal cancers. In this protocol T cell cultures are generated from fragments of 
resected metastatic tumors. T cell cultures are screened for reactivity against HPV E6 and E7. 
Reactive cultures are preferentially selected for further expansion and administration to the 
patient. We have reported the results of treatment of nine patients with metastatic cervical cancer 
including two patients with ongoing complete responses after a single infusion of T cells (14). In 
these patients the frequency of HPV-reactive T cells in the infused cells correlated positively 
with clinical response to treatment. Patients who received T cells with little or no reactivity 
against the HPV oncoproteins did not experience objective tumor regression. In addition, the 
frequency of peripheral blood T cells with HPV reactivity one month after treatment was 
positively associated with clinical response. While these results suggest a possible role for HPV-
specific T cell in mediating tumor regression limited conclusions can be drawn. The 
administered T cells were not purified for HPV reactivity; hence T cells with non-HPV 
reactivities were also given and may have played an important role in the clinical responses that 
were observed. Furthermore, the treatment is logistically complicated as it requires a surgical 
procedure, prolonged cell culture, and an HPV reactivity screening assay. Finally, not all tumor 
specimens yield T cells with HPV reactivity, and when this is the case it is not possible to confer 
reactivity. A more “off-the-shelf” cell therapy in which T cells are generated without an 
operation and have consistent reactivity against an HPV oncoprotein would be desirable.
1.2.2
Targeting of HPV oncoproteins with TCR Gene Therapy
The HPV-16 E6 and E7 oncoproteins are constitutively expressed by and important to the 
survival of HPV-16+ tumor cells, and absent from healthy human tissues. Approximately 65 
percent of cervical, 70 percent of oropharyngeal, and 90 percent of anal cancers, as well as many 
vulvar, vaginal, and penile cancers, express these antigens, making them highly attractive 
therapeutic targets. (1, 2) T cells recognize epitopes of intracellular antigens that are presented by 
HLA molecules on the surface of tumor cells.  CD8+ T cells, which specialize in direct 
recognition and killing of virally infected cells and tumor cells, require presentation of cognate 
peptide by a class I HLA molecule.  HLA-A*02:01 is the most common class I HLA allele in the 
United States population, expressed by 40 to 50 percent of Caucasians.
We are presently conducting a clinical trial of TCR gene engineered T cells targeting an HLA-
A2 restricted epitope of HPV-16 E6 (E6 TCR). In this protocol, T cells from the patient’s 
peripheral blood are transduced with a retrovirus to express the E6 TCR. The transduced T cells 
are expanded ex vivo and administered back to the patient intravenously. Before cell 
administration the patient receives a lymphodepleting chemotherapy conditioning regimen to 
promote infused T cell engraftment. Following cell infusion the patient receives high-dose bolus 
aldesleukin, which is dosed to individual patient tolerance. We have, in a dose escalation trial, 
treated nine patients with this regimen. Dose limiting toxicity was not encountered (the 
maximum dose tested was in the range of 1 x 1011 to 2 x 1011 cells). Off target toxicity was not 
observed. Cytokine storm was not observed. Of the initial seven evaluable patients, one patient 
has experienced a partial tumor response that is ongoing after 6 months. (15) 

Abbreviated Title: HPV-16 E7 TCR
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1.2.3
E7 TCR discovery and characterization
E711-19 is a naturally processed epitope of HPV-16 E7 that binds to HLA-A*02:01 and that has 
been isolated from the surface of HPV-16+ HLA-A*02:01+ tumor cells. (16) We identified the 
nucleotide sequence of a TCR targeting E711-19 from the cervix-infiltrating T cells of a patient 
with cervical intraepithelial neoplasia who received a therapeutic cancer vaccine targeting HPV-
16 E7. The nucleotide sequence was codon optimized for expression in human tissues and the 
TCR constant regions were swapped for their mouse counterparts, which in other receptors has 
improved TCR alpha/beta chain pairing. TCR expression was improved by reversing the order of 
the alpha and beta genes, and by making cysteine substitutions in the TCR constant regions and 
hydrophobic substitutions in the transmembrane region of the alpha chain constant region. (17, 
18) The TCR sequence insert was cloned into the MSGV1 retroviral vector (Figure 1), which 
was chosen for this clinical trial based on its excellent safety record in treating greater than 200 
patients. 
Figure 1:  E7 TCR vector map. A TCR targeting E711-19 was isolated from the cervix-infiltrating 
lymphocytes of a patient with cervical intraepithelial neoplasia. The nucleotide sequence of the alpha 
and beta chains was determined, codon optimized for expression in human tissues, and the constant 
regions swapped for their mouse counterparts. A MSGV1 retroviral vector encoding this TCR was 
constructed. This retroviral vector consists of 7,310 base pairs and includes a 5’LTR from the murine 
stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor sites 
(SA).  Alpha and beta chains of the E7 TCR are linked by a furin 2A peptide.
E7 TCR
7310 bp
AmpR
SD
SA
3' LTR
5' LTR
Furin 2A linker
Beta Chain
Alpha Chain
Eco RI (1804)
Nco I (2)

Abbreviated Title: HPV-16 E7 TCR
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Peripheral blood T cells transduced to express the E7 TCR display high avidity for the E711-19 
peptide (Figure 2) and CD8-independent HLA-A*02:01/E711-19 tetramer binding (Figure 3). 
They specifically recognize a panel of HPV-16+ HLA-A*02:01+ cervical and oropharyngeal 
cancer cell lines but not cell lines that lack HLA-A*02:01 or HPV-16 (Figure 4). Thus, gene 
engineered T cells expressing the E7 TCR can specifically target HPV-16+ HLA-A*02:01+ 
cancers. In contrast to TCRs that have had unexpected cross-reactivity against normal human 
proteins, this TCR was isolated directly from a human T cell.(2) Hence, it was subjected to 
thymic selection and is unlikely to possess avid reactivity against self-antigens. The 
complementarity determining regions of the TCR have not been modified; therefore, there is no 
chance that cross-reactivity has been artificially introduced.  The target epitope is derived from a 
viral protein, and no more than 6 of its 9 amino acids are shared with any human protein (Table 
2). There is no cross reactivity of this TCR with epitopes of human proteins that share six amino 
acids or five amino acids plus a conservative amino acid substitution (Figure 5). In addition, 
alanine scanning of E711-19 identified four important residues for recognition (Figure 6). Cross 
reactivity was not detected against epitopes of human proteins that shared these residues (Table 
2). 
IFN- (pg/mL)
6
7
8
9
10
11
12
No peptide
0
5000
10000
E7 TCR
E6 TCR
>
-log[E711-19] (M)
Figure 2:  T cells transduced to express the E7 TCR demonstrated high avidity for the E711-19 
peptide. T cells from PBMC were transduced to express the E7 TCR.  Functional avidity was tested by 
coculture with T2 cells pulsed with titrated concentrations of E711-19 peptide.

Abbreviated Title: HPV-16 E7 TCR
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Figure 3:  Peripheral blood T cells transduced to express the E7 TCR display CD8-independent 
HLA-A*02:01/E711-19 tetramer binding. T cells from PBMC were transduced to express the E7 TCR. 
Dot plots shown are gated on PI- lymphocytes and either CD8+ or CD8- cells as indicated above the dot 
plots. The x-axis is mouse T cell receptor beta chain expression. The y-axis is tetramer binding.
IFN- (pg/mL)
293-A2 + E7(11-19)
293-A2 + E6(29-38)
CaSki
SCC90
SCC152
624 E7
624 E6
Alb
Panc1
SiHa
Ane
0
5000
10000
10000
50000
Untransduced
E7 TCR
+   +   +   +   -   -   -   +   -
HPV-16
>
+   +   +   +   +   +   -   -   -
HLA-A2
Figure 4:  T cells transduced to express the E7 TCR specifically recognized HPV-16+ HLA-
A*02:01+ tumor lines   T cells transduced with E7 TCR were cocultured with targets expressing HPV-
16 and HLA-A2 or with negative controls. Target cell line expression of HPV-16 and HLA-A2 is 
indicated below each label on the x-axis.  
Donor 1
CD8 +
CD8 -
Donor 2
79
2
0
19
84
1
0
15
70
2
0
27
68
3
0
29
HLA-A2/E711-19 tetramer
mTRBC

Abbreviated Title: HPV-16 E7 TCR
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A)
B)
 
Figure 5: E7 TCR transduced T cells did not show cross reactivity against human peptides. E7 TCR 
transduced human T cells were tested for recognition of peptides identified by the BLAST search shown 
in Table 2. Target cells were T2 cells loaded with either the E7 peptide (E7) as a positive control, 
peptides identified by number in Table 2, or no peptide (A).  Peptides which elicited a weak response by 
E7TCR were further tested for recognition at titrated concentrations (B).
IFN-(pg/mL)
E7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
no peptide
0
5000
10000
15000
20000
IFN-(pg/mL)
E7
1
6
7
9
12
17
no peptide
0
10000
20000
30000
1
0.1
0.01
0.001
>
Peptide Conc. [uM]

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Figure 6: Serial alanine substitutions to the E711-19 target peptide revealed positions 4-7 to be the 
most crucial for recognition by E7 TCR transduced T cells. Human T cells were transduced to express 
the E7 TCR. The transduced cells with cocultured with T2 cells loaded with varying concentrations of 
E711-19 peptide (E7) or E711-19 with an alanine substitution at the position indicated by the x-axis labels. E6 
peptide (E6) is an HLA-A2 restricted negative control peptide.
Target peptide
IFN- (pg/mL)
E7
1A
2A
3A
4A
5A
6A
7A
8A
9A
E6
0
4000
8000
12000
16000
1
0.1
0.01
0.001
>
Peptide Conc. [uM]

Abbreviated Title: HPV-16 E7 TCR
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Table 2 BLAST search for peptides with at least 6 (or least 5 identical + 1 conservative change) 
amino acids shared with E711-19. Capital/Underlined = Amino Acid Identical to E7 epitope, Capital/Not 
Underlined = Conservative change. *=Peptides that demonstrates weak cross-reactivity only at 
supraphysiological concentrations.
1.2.4
Safety Considerations
The safety of infusion of large numbers of retrovirally modified tumor reactive T-cells has been 
demonstrated in clinical studies conducted at the NIH Clinical Center. (19, 20) Non-
myeloablative chemotherapy conditioning and high-dose aldesleukin have well-characterized 
toxicity which is discussed in Section 14.1 of this study. (21) The chemotherapy used in this 
protocol has been administered to over 500 patients and all have reconstituted their 
hematopoietic system.
Patients at the NIH Clinical Center have been treated with up to 1.77 x 1011 gene engineered 
cells. The upper limit of the dose range for this trial was therefore set at 1 x 1011 transduced cells. 
The protocol is designed with a run in dose escalation but unexpected toxicities are unlikely 
because 1) the TCR targets a foreign viral protein that does not exist in the human genome so 
there is no chance of toxicity from targeting healthy tissue that unexpectedly expresses the target, 
2) the TCR came from a human and therefore has been selected in thymus to not have 
autoreactivity, so autoimmunity is unlikely, 3) the TCR specificity has not been altered by 
affinity enhancement so there is no chance that cross reactivity against normal human proteins 

Abbreviated Title: HPV-16 E7 TCR
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15
has been introduced, and 4) testing against human peptides with similarity to the target epitope 
and with human peptides identified by alanine scanning revealed no cross reactivity (2).
Other protocols at the NIH Clinical Center have administered over 1 X 1011 tumor infiltrating 
lymphocytes (TIL) with widely heterogeneous reactivity including CD4, CD8, and NK cells 
without infusional toxicities. Experience at the NIH Clinical Center treating more than 200 
patients with advanced cancers with genetically engineered T cells indicates that these cells do 
not have a significant risk of malignant transformation in this setting. While the risk of 
insertional mutagenesis is a known possibility using retroviral vectors, this has only been 
observed in the setting of infants treated for XSCID, WAS and X-CGD using retroviral vector-
mediated gene transfer into CD34+ bone marrow cells. In the case of retroviral vector-mediated 
gene transfer into mature T cells there has been no evidence of long-term toxicities since the first 
NCI sponsored gene transfer study in 1989. Although continued follow-up of all gene therapy 
patients will be required, data suggest that administration of retrovirally transduced mature T 
cells is a safe procedure. While the risk of insertional mutagenesis is extremely low, the 
proposed protocol follows all current FDA guidelines regarding testing and follow up of patients 
receiving gene transduced cells.
Update with amendment H: The initial protocol included combination of E7 T cells with 
pembrolizumab in additional dose levels (dose level 4 and dose level 5). Clinical responses to E7 
T cells without pembrolizumab were observed at the lower dose levels. The decision was made 
to remove dose level 4 and dose level 5 from the protocol due to the unknown safety of 
combination therapy and the apparent clinical activity of E7 T cells without pembrolizumab.
Because a safe dose of cells was determined in the phase I part of the trial, and some patients 
experienced a partial response, and each treatment is a single dose of E7 T cells, the protocol was 
amended to permit retreatment of patients with a partial response.
Update with amendment I: One dose-limiting toxicity occurred in the first 11 patients on this 
protocol. The patient had impaired lung function from rapidly progressing cancer in the lungs 
and experienced severe lung, cardiovascular, and kidney toxicity that required temporary 
mechanical ventilation, pressors, and hemodialysis, that resulted in soft tissue injury to the distal 
lower extremities. To increase safety, patients will be required to have a resting pulse oxygen 
measurement on room air as outlined in Sections 2.1.2.9, 2.4.2 and 2.4.3. The maximum 
tolerated dose found in the phase I portion of the study was 1 x 1011 E7 TCR T cells.  
Update with amendment J: One patient treated on the phase II portion of the study experienced 
delirium and hypotension after E7 TCR T Cells and one dose of aldesleukin that required 
mechanical ventilation, vasopressors and hemodialysis. The patient also developed a HLH-like 
disorder characterized by fevers, prolonged low blood counts, and elevated ferritin and soluble 
CD25 that resolved following treatment with steroids. The patient also had delayed recovery of 
blood counts that was contributed to prior chemotherapy, prior pelvic radiation and poor 
nutrition. To further assess safety, patients will now also have a neurological assessment with 
neurological exam performed at baseline and daily during treatment with aldesleukin as outlined 
in Sections 2.2.2.2, 3.3 and 0. 

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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria
2.1.1.1
Measurable (per criteria in Section 6.3) metastatic or refractory/recurrent HPV-16+ 
cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction 
(PCR)-based test).
2.1.1.2
Patients must be HLA-A*02 by low resolution typing, and HLA-A*02:01 by one of the 
high resolution type results.
2.1.1.3
All patients must have received prior first line standard therapy or declined standard 
therapy.
2.1.1.4
Patients with three or fewer brain metastases that have been treated with surgery or 
stereotactic radiosurgery are eligible.  Lesions that have been treated with stereotactic 
radiosurgery must be clinically stable for one month before protocol treatment. Patients 
with surgically resected brain metastases are eligible. 
2.1.1.5
Greater than or equal to 18 years of age
2.1.1.6
Able to understand and sign the Informed Consent Document.
2.1.1.7
Clinical performance status of ECOG 0 or 1, as shown in Appendix E.
2.1.1.8
Individuals must be willing to practice birth control from the time of enrollment on this 
study up to twelve (12) months after treatment.  Individuals must be willing to undergo 
testing for HPV-16 prior to becoming pregnant after this period. 
2.1.1.9
Individuals of childbearing potential must have a negative pregnancy test because of the 
potentially dangerous effects of the treatment on the fetus. Individuals of childbearing 
potential are defined as all individuals except individuals who are postmenopausal or 
who have had a hysterectomy.  Postmenopausal will be defined as individuals over the 
age of 55 who have not had a menstrual period in at least one year. Because there is a 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with E7 TCR transduced PBL, breastfeeding should be discontinued if the individuals is 
treated with E7 TCR transduced PBL. These potential risks may also apply to other 
agents used in this study.
2.1.1.10 Serology:
•
Seronegative for HIV antibody.  (The experimental treatment being evaluated in 
this protocol depends on an intact immune system.  Patients who are HIV 
seropositive can have decreased immune-competence and thus are less responsive 
to the experimental treatment and more susceptible to its toxicities.)
•
Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody.  If 
hepatitis C antibody test is positive, then the patient must be tested for the 
presence of antigen by RT-PCR and be HCV RNA negative.
a.
Hematology:
•
Absolute neutrophil count greater than 1000/mm3 without the support of 
filgrastim.

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•
WBC ≥ 3000/mm3
•
Platelet count ≥ 100,000/mm3
•
Hemoglobin > 8.0 g/dL 
b. Chemistry:
•
Serum ALT/AST ≤ 2.5 times the upper limit of normal
•
Calculated creatinine clearance (CCr) ≥50 mL/min/1.732 using the Cockcroft-
Gault equation
•
Total bilirubin ≤ 1.5 mg/dL, except in patients with Gilbert’s Syndrome who must 
have a total bilirubin less than 3.0 mg/dL
c.
More than four weeks must have elapsed since any prior systemic therapy at the time 
the patient receives the E7 TCR cells.
Note: Patients may have undergone minor surgical procedures within the past three 
weeks, as long as all toxicities have recovered to Grade 1 or less or as specified in the 
eligibility criteria in Section 2.1.1.
2.1.2
Exclusion Criteria
2.1.2.1
Active systemic infections (for e.g.: requiring anti-infective treatment), coagulation 
disorders or other active major medical illnesses of the cardiovascular, respiratory or 
immune system, as evidenced by a positive stress thallium or comparable test, 
myocardial infarction, cardiac arrhythmias, severe obstructive or restrictive pulmonary 
disease.  Patients with abnormal pulmonary function tests but stable obstructive or 
restrictive pulmonary disease may be eligible. 
2.1.2.2
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency 
Disease).
2.1.2.3
Concurrent opportunistic infections (The experimental treatment being evaluated in this 
protocol depends on an intact immune system.  Patients who have decreased immune 
competence may be less responsive to the experimental treatment and more susceptible 
to its toxicities).
2.1.2.4
Patients with autoimmune diseases such as Crohn’s disease, ulcerative colitis, 
rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus 
erythematosus.  Hypothyroidism, vitiligo and other minor autoimmune disorders are not 
exclusionary.
2.1.2.5
Patients on immunosuppressive drugs including corticosteroids. With the exception of:
•
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection)
•
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent; or,
•
Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication)

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2.1.2.6
History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine 
or aldesleukin.
2.1.2.7
Patients with a history of coronary revascularization or ischemic symptoms unless 
patient has a normal cardiac stress test.
2.1.2.8
Documented LVEF of less than or equal to 45% tested.  The following patients will 
undergo cardiac evaluations
•
Clinically significant atrial and/or ventricular arrhythmias including but not 
limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart 
block or 
•
Age ≥ 50 years old
2.1.2.9
Any other condition, which would, in the opinion of the Principal Investigator, indicate 
that the subject is a poor candidate for the clinical trial or would jeopardize the subject 
or the integrity of the data obtained. 
2.1.2.10 Subjects with baseline screening pulse oxygen level of < 95% on room air will not be 
eligible. If the underlying cause of hypoxia improves, then they may be reevaluated.
2.1.3
Recruitment Strategies
Patients for this protocol will be recruited via standard CCR mechanisms including posting to 
NIH websites (i.e., clinicaltrials.gov) and social media platforms, physician and self-referrals as 
well as various advertising venues.  All advertisements, letters and other recruitment efforts will 
be submitted to the IRB for approval prior to their implementation.
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective subjects 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing  MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in Section 12.6.2.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a patient has signed 
the consent.
2.2.2.1
Any time prior to starting the chemotherapy regimen:
a.
HLA typing 

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b. HPV genotype testing of tumor. Archival tissue may be used or a new biopsy may be 
obtained.
c.
Venous assessment (as per apheresis clinic policy)
2.2.2.2
Within 4 weeks prior to starting the chemotherapy regimen:
a.
Complete history and physical examination, including weight, and vital signs noting 
in detail the exact size and location of any lesions that exist.  (Note: Patient history 
may be obtained within 8 weeks.)
b. EKG
c.
Pulmonary Function Testing for patients with a prolonged history of cigarette 
smoking (20 pack/year of smoking within the past 2 years) or symptoms of 
respiratory dysfunction. (Note: If performed prior to receiving treatment, this does not 
need to be repeated unless clinically indicated.  Test results from outside NIH may be 
accepted per investigator discretion).
d. If available, previous CT of the chest, abdomen and pelvis, and brain MRI or PET to 
evaluate the status of disease.   Additional scans and x-rays may be performed if 
required to determine patient eligibility or if clinically indicated based on patients’ 
signs and symptoms. (Note: Brain MRI from outside the CCR may be accepted per 
investigator discretion if performed within 3 months of initiation of chemotherapy 
regimen).
2.2.2.3
Within 3 months prior to starting the chemotherapy regimen:
e.
Cardiac evaluation for patients who are greater than or equal to age 50, or who have a 
history of ischemic heart disease, chest pain, or clinically significant atrial and/or 
ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular 
tachycardia, heart block.  Patients with a LVEF of less than or equal to 45% will not 
be eligible.  Patients under the age of 50 who present with cardiac risk factors may 
undergo cardiac evaluation as noted above (e.g., diabetes, hypertension, obesity.)  
f.
HIV antibody titer and HbsAG determination, anti-HCV.  (Note: may be performed 
within 3 months of chemotherapy start date but must be within one month before 
initial apheresis for generation of a cell product).
g. Anti CMV antibody titer, HSV serology, and EBV panel.  (Note:  patients who are 
known to be positive for any of the above do not need to be retested).
2.2.2.4
Within 14 days prior to starting the chemotherapy regimen:
a.
Blood tests:
•
Chemistries: (Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(Bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium 
total, Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, 
ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total 
CK, Uric Acid).
•
Thyroid Panel
•
CBC with differential and TBNK PT/PTT
b.  Urinalysis and culture if indicated

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2.2.2.5
Within 7 days prior to starting the chemotherapy regimen:
a.
Beta-HCG pregnancy test (serum or urine) on all individuals of child-bearing 
potential
b. ECOG performance status of 0 or 1
2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found at:  
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.
2.3.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
2.3.2
Treatment Assignment Procedures
Cohorts
Number
Name
Description
1
Phase I:  Dose Escalation 
Cohort
Up to 18 evaluable patients  with HPV-16 positive cancer to 
determine MTD of E7 cells + aldesleukin
2
Phase II Cohort
Patients with HPV-16 positive cancer enrolled after the RP2D of 
1 x 1011E7 cells  + aldesleukin has been determined (total 
enrollment including Phase I not to exceed 40)
Arms
Number
Name
Description
1
Dose level 1 through 3
Non-myeloablative, lymphocyte depleting preparative regimen, 
followed by E7 TCR Cells at escalating doses, followed by 
aldesleukin
2
Phase II arm
1 x 1011 E7 Cells that was determined in Phase I + aldesleukin 
Arm Assignment
Patients in Cohort 1 will be directly assigned to Arm 1, and patients in Cohort 2 will be directly 
assigned to Arm 2.  

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2.4
BASELINE EVALUATIONS
The following are baseline evaluations that are not included in the screening process. Some of 
the screening evaluations may be used as baseline. 
2.4.1
Within 4 weeks prior to starting the chemotherapy regimen:
a.
Patients with lesions that can be biopsied under sedation and/or local anesthesia (skin 
lesions, visceral lesions approachable by CT, USG or MRI guided core biopsy) and who 
are willing to have biopsies performed, will have a baseline pre-treatment biopsy 
followed by two additional biopsies, one following treatment (6 weeks post treatment 
preferred) and the second at the time of progression.  Refer to Section 5.1.3 for guidelines 
for handling specimens.
b. CT of the chest, abdomen and pelvis.
c.
PET or brain MRI may be performed if clinically indicated to evaluate the status of 
disease.  
d. Evaluation with colonoscopy, esophagogastroduodenoscopy or other form of endoscopy 
may be performed to evaluate for the presence of disease in the GI tract or if clinically 
indicated.
e.
Neurological assessment with a neurological exam.
2.4.2
Within 24 hours before starting intravenous fluid hydration for chemotherapy
a.
Pulse oxygen level on room air will be assessed at a timepoint within 24 hours before   
starting intravenous fluid hydration for chemotherapy. If this value is < 95% hydration 
then chemotherapy will be held until it is ≥ 95%, or it is determined that the patient’s 
hypoxia is irreversible, in which case the patient will be considered ineligible.
2.4.3
Within 24 hours before infusion of E7 T cells
a.
Pulse oxygen level on room air will be assessed at a timepoint within 24 hours before 
infusion of E7 T cells. If this value is < 95% T cell infusion will be held until it is ≥ 95%. 
Cell infusion may be delayed for up to 48 hours.
3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
This is a phase I/II clinical trial that will test the safety and efficacy of E7 TCR cells. 
A small number of subjects may be eligible for re-enrollment, and would be required to meet all 
eligibility criteria at the time of re-enrollment. Patients will be assigned a new sequential study 
number for the re-enrollment study period. Any cryopreserved cells produced from a patient who 
was removed from the study can be used to treat that patient after re-enrollment. We do not 
anticipate changes in the risk profile for the initial versus re-enrollment

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Schema:
*Details regarding the number of patients in each dose level group are provided in Section 3.1.5.
3.1.1
Leukapheresis
The patient will undergo a 10-15 liter leukapheresis (generally, 12 liters will be processed to 
target a yield of 6-10 x109 lymphocytes) in the Department of Transfusion Medicine (DTM) 
Dowling Apheresis Clinic according to DTM standard operating procedures.  This procedure 
may occur on this protocol, or protocol 16C0061, if the patient chooses to co-enroll on that 
protocol.  The procedure requires dual venous access, and takes approximately 3-4 hours to 
complete.  A central line will be placed if peripheral venous access is not sufficient. The 
leukapheresis collection will be obtained at least 21 days prior to the cell infusion. Leukapheresis 
material that is not required for clinical use will be retained and cryopreserved in 10 vials at 
100x106 cells per vial with remaining cells stored at 300x106 cells per vial for research and 
banked on protocol 16C0061 (Tissue Procurement Protocol).
3.1.2
E7 TCR T cell preparation
After cells are obtained by apheresis (either on this protocol or protocol 16C0061 if the patient 
has co-enrolled on that protocol), further cell processing to generate E7 TCR cells will occur in 
the DTM according to standard operating procedures and the E7 TCR investigational new drug 
application.  If apheresis has been performed on protocol 16C0061 and the patient consents and 
is eligible for treatment on this study, cells will be transferred to this study and all cell 
preparation will occur as part of this protocol.  Any unused cells from this protocol can be 
transferred to 16-C-0061 and banked for research if a patient is co-enrolled. E7 TCR cells can be 
produced in approximately 21 to 27 days. Cell products may be cryopreserved during production 
to accommodate patient treatment schedules. Either freshly-collected cells or cryopreserved cells 
can be used to initiate the cell-preparation process.  Peripheral blood mononuclear cells (PBMC) 
will be isolated. Sufficient cells for three complete cell productions (2-3 vials at 3-4.5 x 109 
cells/vial) will be retained in the DTM; the remaining cells will first be frozen in 10 vials at 100 
x 106 cells per vial with excess frozen at 300 x 106 cells/vial. Cells will be frozen in the DTM and 
then transferred to the Blood Processing Core (BPC).   
-7
-6
-5
-4
-3
-2
-1
2
1
 
Cyclophosphamide 30 mg/kg 
Fludarabine 25 mg/m
2
E7 TCR cells 
Aldesleukin 720,000 IU/Kg 
0
3

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Before infusion, the percentage of T cells expressing the E7 TCR will be determined by flow 
cytometry.  In addition to flow cytometry, further testing of the cells will take place prior to 
infusion to evaluate for microbial contamination, replication-competent retroviruses, and 
viability.  Details of this testing can be found in the appropriate DTM SOPs. When a patient is no 
longer eligible for retreatment on this protocol due to meeting any of the off-study criteria listed 
in Section 3.8.2, any remaining cryopreserved pretreatment PBMC collected on this protocol will 
be transferred from the Department of Transfusion Medicine to the Principal Investigator of this 
protocol for storage in the Blood Processing Core and possible use in research and banked 
according to protocol 16-C-0061 (Tissue Procurement Protocol). 
3.1.3
Treatment Phase
PBMC will be obtained by leukapheresis (approximately 2x109 to 1x1010 cells are obtained).  
PBMC will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate 
T-cell growth.  Transduction is initiated by exposure of approximately 10x106 to 500x106 cells to 
supernatant containing the E7 TCR retroviral vector.  These transduced cells will be expanded 
and tested for their anti-tumor activity.  Successful TCR gene transfer will be determined by 
FACS analysis for the TCR protein.  Successful TCR gene transfer for each transduced 
peripheral blood lymphocyte (PBL) population will be defined as greater than 10% TCR positive 
cells.  A central line catheter may be used for the intravenous infusion of E7 TCR T cells.
Prior to receiving the engineered PBL cells, patients will receive a non-myeloablative but 
lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine, on 
days -7 to -3 before the intravenous infusion of in vitro tumor reactive TCR gene-transduced 
PBL plus IV high dose aldesleukin, as indicated in Section 3.2.4. Patients will receive one course 
of treatment.  The start date of the course will be the start date of the chemotherapy; the end date 
will be the day of the first post-treatment evaluation and the first safety and response assessment 
at the first follow-up visit.  
3.1.4
Dose Limiting Toxicities (DLTs)
All Grade 3 and greater toxicities occurring within 30 days of the cell infusion with the exception 
of:
•       Cytokine Release Syndrome (CRS) that resolves ≤ grade 2 within 14 days of the last dose 
of aldesleukin 
•       Autoimmune toxicity that resolves to ≤ grade 2 within 14 days for starting symptom 
treatment (e.g. steroids)
•       Cardiac, gastrointestinal, dermatological, hepatic, pulmonary, renal, hematologic, 
neurologic toxicity, or toxicity in Appendix C attributable to aldesleukin that resolves to 
≤ grade 2 within 14 days of the last dose of aldesleukin
•
Transient grade 3 hypoxia associated with cell infusion that corrects to ≤ grade 2 with 
supplemental oxygen and/or that resolves to ≤ grade 2 within 24 hours or before starting 
aldesleukin.
•       Hemorrhage due to underlying cancer or prior radiotherapy
•       Infection that is controlled within 7 days of onset
•       Hematological toxicities because they are expected from the conditioning regimen and 
their duration is unpredictable

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•
If a DLT is clearly due to progressive disease the subject will be replaced and the DLT 
will not be included.
Note:  Any adverse event that leads to a discontinuation of T-cell infusion will be considered 
a DLT. 
3.1.5
Dose Escalation
Phase I of the protocol will follow a 3+3 phase 1 dose escalation design. At each dose level, 
three patients will be treated initially*. Should none of the first 3 patients treated on a dose level 
experience a DLT enrollment can start on the next higher dose level.  Should 1 of 3 patients 
experience a dose limiting toxicity on a particular dose level, three more patients would be 
treated at that dose level to confirm that no greater than 1/6 patients have a DLT prior to 
proceeding to the next higher level.  If 1/6 patients have a DLT at a particular dose level, accrual 
can proceed to the next higher dose level.  If a level with 2 or more DLTs in 3-6 patients has 
been identified, 3 additional patients will be accrued at the next-lowest dose for a total of 6, in 
order to further characterize the safety of the maximum tolerated dose.  The maximum tolerated 
dose is the dose at which a maximum of 1 of 6 patients has a DLT. If 2 DLTs occur on dose level 
1, study will be stopped. 
With Amendment G, an additional three patients have been added to dose level three to allow 
for collection of additional data on E7 TCR T cells without pembrolizumab (no DLT has been 
encountered).
With Amendment H, a total of 40 patients will be treated in Phase II, including the 3 additional 
patients added via amendment G, to dose level 3. The maximum tolerated dose was not reached 
in the Phase I portion, so the maximum administered safe dose will be designated as the 
recommended Phase II dose (RP2D). These patients will also be evaluated for safety and 
efficacy (see Section 8).
There will be a 12 day delay in treatment between the patients within each dose level. Therefore, 
after a patient in a dose level starts chemotherapy, the next patient in the same dose level will not 
start chemotherapy until at least 12 days later to allow more time for the analysis of adverse 
events. There will also be a 4 week delay between each dose level in order to further increase 
patient safety.
The total number of anti-HPV-16 E7 engineered PBL cells transferred for each dose level will be 
in the ranges of:
•
Dose level 1
1 x 109 transduced E7 TCR cells
•
Dose level 2
1 x 1010 transduced E7 TCR cells
•
Dose level 3
1 x 1011 transduced E7 TCR cells 
The cell dose administered will be in a range of +/- 30% of the target dose above. The number of 
transduced cells will be quantified by multiplying the frequency of cells expressing the mouse 
TCR constant region (determined by flow cytometry) by the number of cells produced. If fewer 
than the target number of cells are generated the patient will still be treated but toxicity data from 
the patient will not be used in determining the MTD. Participants in the phase II portion of the 
study who receive treatment with a cell dose more than 30% below the RP2D will be evaluable 
for safety but will not be included in the primary efficacy analysis. 

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With Amendment I, a total of 40 patients will be treated in Phase II, including the 3 additional 
patients added via amendment G, to dose level 3. The maximum tolerated dose was reached in 
the Phase I portion. The dose that will be used in the Phase II portion of the study is 1 x 1011 
transduced E7 TCR cells  (Dose level 3). These patients will also be evaluated for safety and 
efficacy (see Section 8).
3.1.6
Safety Protocol Stopping Rules
The study will be halted (immediately stop accrual and treatment) if any of the following safety 
conditions are met during phase I portion and we will promptly investigate and submit an 
amendment to the IRB and FDA if necessary:
1.
If one or more deaths (other than death related to progressive disease) occurs within 30 
days of treatment regimen.
2.
If two or more patients develop a Grade 3 or greater toxicity at any point in the study not 
attributable to the chemotherapy preparative regimen or aldesleukin (or circumstances 
unrelated to the study) that does not resolve to Grade 2 within 10 days.
3.
If 2 DLTs occur on dose level 1. 
3.2
DRUG ADMINISTRATION
Treatment schedule will be according to the following schedule (See Schedules 3.2.4).  (Times are 
offered as examples and may be changed as long as a similar time relationship between 
administrations of the drugs is maintained. Study medication start times for drugs given once daily 
may be within 2 hours of the scheduled time [once it is established at the first administration].  All 
other medications may be given +/- one hour of the scheduled time; the length of administration 
may be +/- 15 minutes.  Administration of diuretics, electrolyte monitoring and replacement, and 
hydration should all be performed as clinically indicated – the times noted below are offered only 
as examples. Chemotherapy infusions maybe slowed or delayed as medically indicated.) 
Intravenous hydration administered during cyclophosphamide will be individualized for patient 
clinical factors. Patients at risk of adverse clinical consequences from volume overload (e.g. 
patients with history of pulmonary hypertension or cardiac dysfunction) may be considered for 
low-dose hydration rates or hemorrhagic cystitis prevention strategies that include mesna alone 
without intravenous hydration.
3.2.1
Preparative Regimen 
The following will comprise a course of therapy for Day -7 through Day -3:
The following will comprise a course of therapy:
Drug
Dose
Route and 
Administration
Treatment Days
Cyclophosphamide
30 mg/kg 
IV infusion over 1  
hour (± 15 min)
Once daily x 2 doses
Days -7 and -6
Fludarabine
25 mg/m2
IV infusion over 30 
minutes (± 15 min)
To be administered 
following completion 
of cyclophosphamide.
Once daily x 5 doses
Days -7, -6, -5, -4, -3
Dose modifications: Cyclophosphamide and fludarabine will be dosed on actual body weight unless the 

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patient has a body mass index (BMI) > 35. Note: Chemotherapy infusions maybe slowed or delayed as 
medically indicated.
3.2.2
Day -7 and -6 
•
9 am:  Hydrate (if applicable). Begin hydration with 0.9% sodium chloride injection 
with or without 10 meq/L of potassium chloride at approximately 1.5 ml/kg/hour 
(recommend starting at least 6 hours pre-cyclophosphamide and continue hydration 
until 24 hours after last cyclophosphamide infusion). The hydration rate will be capped 
at 100 mL/hr.  Furosemide may be given once daily on cyclophosphamide treatment 
days to promote diuresis. Furosemide may be held if hydration is not employed or 
based on clinical factors.  At any time during the preparative regimen, if the urine 
output <1.5 ml/kg/hour or if body weight >2 kg over pre-cyclophosphamide value, 
additional doses of furosemide may be administered.  The rate of hydration and total 
time of hydration may be reduced or increased based on urine output and other clinical 
considerations per the primary investigator.
•
2 pm: Ondansetron (0.15 mg/kg/dose [rounded to the nearest even mg dose between 8 
mg and 16 mg based on patient weight] IV q 12 hours X 3 days),Olanzapine (5 to 10 
mg PO once daily for 5 days), and Aprepitant (125 mg PO on day -7, 80 mg PO daily 
on days -6 and -5) will be utilized for prophylaxis for chemotherapy induced nausea 
and vomiting. Modifications to the antiemetic regimen may be made per PI discretion 
but corticosteroids should be avoided. 
•
4 pm: Cyclophosphamide  30 mg/kg/day X 2 days IV in 250 ml D5W with mesna 15 
mg/kg/day over 1 hour (± 15 min) X 2 days. If the patient is obese (BMI > 35) drug 
dosage will be calculated using practical weight as described in Table 3.  
Mesna will be administered at 7.5 mg/kg IV infusion over 1 hour concurrent with 
cyclophosphamide and then 1.5 mg/kg/hour IV infusion over 23 hours to be started after the 
completion of cyclophosphamide.
3.2.3
Day -7 to Day-3
•
Fludarabine 25 mg/m2/day IVPB daily over 30 minutes (± 15 min) for 5 days. To be 
administered following completion of cyclophosphamide. (The fludarabine will be 
started approximately 1-2 hours after the cyclophosphamide and mesna on Days -7 and 
-6).If the patient is obese (BMI > 35) drug dosage will be calculated using practical 
weight as described in Table 3. (Fludarabine will be dose adjusted for renal 
impairment. Renal function may be determined based on estimated equations (e.g. CKI-
EPI, Cockroft Gault) or by measured and timed urine collections based on the clinical 
judgement of the investigator team.
Creatinine clearance
Fludarabine daily dose
> 80 ml/min/1.73 m2
25 mg/m2/dose
50-79 ml/min/1.73 m2
20 mg/m2/dose
30-49 ml/min/1.73 m2
15 mg/m2/dose
< 30 ml/min/1.73 m2
Hold dose

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3.2.4
Cell Infusion and other treatment Administration
The E7 TCR cells will be delivered to the patient care unit by an authorized staff member.  Prior 
to infusion, the cell product identity label is double-checked by two authorized staff (MD or 
RN), an identification of the product and documentation of administration are entered in the 
patient’s chart, as is done for blood banking protocols.
Day 0 (two to four days after the last dose of fludarabine):
•
 E7 TCR T cells will be administered intravenously via infusion pump over 
approximately 20 to 30 minutes via non-filtered tubing, gently agitating the bag during 
infusion to prevent cell clumping.  
•
Aldesleukin as described in Section 3.3 below. 
Day 0-4 (Day 0 is the day of cell infusion): 
•
Fluconazole: can be used at the discretion of the treating clinician
•
Valacyclovir po or Acyclovir PO or IV: will be administered until CD4 counts > 
200/mm3 X 2
Day 1-4 (Day 0 is the day of cell infusion):
•
Aldesleukin as described in Section 3.3 below. 
TMP/SMX may be administered at 160mg/800mg every other day at the time of count recovery. 
Dose 1-3 Schedule
Day
Therapy
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
Cyclophosphamide 30 
mg/kg IV once daily x 2 
days
X
X
Ondansetron 0.15 
mg/kg IV every 12 
hours x 3 days
X
X
X
Olanzapine 5-10mg PO 
once daily x 5 days
X
X
X
X
X
Aprepitant 125 mg PO x 
1 day, then 80 mg PO 
daily x 2 days
X
X
X
Mesna 7.5 mg/kg IV 
infusion over 1 hour 
concurrent with 
X
X

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Day
Therapy
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
cyclophosphamide then 
1.5 mg/kg/hour IV 
infusion over 23 hours
Fludarabine 25 mg/m2 
IV once daily x 5 days
X
X
X
X
X
E7 TCR cells
X
Aldesleukin
X
X
X
X
X
Valacyclovir PO or 
Acyclovir PO or IV
X
X
X
X
X
3.3
ALDESLEUKIN: INTRAVENOUS ADMINISTRATION
Aldesleukin will be administered at a dose of 720,000 IU/kg (based on total body weight) as an 
intravenous bolus over a 15 minute period beginning within 24 hours of cell infusion and 
continuing for up to four days (maximum 12 doses). The start of aldesleukin treatment may be 
delayed up to 3 days after cell infusion if medically necessary. Doses will be preferentially 
administered every eight hours; however, up to 24 hours may elapse between doses depending 
on patient tolerance.  Aldesleukin dosing will be stopped if toxicities are not sufficiently 
recovered with supportive measures within 24 hours of the last dose of aldesleukin.  Doses will 
be delayed or stopped if patients reach Grade 3 or 4 toxicity due to aldesleukin except for the 
reversible Grade 3 toxicities common to aldesleukin such as diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional symptoms and 
laboratory changes as detailed in Appendix D.  Toxicities will be managed as outlined in 
Appendix C.  In addition, dosing may be held or stopped at the discretion of the treating 
investigator.  Because confusion is a possible side effect of aldesleukin administration, a Durable 
Power of Attorney is strongly recommended to be signed by the patient to identify a surrogate to 
make decisions if a patient becomes unable to make decisions. Neurological assessment will be 
performed daily on patients who are receiving aldesleukin. 
3.4
POTENTIAL REPEAT TREATMENT 
Patients who were enrolled before the RP2D was established and have experienced a PR may be 
retreated at the RP2D (1 x 1011 transduced E7 TCR cells). Additionally, patients who 
experienced a partial or complete response (at the RP2D Dose level 3) by RECIST criteria and 
subsequently progress by RECIST criteria may receive a second treatment course. Patients must 
continue to meet the original eligibility criteria to be considered for retreatment. Research 
assessments will be performed at the same time intervals used for initial treatment. Patients will 
be treated at the RP2D (1 x 1011 transduced E7 TCR cells). Patients who develop grade 3 or 4 
toxicity due to cell infusion will not be retreated. A maximum of 1 retreatment course may occur.  
The second treatment will not begin prior to 6-8 weeks after the last dose of aldesleukin.

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Note: Response data for all treatments will be captured in the database however only the 
response data from the first treatment will be used in the determination of response.
3.5
ON STUDY EVALUATION
Note:  Refer to Section 5 for research evaluations
3.5.1
Prior to starting the preparative regimen
•
Apheresis as indicated
o
Within 14 days prior to starting the preparative regimen, patients will have a 
complete blood count (CBC with differential), electrolytes, BUN, creatinine, liver 
function tests, TBNK, and serum chemistries performed.  If any results are 
beyond the criteria established for eligibility, the patient will not proceed until the 
abnormalities can be resolved.  
3.5.2
During the preparative regimen: (day -7 to cell infusion)
•
Tests will be performed every 1-2 days, including Complete Blood Count (CBC with 
differential) Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 
Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid
•
E7 TCR assay may be collected 1-2 times per week following cell infusion
•
Urinalysis (every 1-2 days)
3.5.3
After Cell Infusion
3.5.3.1
Daily (Day +1 to Day +7)
•
Following cell administration - Vital signs will be monitored hourly (+/- 15 minutes) 
for four hours and then routinely (every 4-6 hours) unless otherwise clinically indicated
•
CBC
•
Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin
•
Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly (within one business day, while the patient is hospitalized)
•
Other tests will be performed as clinically indicated including Calcium total, 
Magnesium total (Mg), Phosphorus, LD, Total Protein, Total CK, Uric Acid
3.5.4
During Hospitalization
3.5.4.1
Every 1-2 days
•
A review of systems and physical exam as clinically indicated
•
Tests will be performed as clinically indicated including Complete Blood Count (CBC 
with differential), Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 
(bicarbonate), Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, 

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Magnesium total (Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, 
AST/GOT, Total Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid
•
Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly Monday through Thursday (within one business day, while 
the patient is hospitalized). 
•
Surveillance blood cultures may be drawn at the discretion of the investigator and 
continue as clinically indicated.
•
Other tests will be performed as clinically indicated.
3.6
POST TREATMENT EVALUATION (FOLLOW-UP)
At each scheduled evaluation for response, patients will undergo:
•
Physical examination 
•
Chemistries: Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid 
•
Complete blood count
•
Thyroid panel as clinically indicated
•
TBNK, until CD4 > 200/mm 3 x 2 
•
Toxicity assessment, including a review of systems
•
CT of the chest, abdomen and pelvis as clinically indicated. If clinically indicated, other 
scans or x-rays may be performed, e.g. PET, brain MRI, bone scan
•
An approximately 5 liter apheresis may be performed at the first follow up visit, if the 
patient is unable to undergo apheresis, approximately 96 ml of blood may be obtained.   
Subsequently, approximately 60 ml of blood will be obtained at follow up visits for at 
least three months. Peripheral blood mononuclear cells will be cryopreserved so that 
immunologic testing may be performed and will be banked under protocol 16-C-0061 
(Tissue Procurement Protocol).  PBMC from apheresis will be stored in 10 vials at 
100x106 cells per vial with remaining cells stored at 300x106 cells per vial.
3.6.1
Post Cell Product Administration 
All patients will return to the NIH Clinical Center for evaluation 40 days (+/- 2 weeks) following 
administration of the cell product.  Patients discharged with Grade 3 or greater significant adverse 
events should be evaluated by their referring physician within 2 weeks of discharge.   
3.6.2
Stable Disease, Partial Response, Complete Response or Unresolved Toxicities
Patients who experience stable disease, a partial response, or a complete response or have 
unresolved toxicities will be evaluated for response as noted below:
•
Week 12 (+/- 2 weeks) 
•
Every 3 months (+/- 1 month) x3
•
Every 6 months (+/- 1 month) x 5 years

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•
As per PI discretion for subsequent years
Note: Patients may be seen more frequently as clinically indicated
3.6.3
Telephone Follow-up
Patients who are unable or unwilling to return for follow up evaluations will be followed via 
phone or e-mail contact and if there are any safety issues, will be advised to have a follow-up 
visit with their local oncologist. Patients may be asked to send laboratory, imaging and physician 
exam reports performed by their treating physician.
3.6.4
Long-Term Follow-up
Long-term follow up of patients receiving gene transfer is required by the FDA and must 
continue even after the patient comes off the study. Long-term follow-up will be done under a 
different protocol, 20C0051. After the patient comes off study, health status data will be obtained 
from surviving patients via telephone contact or mailed questionnaires for a total of 15 years 
after cell infusion. 
3.7
COST AND COMPENSATION 
3.7.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures are 
performed outside the NIH Clinical Center, participants may have to pay for these costs.  
3.7.2
Compensation
Participants will not be compensated on this study.
3.7.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.
3.8
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 40 days following the last dose of study therapy.
3.8.1
Off Treatment Criteria
Patients will be taken off treatment (and followed for survival) for the following:
•
Completion of treatment
•
Grade 3 or greater autoimmunity that involves vital organs (heart, kidneys, brain, eye, 
liver, colon, adrenal gland, lungs). 
•
If a subject experiences Grade 3 or higher toxicity due to cell infusion (reaction to 
cellular product or infusion reaction), the patient will receive no further treatment.
•
Patient requests to be withdrawn from active therapy
•
Investigator Discretion

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•
Positive pregnancy test
3.8.2
Off Study Criteria
Patients will be taken off study for the following:
•
Screen failure
•
The patient voluntarily withdraws
•
There is significant noncompliance
•
Progressive disease
•
General or specific changes in the patient’s condition which render continued 
participation unacceptable in the judgment of the investigator.
•
Death
•
Study closure
•
Completion of study follow-up period
•
Patient meets criteria listed in Section 2.4.2
•
Patient lost to follow-up
•
Investigator discretion
Note: patients who are taken off study for study closure may be followed on the Long-term Gene 
Therapy Follow-up protocol (20C0051). 
3.8.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site will attempt to contact the participant and reschedule the missed visit within 1-2 
days and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file. 
•
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.

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3.9
SCHEDULE OF EVALUATIONS
For the treatment schedule, please refer to Section 3.2.4.
Note:  the retreatment schedule (see Section 3.4) will be identical to the schedule for patients 
being treated for the first time, including eligibility assessments.  A maximum of one course of 
treatment will be allowed on retreatment.
Procedure
Screening/ 
Baseline2
Before 
treatment
Preparative 
regimen5
Day 0
During 
hospitalization6
Follow-up9
(End of Treatment)
Medical history
X
Physical
X
X
X
X
ECOG performance status
X
Neurological Assessment
X
X19
X19
NIH Advance Directives Form16
EKG
X
Chest CT and MRI or PET
X
X
Pulmonary Function Test1
X
Cardiac evaluation10
X
Viral titers
X
Biopsy
X
X12
Blood chemistries8
X
X
X
X
X
Complete blood count (CBC with diff.)
X
X
X
X
X
Thyroid panel
X
X13
HLA typing
X
TBNK
X
X7
X
Urinalysis
X
X
Pregnancy test3
X
Leukapheresis
X17
X15
Infusion of transduced cells4
X
Additional apheresis or blood draw11
X
Research blood
X
X
X14
X
E7 TCR assay18
X
X

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1. For patients with a prolonged history of cigarette smoking, as indicated in Section 2.2.1
2. Exact timeline is indicated in Section 2.1.3
3. For women of child-bearing potential as defined in Section 2.1.1.9
4. See other treatments in Schedules, Section 3.2.4
5. On days -7 to -1, every 1 -2 days as clinically indicated
6. Every 1 to 2 days while hospitalized
7. Once total lymphocyte count is greater than 200/mm3, TBNK for peripheral blood CD4 
count will be drawn weekly (within one business day, while the patient is hospitalized)
8. Chemistries Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), 
Creatinine, Glucose, Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total 
(Mg), Inorganic Phosphorus, Alkaline Phosphatase, ALT/GPT, AST/GOT, Total 
Bilirubin, Direct Bilirubin, LD, Total Protein, Total CK, Uric Acid
9. 40 days (+/- 2 weeks) after cell infusion, additional visits as indicated in Section 3.6
10. For patients who are greater than or equal to 50 years of age, or who have a history of 
ischemic heart disease, chest pain or clinically significant atrial and/or ventricular 
arrhythmias.  Patients with a LVEF of less than or equal to 45% will not be eligible, as 
noted in Section 2.2.2.2
11. As described in Section 3.6.
12. Following treatment (6 weeks post treatment preferred) and at disease progression only.
13. As clinically indicated
14. Monday, Wednesday, Friday during hospitalization once ALC > 200/mm3
15. If the patient is unable to undergo apheresis, approximately 96 ml of blood may be 
obtained. Apheresis will only be done in the first follow-up visit; in the following visits, 
blood will be collected.
16. As indicated in Section 12.3, all subjects will be offered the opportunity to complete an 
NIH advanced directives form.  This should be done preferably at baseline but can be 
done at any time during the study as long as the capacity to do so is retained.  The 
completion of the form is strongly recommended but is not required.
17. This can occur at any time prior to treatment on protocol 16C0061 if the patient is co-
enrolled on that protocol. See Section 3.1.1 for further details.  For patients undergoing 
retreatment, retreatment will only occur if there are enough cells stored from their prior 
course.  See Section 3.4 for details on retreatment.
18. Clinical assay performed by the NCI Flow Cytometry Laboratory in the Laboratory of 
Pathology. The assay may be collected at follow-up visits. 
19. Performed daily on patients while receiving aldesleukin.

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4
CONCOMITANT MEDICATIONS/MEASURES
Patients needing systemic steroid therapy may not participate in this study.  
4.1
PROHIBITED MEDICATIONS
Current use of immunosuppressive medication, EXCEPT for the following:
•
Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection)
•
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; 
or,
•
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
4.2
INFECTION PROPHYLAXIS
Note: Other medications may be substituted or held at the discretion of the treating investigator. 
Below are guidelines and suggested medications and schedule to be used, however they can be 
altered by the treating physician as clinically indicated.
4.2.1
Pneumocystis Jirovecii Pneumonia
Patients may receive the fixed combination of trimethoprim and sulfamethoxazole [SMX] as 
double strength (DS) tab (DS tabs = TMP 160 mg/tab, and SMX 800 mg/tab) P.O. daily three 
times a week on non-consecutive days, beginning between days -8 and -5. 
Pentamidine may be substituted for TMP/SMX-DS in patients with sulfa allergies. It may be 
administered aerosolized at 300 mg per nebulizer within one week of chemotherapy start date.
4.2.2
Herpes Virus Prophylaxis
Patients will be given either acyclovir 800mg PO twice daily (preferred) or valacyclovir 500mg 
PO twice daily (alternate) or, if unable to tolerate PO: acyclovir 250mg/m2 IV q 12 hr.  
Reversible renal insufficiency has been reported with IV but not oral acyclovir.  Neurologic 
toxicity including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs 
have been reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will 
be made or the drug will be discontinued.  Acyclovir will not be used concomitantly with other 
nucleoside analogs which interfere with DNA synthesis, e.g. ganciclovir.  In renal disease, the 
dose is adjusted as per product labeling.
Prophylaxis for Pneumocystis and Herpes will continue for 6 months post chemotherapy.  If the 
CD4 count is less than 200 at six months post chemotherapy, prophylaxis will continue for at 
least six months and until the CD4 count is greater than 200 for two consecutive measures.
4.2.3
Fungal Prophylaxis (Fluconazole)
Patients may start Fluconazole 400 mg po. starting on the day of cell infusion and continue until 
the absolute neutrophil count is greater than 1000/mm3.  The drug may be given IV at a dose of 
400 mg in 0.9% sodium chloride USP daily in patients unable to take it orally.
4.2.4
Empiric Antibiotics 
Patients will start on broad-spectrum antibiotics as per current institutional guidelines for fever.  
Infectious disease consultation will be obtained for all patients with unexplained fever or any 
infectious complications.

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4.2.5
Blood Product Support 
Using daily CBC’s as a guide, the patient will receive platelets and packed red blood cells 
(PRBC’s) as needed.  As a general guideline, patients may be transfused for: 
•
Hemoglobin < 8 gm/dl
•
Platelets < 10,000/mm3 
Note: Patients may be transfused at a higher platelet count as clinically indicated, e.g.:
o
Increased risk for bleeding such as undergoing an invasive procedure or 
presence of metastatic lesion likely to bleed 
o
fever greater than 38.5°C
o
sepsis
All blood products will be irradiated.  Leukocyte filters will be utilized for all blood and platelet 
transfusions to decrease sensitization to transfused WBC’s and decrease the risk of CMV 
infection.
4.2.6
Neutrophil Recovery
Patients may receive filgrastim (or filgrastim biosimilar) for count recovery when clinically 
indicated per NIH CC Pharmacy guidelines.
4.3
OTHER CONCOMITANT MEDICATIONS TO CONTROL ALDESLEUKIN SIDE EFFECTS
Concomitant medications to control side effects of aldesleukin therapy may be given.  
Meperidine (25-50 mg) will be given intravenously if severe chilling develops.  Other supportive 
therapy will be given as required and may include acetaminophen (650 mg q4h), indomethacin 
(50-75 mg q8h)  famotidine (20mg IV q12h)If patients require steroid therapy they will be taken 
off treatment.  Patients who require transfusions will receive irradiated blood products.  
Ondansetron 0.15 mg/kg/dose IV every 8 hours will be administered for nausea and vomiting.  
Additional anti-emetics will be administered as needed for nausea and vomiting uncontrolled by 
ondansetron.  Antibiotic coverage for central venous catheters may be provided at the discretion 
of the investigator.
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
BIOSPECIMEN COLLECTION
Please note that tubes and media may be substituted based on availability with the permission of 
the PI or laboratory investigator.
5.1.1
Pre-cell infusion evaluations
•       At baseline/screening 12 CPT tube and 2 SST tubes may be collected. One CPT tube may 
be used to collect 4mL of plasma, which may be frozen in 4mL vials. PBMC from the 
remainder of the CPT tubes may be frozen in aliquots of 10 x 106 cells/vial. Serum from 
SST tubes may aliquoted into four vials of 0.5-1mL each. All samples will be processed 
in the Blood Processing Core (BPC).
•        At day -7 prior to cell infusion 6 CPT tubes and 1 SST tube may be collected. One CPT 
tube may be used to collect 4mL of plasma, which may be frozen in 4mL vials. PBMC 

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from the remainder of the CPT tubes may be frozen in aliquots of 10 x 106 cells/vial. 
Serum from SST tubes may be aliquoted into four vials of 0.5-1mL each. All samples 
will be processed in the Blood Processing Core.
5.1.2
Post cell infusion evaluations
•
2 SST tubes (4mL) may be collected daily for serum starting on the day of chemotherapy 
and continuing through the end of hospitalization. Serum will be processed in the Blood 
Processing Core and may be aliquoted into four vials of 0.5-1 mL each.
•
Once total lymphocyte count is greater than 200/mm3, the following samples may be 
drawn and sent to the BPC on Monday, Wednesday, and Friday x 5 days, then weekly 
(while the patient is hospitalized).
o
6 CPT tubes (8mL each). One CPT tube daily may be used to collect 4mL of 
plasma, which may be frozen in 4mL vials. PBMC from the remainder of the 
CPT tubes may be frozen in aliquots of 10 x 106 cells/vial
•       Following discharge, at each scheduled follow-up visit 6 CPT tubes and 1 SST tube may 
be collected. One CPT tube may be used to collect 4mL of plasma, which may be frozen 
in 4mL vials. PBMC from the remainder of the CPT tubes may be frozen in aliquots of 
10 x 106 cells/vial. Serum from SST tubes may be aliquoted into four vials of 0.5-1mL 
each. All samples will be processed in the BPC.
•
Serum samples may be provided to the laboratory of Liang Cao, Genetics Branch, CCR 
for testing of plasma or serum for HPV DNA.
5.1.3
Tumor Biopsies
•
Tumor may be biopsied pre- and post-treatment in order to test for HPV-16, HLA 
expression, and other characteristics that may affect response to therapy. Biopsies are not 
required; a maximum of three biopsies, with three cores/attempts, may be performed. 
•
Tissue may be obtained pre-treatment, following treatment (6 weeks post treatment 
preferred) and at the time of progression. 
•
Tissue may be obtained via CT, MRI or US guided biopsy under IV sedation as 
appropriate.
•
Specimens may be transported by the assigned research nurse to the Center for Immuno-
Oncology (CIO) cellular therapy laboratory for sample labeling. Contact: Scott Norberg, 
Bldg 10, phone 301-275-9668. 
•
Following labeling, samples may be transported by an assigned lab member to the Blood 
Processing Core where they will be frozen in optimal cutting temperature compound. 
•
Some of these samples will be archived and analyzed under another protocol 16-C-0061 
(Tissue Procurement Protocol) if the subject is also enrolled on that study.  
5.1.4
Immunological Testing
•
Apheresis may be performed prior to and about four to six weeks after the treatment.  
Apheresis product will be transferred to the Blood Processing Core. Cell product may be 

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frozen in 10 vials at concentration 100 x 106 cells/mL and additional vials at 300 x 106 
cells/mL.
•
At other time points, peripheral blood lymphocytes (PBL) and plasma may be obtained 
from whole blood by purification using centrifugation. These samples will be transferred 
directly to the Blood Processing Core lab for processing. Plasma may be frozen in 4mL 
vials. PBL may be frozen in aliquots of 10 x 106 cells/vial
•
Possible laboratory research studies on tumor biopsies are as follows: Expression of p16, 
CD3, CD4, CD8, MHC I, and MHC II by immunohistochemistry; flow cytometry to 
determine the frequency of E7 TCR T cells in the samples; generation and 
characterization of TIL cells; generation and characterization of tumor cell lines. IHC 
quantification may be by blinded scoring of the intensity and frequency of staining. Flow 
cytometry data will be analyzed with FlowJo software. Biopsies - will only be performed 
if minimal morbidity is expected based on the procedure performed and the granulocyte 
and platelet count. 
•
Possible laboratory research studies on PBMC and PBL are as follows:  Specific 
cytolysis determined by impedance-based assay, frequency of effector cells as 
determined by ELISPOT, quantity of cytokine production as determined by coculture 
assay with cytokine quantification, cytokine production by intracellular flow cytometry, 
phenotypic analysis by flow cytometry. Immunological assays may be standardized by 
the inclusion of 1) pre-infusion PBMC and 2) an aliquot of the T cells cryopreserved at 
the time of infusion. 
•
Possible laboratory research on serum or plasma are as follows: HPV DNA 
quantification, cytokine quantification
•
The planned methods for performing the laboratory studies above are as described in 
Stevanovic, et al, Journal of Clinical Oncology, 2015 and Draper, et al, Clinical Cancer 
Research, 2015. (14, 15)
•
The laboratory studies are considered exploratory. Statistical analysis will be performed 
in consultation with a biostatistician. 
•
Specimens collected in the course of this research project may be banked and used in the 
future to investigate new scientific questions related to this study and protocol 16-C-0061 
(Tissue Procurement Protocol).
5.1.5
Data sent to Rutgers Cancer Institute of New Jersey
Clinical outcome data and/or adverse event data may be sent to Rutgers to assist with the safety 
analysis. Data will be deidentified. Identifiable information will only be provided, if needed, to 
interpret data. 
5.2
GENE-THERAPY-SPECIFIC FOLLOW-UP 
FDA-required follow-up for participants who have received gene therapy will be performed as 
indicated in the long term gene therapy follow-up protocol (20C0051). Participants will be co-
enrolled on 20C0051. A baseline (pre-treatment) sample will be collected on protocol 20C0051 
to improve analysis of the long term follow up testing.  

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5.3
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management System.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
5.3.1
Samples Managed by the Blood Processing Core (BPC)
5.2.1.1 Blood Collection
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred).
For sample pickup, page 102-11964.
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number).
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov
The samples will be processed, barcoded, and stored in the BPC until requested by the 
investigator.
5.3.1.1
Sample Data Collection
Patient blood and tissue samples, collected for the purpose of research under IRB approved 
protocols of the CIO, may be archived by the Blood Processing Core (BPC) will be barcoded, 
with data entered and stored in Labmatrix utilized by the BPC. This is a secure program, with 
access to Labmatrix limited to defined BPC lab personnel, who are issued individual user 
accounts. Installation of Labmatrix is limited to computers specified by the BPC. These 
computers all have a password restricted login screen.
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.).
5.3.2
CIO - Cellular Therapy Laboratory
Samples transferred to the CIO cellular therapy laboratory will be barcoded and tracked with 
Labmatrix.
Laboratory research data will be stored on the NCI secure server with secure access by laboratory 
personnel only. Access to personally identifiable information (PII) is limited to the PI and study 
personnel who interact directly with the patient and their samples.
5.3.3
Protocol Completion/Sample Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
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Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval.
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material. 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed or returned to the patient, if so requested. The PI will record any loss 
or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of 
Section 7.1.
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables.
6
DATA COLLECTION AND EVALUATION
6.1
DATA COLLECTION
The NIH PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant 
data capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The Principal Investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
The key for assignment of patient code identification numbers with the personal identifiers will 
be stored in a secure data base. This key will not be shared with other investigators. Investigators 
conducting the individual sample testing will only have access to coded identification numbers 
and coded patient information (i.e. treatment regimens, treatment responses, diagnoses, 
pathology information).
Data from analyses performed at participating site will be provided to the NIH team by secure 
email and entered into the study database. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
6.1.1
Adverse Event (AE) Recording
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. All study 
related adverse events, including clinically significant abnormal findings on laboratory 
evaluations, regardless of attribution will be captured in the study database up to 40 days 
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intervention, Study Day 0, through 40 days after the study therapy was last administered. Beyond 
40 days after the last administration, only adverse events which are serious and related to the 
study intervention need to be recorded.
In addition, all incidences of intubation including the duration of and reason for intubation will 
be captured in the database.
6.1.2
Reporting of Laboratory Events
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows:
_x_ Coded, linked data in an NIH-funded or approved public repository.  
_x_ Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
_x_ Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through: 
_x_ An NIH-funded or approved public repository: ClinicalTrials.gov.
_x_ BTRIS (automatic for activities in the Clinical Center)
_x_ Approved outside collaborators under appropriate individual agreements.
_x_ Publication and/or public presentations.
When will the data be shared? 
_x_ Before publication.
_x_ At the time of publication or shortly thereafter.

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6.3
RESPONSE CRITERIA
For the purposes of this study, patients should be re-evaluated for response as indicated in 
Section 3.6.2.  In addition to a baseline scan, confirmatory scans should also be obtained 4 to 8 
weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) for patients with solid tumors (22). In cases where patients have isolated bony 
metastases that do not meet RECIST criteria, Positron Emission Tomography Response Criteria 
in Solid Tumors (PERCIST) (version 1.0) guidelines will be used (23).  Changes in the largest 
diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the 
case of malignant lymph nodes are used in the RECIST criteria.  Normalization of standardized 
uptake value on FDG-PET is used in PERCIST.  For patients that have both bony lesions and 
lesions that meet RECIST criteria, only RECIST criteria will be used to evaluate best overall 
response.
6.3.1
Definitions
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their first 
treatment with E7 TCR transduced PBL.
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.
6.3.2
Disease Parameters
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as: 
•
By chest x-ray:  > 20 mm; 
•
By CT scan: 
o
Scan slice thickness 5 mm or under: as > 10 mm
o
Scan slice thickness > 5 mm: double the slice thickness 
•
With calipers on clinical exam: > 10 mm.  
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.

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Measurable bone metastases: Any size bone lesions with a baseline SUL (standard uptake value, 
corrected for lean body mass) on FDG-PET of 1.5 x mean liver SUL + 2 standard deviations of 
mean SUL is considered measurable. Bone lesions are only measured in patients with isolated 
bone metastases.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI), are considered as non-measurable.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  Lesions that have been previously treated with loco-regional therapy 
or in a previously irradiated area can be considered target lesions if they have demonstrated 
unequivocal progression by radiographic imaging.
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
6.3.3
Methods for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).  Ideally, the same type of 

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scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning techniques, 
if possible.
FDG-PET:  Patients with isolated bony metastases will have FDG-PET to determine if lesions 
meet criteria to be followed by PERCIST version 1.0. While FDG-PET response assessments in 
solid tumors being followed by RECIST need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression of lesions (particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
 Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image.
6.3.4
Response Criteria
6.3.4.1
Evaluation of Target Solid Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.

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6.3.4.2
Evaluation of Bony Lesions in Patients with Isolated Bone Metastases
Complete Response (CR): Normalization of all bony lesions (target and nontarget) to SUL less 
than mean liver SUL and equal to normal surrounding tissue SUL. Verification with follow-up 
study in 1 month if anatomic criteria indicate disease progression.
Partial Response (PR): > 30% decrease in SUL peak; minimum 0.8 unit decrease. Verification 
with follow-up study if anatomic criteria indicate disease progression. 
Progressive Disease (PD): > 30% increase in SUL peak (minimum 0.8 unit increase in SUL 
peak), > 75% increase in TLG of the 5 most active lesions, Visible increase in extent of FDG 
uptake, or new lesions. Verification with follow-up study if anatomic criteria indicate complete 
or partial response.
Stable Disease (SD): Does not meet other criteria.
6.3.4.3
Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis).
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator).
6.3.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria.
For Patients with Measurable Tumors (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
>4 wks. Confirmation**

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PR
Non-CR/Non-
PD/not evaluated
No
PR
SD
Non-CR/Non-
PD/not evaluated
No
SD
Documented at least once >4 
wks. from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
*
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression.
Note:
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every effort 
should be made to document the objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used 
as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be 
measured is not advised
6.3.5
Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.

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Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
6.3.6
Progression free survival: 
Progression-free survival (PFS) is measured from the start of treatment until the time of disease 
progression or death from any cause.
6.4
TOXICITY CRITERIA
Careful evaluation to ascertain the toxicity, immunologic effects and anti-tumor efficacy of the 
treatment regimens will be performed. This study will utilize the CTCAE version 4.0 for toxicity 
and adverse event reporting.  A copy of the CTCAE version 4.0 can be downloaded from the 
website http://ctep.cancer.gov.  All appropriate treatment areas should have access to a copy of 
the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING/IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem or present new information that 
might affect the willingness of participants to enroll or remain on the study will need to be 
reported per these policies.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.

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7.4
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802: Non-compliance in Human Subjects Research, found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.  The participating site PI must 
immediately report to the coordinating center PI any deaths possibly related to the research 
within 24 hours of PI awareness of the event.  The Site PI must also report any other events 
required by Policy 801 to the coordinating center PI within 7 days of PI awareness.  
A reporting form will be provided with the participating site documents for such reports. 
7.5
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA
7.5.1
Serious Adverse Event Reports to IBC
The NIH Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of E7 TCR transduced PBL cells as soon as 
possible but in no event later than 7 calendar days of initial receipt of the information.  Serious 
adverse events that are unexpected and associated with the use of the E7 TCR transduced PBL, 
but are not fatal or life-threatening, much be reported to the NIH IBC as soon as possible, but not 
later than 15 calendar days after the investigator’s initial receipt of the information.  Adverse 
events may be reported by using the FDA Form 3500a.
7.5.2
Annual Reports to IBC
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the NIH Principal 
Investigator (or delegate) shall submit the information described below.  Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report.  Please include the 
IBC protocol number on the report.
7.5.2.1
Clinical Trial Information 
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information: 
•
the title and purpose of the trial 
•
clinical site
•
the Principal Investigator
•
clinical protocol identifiers; 
•
participant population (such as disease indication and general age group, e.g., adult or 
pediatric); 
•
the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons 
•
the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
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•
if the trial has been completed, a brief description of any study results. 
7.5.2.2
Progress Report and Data Analysis
Information obtained during the previous year's clinical and non-clinical investigations, 
including: 
•
a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system
•
a summary of all serious adverse events submitted during the past year
•
a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications
•
if any deaths have occurred, the number of participants who died during participation in 
the investigation and causes of death
•
a brief description of any information obtained that is pertinent to an understanding of the 
gene transfer product’s actions, including, for example, information about dose-response, 
information from controlled trials, and information about bioavailability. 
7.6
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.6.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular biweekly basis when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients. 
All data will be collected in a timely manner and reviewed by the Principal Investigator. Events 
meeting requirements for expedited reporting as described in Section 7.2.1 will be submitted 
within the appropriate timelines. 
The NIH Principal Investigator will review adverse event and response data on each patient to 
ensure safety and data accuracy. The site Principal Investigator will personally conduct or 
supervise the investigation at the respective site and provide appropriate delegation of 
responsibilities to other members of the research staff. 
7.6.2
Safety Monitoring Committee (SMC) – NCI CCR SMC
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NIH Intramural IRB continuing review 
date.   Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC. For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal Investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.

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8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2))
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see Section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization 
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event.
o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
•
A congenital anomaly/birth defect
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.

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8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site Principal Investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site Principal Investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site Principal Investigator or sub-investigator.
For timeframe of recording adverse events, please refer to Section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in Section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form.  Any exceptions to the 
expedited reporting requirements are found in Section 8.4.
All SAE reporting must include the elements described in Section 8.2.
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions

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Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
WAIVER OF EXPEDITED REPORTING TO CCR 
Hematological toxicities as outlined below will not be included in expedited reporting to CCR 
because these are expected toxicities from the conditioning regimen (commercial product):
CTCAE System 
Organ Class
Adverse Event
Grade
Prolongation of 
Hospitalization
Expected 
Frequency
Attribution
Investigations
Neutrophil count 
decreased
1-3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Neutrophil count 
decreased
4 if < 14 
days
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Blood and 
lymphatic system 
disorders
Anemia
1-3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Platelet count 
decreased
1-3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Platelet count 
decreased
4 if < 14 
days
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
White blood cell 
decreased
1-4
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
Lymphocyte 
count decreased
1-4
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
Investigations
CD4 
lymphocytes 
decreased
1-4
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)

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CTCAE System 
Organ Class
Adverse Event
Grade
Prolongation of 
Hospitalization
Expected 
Frequency
Attribution
Blood and 
lymphatic system 
disorders
febrile 
neutropenia 
(without an 
associated 
infection)
3
Expected
100%
Commercial Product 
(Cyclophosphamide and 
fludarabine)
The PI will submit a summary table of all grade 3-5 events, whether or not considered related to 
the product, every 6 months. The report shall include the number of patients treated in the 
timeframe, the number of events per AE term per grade which occurred in the 6-month 
timeframe and in total since the start of the study, attribution, and type/category of serious. 
Reports will be submitted to the Center for Cancer Research (CCR) at 
OSROSafety@mail.nih.gov
The Sponsor might request case summaries for those events if, upon review, the Sponsor 
determines that an aggregate safety report is required (21CFR312.32(c)(1)(iv)).
8.5
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement. 
8.6
REPORTING PREGNANCY 
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 
8.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (Section 8.1.2) should be reported as 
SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.6.2
Paternal exposure
Patients should refrain from fathering a child or donating sperm during the study and for 4 
months after the last dose of E7 TCR Transduced PBL.
Pregnancy of the patient’s partner is not considered to be an AE. The outcome of all pregnancies  
occurring from the date of the first dose until 4 months after the last dose should, if possible, be 
followed up and documented. Pregnant partners may be offered the opportunity to participate in 

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an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to 
provide data about the outcome of the pregnancy for safety reporting purposes.
8.7
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected in expedited manner to the FDA in 
accordance to 21 CFR 31.2.32.  CCR will report an AE as a suspected adverse reaction only if 
there is evidence to suggest a causal relationship between the study product and the adverse 
event.  CCR will notify FDA and all participating investigators (i.e., all investigators to whom 
the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety 
report of potential serious risks from clinical trials or any other source, as soon as possible, in 
accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
8.8
SPONSOR PROTOCOL DEVIATION REPORTING
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial.
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements. 
Non-NIH participating sites not using the CCR Protocol Deviation Tracking System 
(PDTS) will report any protocol deviation on the OSRO Site Protocol Non-
Adherence/Deviation Log, or a site-generated protocol deviation report approved by 
OSRO. The Non-Adherence/Deviation Log should be maintained in the site essential 
documents file and submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first 
business day of each month throughout the study. 
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 
•
the quality and integrity of study data and data collection methods are maintained.  

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Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study 
site(s). Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS
For Phase I, the objective of this study is to determine a safe dose for E7 TCR cells plus 
aldesleukin for the treatment of metastatic HPV-16+ cancers. The study may require up to 6 
patients per dose level. For purposes of sample size estimation, we will assume that as few as 9 
and no more than 18 patients will be required to perform the initial safety evaluation for E7 
during the phase I portion. As of March 2nd, 2018, a total of 9 patients have been treated with no 
dose-limiting toxicities encountered. 
With Amendment H
A total of 40 patients will be treated, including the 3 additional patients added to dose level 3 via 
amendment G to confirm safety.
These patients will be evaluated for efficacy and for safety as follows. With 40 patients treated at 
a single dose level, there will be 90% power to rule out a 10% overall response rate (PR +CR) in 
favor of a targeted alternative response rate of 25%, with a one-sided 0.10 significance level 
exact binomial test. These levels were selected to account for a variety of tumor types which may 
have varying degrees of response. In practice, if there are 7 responses out of 40 patients (17.5%), 
then the lower one-sided exact 90% confidence bound about this fraction is 10.0%, which 

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matches the level to be ruled out. Thus, 7 responses in 40 patients would be considered a 
minimally acceptable overall response rate for the cohort. After the trial, the results obtained will 
be reported along with a one-sided lower 90% confidence interval bound as well as two-tailed 
80% and 95% confidence intervals.
In addition, to ensure that enrollment to the RP2D level is not continued if response rates are 
insufficient, an early stopping rule will be imposed. If after 21 evaluable patients there are 0 or 1 
responses, then no further patients will be enrolled as soon as this can be determined because the 
upper one-sided exact 90% confidence interval bound on 1/21 is 17.3%, which is marginally 
inconsistent with the intended 7/40 (17.5%) minimally necessary to consider the results to be 
positive overall.
This cohort of 40 patients may consist of patients with any of 6 possible tumor types, but all of 
which are HPV-16+. As such, they will be considered together for a primary evaluation because 
of this common characteristic. In addition to evaluating the results in the full set of 40 patients, 
there will be individual exploratory evaluations of response for the patients according to their 
type of tumor along with 80% and 95% two-sided confidence intervals. The results obtained in 
this exploratory fashion may be used to guide parameter selection for subsequent trials if 
appropriate. 
As indicated in Section 3.4, patients may be re-enrolled on the study as new patients to allow re-
treatment, and these patients will be considered both times in the total accrual ceiling for the 
study. This re-enrollment of patients will not be used in the analysis of the 40-patient cohort. 
Provided that about 2 patients every month will be enrolled onto this trial, with a 4-week time 
frame between each dose level, approximately 1 ½ - 2 years may be needed to accrue the maximum 
number of patients. Participants in the phase II portion of the study who receive treatment with a 
cell dose more than 30% below the RP2D will be evaluable for safety but will not be included in 
the primary efficacy analysis. 
With up to 40 evaluable participants needed for treatment, as well as planning for a small number 
of inevaluable participants (15), we intend to initiate intervention in up to 55 participants.  Note:  
To allow for screen failures (305), a total of 360 will be set for the purposes of the NIH accrual 
ceiling.
11 COLLABORATIVE AGREEMENTS 
De-identified samples may be provided to Kite Pharma for assistance in performing the research 
studies described in Section 5.1. Kite Pharma is collaborating in the development of the E7 TCR. 
A CRADA between NCI and Kite Pharma is now terminated(CRADA # 03022). Kite Pharma 
provided funding for this study.
11.1 MULTI-INSTITUTIONAL GUIDELINES
Documents requiring submission to the reviewing IRB as provided in the Participating Site 
Information Sheet should be provided to the coordinating center for submission to the IRB.  

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12 HUMAN SUBJECTS PROTECTIONS
12.1 RATIONALE FOR SUBJECT SELECTION
The patients to be entered in this protocol have metastatic or recurrent/refractory locally 
advanced HPV-associated cancer that is refractory to standard therapy, and limited life 
expectances.
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria.  To date, there is no information that suggests that differences in drug 
metabolism or disease response would be expected in one group compared to another.  Efforts 
will be made to extend accrual to a representative population, but in this preliminary study, a 
balance must be struck between patient safety considerations and limitations on the number of 
individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the 
need to explore gender and ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a 
follow-up study may be written to investigate those differences more fully.
12.2 PARTICIPATION OF CHILDREN
The use of the non-myeloablative regimen in this protocol entails serious discomforts and 
hazards for the patient, such that fatal complications are possible.  It is therefore only appropriate 
to carry out this experimental procedure in the context of life threatening metastatic cancer.  
Since the efficacy of this experimental procedure is unknown, it does not seem reasonable to 
expose children to this risk without further evidence of benefit.  Should results of this study 
indicate efficacy in treating metastatic cancer, which is not responsive to other standard forms of 
therapy, future research can be conducted in the pediatric population to evaluate potential benefit 
in that patient population.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 12.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) to assess ongoing capacity of the subjects and to 
identify an LAR as needed.
Please see Section 12.6.1 for consent procedure.
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
The experimental treatment has a chance to provide clinical benefit though it is not known if it 
will do so.  
Over 400 patients have been treated in the Surgery Branch, NCI with TIL.  Early toxicities 
related specifically to the infusion of the cells (those which are seen immediately following cell 
infusion and prior to aldesleukin administration) are generally mild and include fevers, chills, 
headache, and malaise. Toxicities which occur following administration of aldesleukin but are 

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thought to be related to the cells include immune mediated events such as vitiligo, transient 
uveitis, hearing loss and vestibular dysfunction.  The use of the non-myeloablative regimen prior 
to cell administration increases the toxicity of this treatment as profound myelosuppression 
occurs in all patients.  In 93 patients treated with TIL using the non-myeloablative chemotherapy 
regimen with or without total body irradiation, there was one treatment related death (NMA + 
200 cGy TBI) due to an unexpected but preexisting diverticular abscess.  In the 101 patients 
treated in a subsequent randomized trial, 2 treatment-related deaths occurred – both due to the 
TBI component of the treatment regimen. 
The standard approach to the administration of high-dose aldesleukin in all studies is to continue 
dosing until Grade 3 or 4 events occur. The most commonly seen Grade 4 events are pulmonary 
and renal impairment, and mental status changes.  These toxicities may sometimes require 
intubation for protection of the patient’s airway.  It is important to note that although these 
patients require significant supportive measures during this period, all toxicities are reversible 
and the overwhelming majority of patients have suffered no long term sequelae following this 
treatment regimen.  However, fatal complications are possible and it is therefore only 
appropriate to carry out this experimental treatment in the context of life threatening metastatic 
cancer.
Toxicities seen on protocols using this non-myeloablative regimen and aldesleukin that occur 
during the follow up period are rare but have included EBV lymphoma following prolonged 
lymphopenia, herpes zoster infection, and sensory neuropathy likely related to fludarabine.  
The major discomforts of the research are those of nausea and vomiting, mucositis, anorexia, 
diarrhea, fever and malaise.  Side effects of common drugs used in this regimen include:
•
Cyclophosphamide: Marrow suppression, nausea, mucositis, rash, hemorrhagic cystitis, 
myocardial damage, alopecia, infertility, nausea and vomiting, SIADH.  
•
Fludarabine: Myelosuppression, fever and chills, nausea and vomiting, malaise, fatigue, 
anorexia, weakness, neurologic toxicity, and interstitial pneumonitis.  Serious 
opportunistic infections have occurred in CLL patients treated with fludarabine.
•
Antimicrobials in general: Allergic reactions, renal impairment, nausea, vomiting, 
hepatic damage, marrow suppression, photosensitivity. 
•
High-dose aldesleukin administration: A listing of these side effects in 525 patients who 
received 1,039 treatment courses are listed in Appendix D.
12.4.1 Cell Infusion
The cells have a type of virus (retrovirus) put into them that recognizes the HPV E7 protein.  
Although this retrovirus is not active, there is the rare possibility that it may cause infection. The 
cells could also cause subjects to develop another type of cancer, such as leukemia or lymphoma.  
These specific gene-modified cells have not been given before so we do not have much 
information about the side effects.  
Potential risks include: 
•
Fever, chills and shortness of breath, which may last for a few hours (common)
•
Lung congestion causing shortness of breath 

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•
Severe reaction to the cells which would include very low blood pressure and damage to 
heart, lung, and/or kidneys
•
As this is a new experimental therapy which has not been given to patients, side effects 
that we do not anticipate that may cause conditions to deteriorate may be encountered.  
Any new information that becomes available during the course of this study will be 
shared.
•
Experience with diverse types of cell therapy including tumor-infiltrating lymphocytes, 
CAR-T cells, and TCR-T cells, indicates that the risk of cell therapy may include 
cytokine release syndrome (where the T cell therapy causes the release of chemicals 
called cytokines that aggressively ramp up the immune system), autoimmunity (an 
immune reaction against normal tissues) and neurotoxicity (damage to the nervous 
system). Cytokine release syndrome may cause mild symptoms such as fever, fatigue, 
headache, rash, joint stiffness, and muscle aches, or severe symptoms such as low blood 
pressure, high fever, uncontrolled systemic inflammatory response, hemophagocytic 
lymphohistiocytosis (a rare condition in which certain types of white blood cells build up 
in organs and destroy other blood cells), shock, vascular leakage (where fluids and 
proteins leak out of small blood vessels and into surrounding tissues), disseminated 
intravascular coagulation (a serious disorder where proteins that control blood clotting 
become overactive), and multi-organ system failure.  
•
A patient treated on the phase I portion of the protocol, who had breathing problems from 
advanced cancer in the lungs, developed severe breathing, blood pressure, and kidney 
toxicity that required temporary support with a breathing machine, blood pressure 
medicines, and dialysis and this resulted in injury to her toes and feet.
12.4.2 Biopsy
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. 
12.4.3 Blood Sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. Up 
to 200 ml of blood may be collected at any visit on study (at screening this maximum at a single 
visit is 100 ml of blood), but no more than 473 ml per 8 weeks period.  
12.4.4 Electrocardiogram (ECG)
An electrocardiogram or ECG is a test that records the electrical activity of the heart. It is used to 
measure the rate and regularity of heartbeats as well as the size and position of the heart 
chambers, and the presence of any damage to the heart. For this test, participants will be asked to 
lie down, and small patches that have an adhesive edge with a gel in the middle, called 
electrodes, will be placed on the arms, legs, and chest. The areas where the electrodes are placed 
will be cleaned and, if needed, some hair may be shaved or clipped to allow for better attachment 
of the electrodes. The adhesive from the patches may irritate the skin.
12.4.5 Leukapheresis
There may be some tingling in the face, mouth and fingers due to the medicine used to keep the 
blood from clotting during the procedure. The nurses may give a calcium-containing antacid to 
take away this tingling. Rarely, people may experience lightheadedness or dizziness. Rare 

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complications of this procedure are lowered blood pressure, lightheadedness, dizziness, nausea, 
possible problems with the cell separator machine which would not allow the red cells and 
plasma to be returned and bleeding or bruising where the needles are put in the arms.
12.4.6 Intravenous Catheter
The risks associated with placing some catheters include pain, bleeding, infection and collapsed 
lung. The long-term risks of the catheter include infection and clotting of the veins. It may be 
necessary to remove the catheter. 
12.4.7 Pulmonary Function Tests (PFT)
PFTs are safe for most participants; however, some may experience dizziness, shortness of breath 
and fainting. In rare PFTs may lead to a collapsed lung.  In participants with asthma, PFTs may 
precipitate an asthma attack. 
12.4.8 CT and PET Scans
During a CT scan and PET, participants are briefly exposed to much more radiation than they 
would be during a plain X-ray. Radiation exposure potentially increases the risk of developing 
cancer. Although rare, the intravenous (IV) contrast material involved in some CT and PET 
scans causes medical problems or allergic reactions in some people. Most reactions are mild and 
result in hives or itchiness. In rare instances, an allergic reaction can be serious and potentially 
life threatening. Participants are to tell the study doctor if they've ever had a prior reaction to 
contrast material during medical tests. 
12.4.9 MRI & Gadolinium-enhanced MRI
12.4.9.1 MRI 
Participants might be at risk for injury from the MRI magnet if they have some kinds of metal in 
their body.  It may be unsafe for them to have an MRI scan if they have:
•
pacemakers or other implanted electrical devices, 
•
brain stimulators, 
•
some types of dental implants, 
•
aneurysm clips (metal clips on the wall of a large artery), 
•
metal prostheses (including metal pins and rods, heart valves, and cochlear implants), 
•
permanent eyeliner, 
•
tattoos, 
•
an implanted delivery pump, 
•
or shrapnel fragments. Welders and metal workers may have small metal fragments in the 
eye. 
Participants will be screened for these conditions before having any MRI scan.  If they have a 
question about metal in their body, they should tell us. They will be asked to fill out an MRI 
screening form before each MRI scan they have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before they enter the MRI scan room.

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If participants are afraid of confined (small, cramped) spaces, they may get anxious during an 
MRI. If they have back problems, they may have back pain or discomfort from lying in the 
scanner.  
The noise from the scanner is loud enough to damage hearing, especially if they already have 
hearing loss. We will give them hearing protection. If the hearing protection comes loose during 
the scan, they should let us know right away.
There are no known long-term risks of MRI scans.
12.4.9.2 Gadolinium-enhanced MRI
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, 
hives, and lowering of blood pressure. Participants should not receive gadolinium if they 
previously had an allergic reaction to it.  They will be asked about such allergic reactions before 
gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of 
deaths.  A blood test of kidney function may be done within the month before an MRI scan with 
gadolinium contrast. Participants will not receive gadolinium for a research MRI scan if kidney 
function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine. However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years. The effects of the retained gadolinium are not clear. At this time, retained gadolinium has 
not been linked to health risks in people whose kidneys work well. Some types of gadolinium 
contrast drugs are less likely to remain in the body than others. In this study, we will use the 
gadolinium contrast drugs that are less likely to remain in the body. We will also give 
participants additional information called a “Medication Guide.”  Upon request, we will give 
individual information about retained gadolinium we see on their studies.
12.4.10Radiation Exposure
Including assessments at screening, this research study involves up to 3 CT CAP scans, 4 CT 
guided biopsies, and 3 PET scans collected for research purposes.
Subjects undergoing these scans and biopsies will be exposed to 8.3 rem per year. The CT scans, 
CT guided biopsies, and PET scans, in this study will expose the research participant to 27.7 
years’ worth of background radiation. This level of exposure results in an increased risk of 
cancer.

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12.5 RISKS/BENEFITS ANALYSIS
The success of this effort cannot be predicted at this time.  Since all patients in this protocol have 
metastatic or recurrent/refractory locally advanced HPV16-associated cancer and limited life 
expectancies the potential benefit is thought to outweigh the potential risks. 
12.5.1 Adult Patients (including who are or may become unable to consent)
As outlined above, although there is prospect of direct benefits to individual subjects. We believe 
that procedures performed on this study will pose more than a minimal risk to the patients.
12.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) as applicable for review prior to consenting.  A designated 
study investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
local policy, including HRPP Policy 303) per discretion of the designated study investigator and 
with the agreement of the participant/consent designee(s).  Whether in person or remote, the 
privacy of the subject will be maintained. Consenting investigators (and participant/consent 
designee, when in person) will be located in a private area (e.g., clinic consult room). When 
consent is conducted remotely, the participant/consent designee will be informed of the private 
nature of the discussion and will be encouraged to relocate to a more private setting if needed.  
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.  
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures:
•
Adobe platform (which is not 21 CFR Part 11 compliant); or,  
•
iMedConsent platform (which is 21 CFR Part 11 compliant)
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location, but is not required.  
Both the investigator and the participant will sign the document using a finger, stylus or mouse. 
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent Process 
for additional information (e.g., verification of participant identity when obtaining consent 
remotely) 
found 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825.

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12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in Section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.6. 
12.6.2 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in Section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects. A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols. These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources. The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigators, funding agency, the Investigational New Drug (IND) sponsor and regulatory 
authorities.  If the study is prematurely terminated or suspended, the Principal Investigator (PI) 
will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and 
will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
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Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 

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clinical sites and by NCI research staff will be secured and password protected. At the end of the 
study, all study databases will be archived at the NCI.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
14 PHARMACEUTICAL INFORMATION
Note:  The package insert/prescribing information for each commercial supply used should 
supersede any information included below.
14.1 INTERLEUKIN-2 
14.1.1 Other Names
Aldesleukin, Proleukin, Recombinant Human Interleukin 2
14.1.2 How Supplied
Aldesleukin (interleukin-2) will be provided by the NIH Clinical Pharmacy Department from 
commercial sources.
14.1.3 Formulation/Reconstitution
Aldesleukin, NSC #373364, is provided as single-use vials containing 22 million IU (~1.3mg) 
IL-2 as a sterile, white to off-white lyophilized cake plus 50mg mannitol and 0.18 mg sodium 
dodecyl sulfate, buffered with approximately 0.17 mg monobasic and 0.89 mg dibasic sodium 
phosphate to a pH of 7.5 (range 7.2 to 7.8).  The vial is reconstituted with 1.2 mL of Sterile 
Water for Injection, USP, and the resultant concentration is 18 million IU/mL or 1.1 mg/mL.  
Diluent should be directed against the side of the vial to avoid excess foaming.  Swirl contents 
gently until completely dissolved.  Do not shake.  Since vials contain no preservative, 
reconstituted solution should be used with 24 hours.
14.1.4 Storage
Intact vials are stored in the refrigerator (2 to 8C) protected from light.  Each vial bears an 
expiration date.
14.1.5 Dilution/Stability
Reconstituted aldesleukin should be further diluted with 50 mL of 5% Human Serum Albumin 
(HSA).  The HSA should be added to the diluent prior to the addition of IL-2.  Dilutions of the 
reconstituted solution over a 1000-fold range (i.e., 1 mg/mL to 1 mcg/mL) are acceptable in 
either glass bottles or polyvinyl chloride bags.  Aldesleukin is chemically stable for 48 hours at 
refrigerated and room temperatures, 2 to 30C. As there are no formal stability studies of 
aldesleukin diluted with HSA, the expiration time will be limited to 4 hours, per pharmacy 
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14.1.6 Administration
The dosage will be calculated based on total body weight.  The final dilution of aldesleukin will 
be infused over 15 minutes.  Aldesleukin will be administered as an inpatient.
14.1.7 Toxicities: 
Expected toxicities of aldesleukin are listed in the product label and in Appendix C.  Grade 3 
toxicities common to aldesleukin include diarrhea, nausea, vomiting, hypotension, skin changes, 
anorexia, mucositis, dysphagia, or constitutional symptoms and laboratory changes as detailed in 
Appendix B.  Additional Grade 3 and 4 toxicities seen with aldesleukin are detailed in 
Appendix C.  
14.2 FLUDARABINE
14.2.1 Description
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is a purine 
antagonist antimetabolite.
14.2.2 How Supplied
It will be purchased by the NIH Clinical Pharmacy Department from commercial sources.  
Fludarabine is supplied in a 50 mg vial either as a fludarabine phosphate powder in the form of a 
white, lyophilized solid cake or as an intravenous solution in a 25 mg/ml concentration.
14.2.3 Stability
For the intravenous powder for solution, following reconstitution with 2 mL of sterile water for 
injection to a concentration of 25 mg/mL, the solution has a pH of 7.7.  The fludarabine powder 
is stable for at least 18 months at 2 to 8C; when reconstituted, fludarabine is stable for at least 16 
days at room temperature.  Since no preservative is present, reconstituted fludarabine will 
typically be administered within 8 hours.  Specialized references should be consulted for specific 
compatibility information.  Fludarabine is dephosphorylated in serum, transported intracellularly 
and converted to the nucleotide fludarabine triphosphate; this 2-fluoro-ara-ATP molecule is 
thought to be required for the drug’s cytotoxic effects.  Fludarabine inhibits DNA polymerase, 
ribonucleotide reductase, DNA primase, and may interfere with chain elongation, and RNA and 
protein synthesis.
14.2.4 Storage
Intact vials should be stored refrigerated (2 to 8C).
14.2.5 Administration
Fludarabine is administered as an IV infusion in 100 mL of 5% dextrose in water or 0.9% 
sodium chloride, USP over 15 to 30 minutes.  The doses will be based on body surface area 
(BSA).  If patient is obese (BMI >35), drug dosage will be calculated using practical weight as 
described in Table 3. 
Table 3.  Modification of Dose Calculations* in patients whose BMI is greater than 35
1. BMI Determination:
BMI = weight (kg) / [height (m)]2

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2. Calculation of ideal body weight
Male = 50kg + 2.3 (number of inches over 60 inches)
Example: ideal body weight of 5’10” male
50 + 2.3 (10) = 73 kg
Female = 45.5kg + 2.3 (number of inches over 60 inches)
Example: ideal body weight of a 5’3” female
45.5 + 2.3 (3) = 57kg
3. Calculation of “practical weight”
Calculate the average of the actual and the ideal body weights.  This is the 
practical weight to be used in calculating the doses of chemotherapy and 
associated agents designated in the protocol.  
14.2.6 Toxicities
At doses of 25 mg/m2/day for 5 days, the primary side effect is myelosuppression; however, 
thrombocytopenia is responsible for most cases of severe and life-threatening hematologic 
toxicity.  Serious opportunistic infections have occurred in CLL patients treated with fludarabine.  
Hemolytic anemia has been reported after 1 or more courses of fludarabine with or without a 
prior history of a positive Coomb’s test; fatal hemolytic anemia has been reported.  In addition, 
bone marrow fibrosis has been observed after fludarabine therapy.  Other common adverse 
effects and potentially fatal central nervous system toxicity in the form of progressive 
encephalopathy, blindness, and coma is only rarely observed at the currently administered doses 
of fludarabine.  More common neurologic side effects at the current doses of fludarabine include 
weakness, pain, malaise, fatigue, paresthesia, visual or hearing disturbances, and sleep disorders.  
Adverse respiratory effects of fludarabine include, cough, dyspnea, allergic or idiopathic 
interstitial pneumonitis.  Tumor lysis syndrome has been rarely observed in fludarabine 
treatment of CLL.  Treatment on previous adoptive cell therapy protocols in the Surgery Branch 
have caused persistently low (below 200) CD4 counts, and 1 patient developed polyneuropathy 
manifested by vision blindness, and motor and sensory defects.
Unless otherwise specified in this protocol, actual body weight is used for dose calculations of 
treatment agents.  In patients who are determined to be obese (BMI >35), the practical weight 
(see 3 below) will be used.
14.3 CYCLOPHOSPHAMIDE 
14.3.1 Description
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkylating agent; the drug also 
possesses potent immunosuppressive activity.  The serum half-life after IV administration ranges 
from 3 to 12 hours; the drug and/or its metabolites can be detected in the serum for up to 72 
hours after administration.
14.3.2 How Supplied
Cyclophosphamide will be obtained from commercially available sources by the Clinical Center 
Pharmacy Department.

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14.3.3 Stability
Following reconstitution as directed with sterile water for injection, cyclophosphamide is stable 
for 24 hours at room temperature or 6 days when kept at 2 to 8C.
14.3.4 Administration
It will be diluted in 250 mL of 5% dextrose in water (D5W) or 0.9% sodium chloride, USP and 
infused over 1 hour.  The dose will be based on the patient’s body weight.  If patient is obese 
(BMI>35) drug dosage will be calculated using practical weight as described in Table 3.
14.3.5 Toxicities
Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia and 
thrombocytopenia.  Anorexia, nausea and vomiting, rash and alopecia occur, especially after 
high-dose cyclophosphamide; diarrhea, hemorrhagic colitis, infertility, and mucosal and oral 
ulceration have been reported.  Sterile hemorrhagic cystitis occurs in about 20% of patients; 
severity can range from microscopic hematuria to extensive cystitis with bladder fibrosis.  
Although the incidence of hemorrhagic cystitis associated with cyclophosphamide appears to be 
lower than that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has been 
used prophylactically as an uroprotective agent in patients receiving cyclophosphamide.  
Prophylactic mesna is not effective in preventing hemorrhagic cystitis in all patients.  Patients 
who receive high dose cyclophosphamide may develop interstitial pulmonary fibrosis, which can 
be fatal.  Hyperuricemia due to rapid cellular destruction may occur, particularly in patients with 
hematologic malignancy.  Hyperuricemia may be minimized by adequate hydration, 
alkalinization of the urine, and/or administration of allopurinol.  If allopurinol is administered, 
patients should be watched closely for cyclophosphamide toxicity (due to allopurinol induction 
of hepatic microsomal enzymes).  At high doses, cyclophosphamide can result in a syndrome of 
inappropriate antidiuretic hormone secretion; hyponatremia with progressive weight gain without 
edema occurs.  At high doses, cyclophosphamide can result in cardiotoxicity.  Deaths have 
occurred from diffuse hemorrhagic myocardial necrosis and from a syndrome of acute 
myopericarditis; in such cases, congestive heart failure may occur within a few days of the first 
dose.  Other consequences of cyclophosphamide cardiotoxicity include arrhythmias, potentially 
irreversible cardiomyopathy, and pericarditis.  Other reported adverse effects of 
cyclophosphamide include headache, dizziness, and myxedema; faintness, facial flushing, and 
diaphoresis have occurred following IV administration.  Mesna (sodium 2-
mercaptoethanesulphonate; given by IV injection) is a synthetic sulfhydryl compound that can 
chemically interact with urotoxic metabolites of cyclophosphamide (acrolein and 4-
hydroxycyclophosphamide) to decrease the incidence and severity of hemorrhagic cystitis.
14.4 CELL PREPARATION (E7 TCR TRANSDUCED PBL)
The procedure for the expanding the human PBL is similar to those approved by the Food and 
Drug Administration, and used at the NCI in ongoing protocols. The PBL will be transduced 
with retroviral supernatant containing the E7 TCR.
14.4.1 Retroviral Vector Containing the E7 TCR gene
The retroviral vector supernatant (PG13-MSGV1-E7-TCR) encoding a T cell receptor directed 
against HPV16 E711-19) was prepared and preserved following cGMP conditions in the Surgery 
Branch Vector Production Facility (SBVPF).  The E7 TCR vector was produced by the Surgery 

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Branch Vector Production Facility. The backbone is the MSGV1 retrovirus that has been used in 
prior gene therapy clinical trials. It was produced using a PG13-based packaging line.
The retroviral vector E7 TCR consists of 7,310 bps including the 5’LTR from the murine stem 
cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor 
sites, alpha and beta chain genes of the E7 TCR.  The alpha and beta chains are linked by a P2A 
peptide.  The vector was codon optimized for expression by human cells with constant region 
exchanged for murine counterparts with an added disulfide bond and hydrophobic substitutions 
in the alpha chain constant region transmembrane domain.    
The physical titer will be determined by transduction of PBL with serial dilutions of the vector.  
TCR expression on the cell surface will be measured using FACS following staining with an 
anti-mouse constant region antibody.  The titer will be measured as transducing units per 
milliliter.  Portions of the supernatant will be stored at -80C at Surgery Branch, NCI, American 
Type Culture Collection (ATCC), Rockville, MD, and the NIH Clinical Center Department of 
Transfusion Medicine.  These storage facilities are equipped with around-the-clock temperature 
monitoring.  Upon request, supernatant will be delivered on dry ice to be used in ex vivo 
transduction of patient PBL.  There will be no re-use of the same unit of supernatant for different 
patients.  Retroviral titer has been shown to be stable after immediate thawing and immediate 
administration (coating the tissue culture wells previously coated with Retronectin).  Handling of 
the vector should follow the guidelines of Biosafety Level-2 (BSL-2). The specific guidelines for 
Biosafety Level-2 (BSL-2) can be viewed at https://www.cdc.gov/labs/pdf/CDC-
BiosafetyMicrobiologicalBiomedicalLaboratories-2009-P.PDF (section IV).
14.5 MESNA
14.5.1 Other Names
Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891
14.5.2  How Supplied
Mesna will be obtained commercially by the Clinical Center Pharmacy Department and is 
supplied as a 100 mg/mL solution.
14.5.3 Storage
Intact ampules are stored at room temperature. 
14.5.4 Stability
Diluted solutions (1 to 20 mg/mL) are physically and chemically stable for at least 24 hours 
under refrigeration.  Mesna is chemically stable at room temperature for 48 to 72 hours in D5W, 
48 to 72 hours in D5W/0.45% NaCl, or 24 hours in 09% NaCl.
14.5.5 Administration
Dilute to concentrations less than or equal to 20 mg Mesna/mL fluid in D5W or 0.9% NaCl and 
to be administered intravenously as a continuous infusion.  If patient is obese (BMI >35) drug 
dosage will be calculated using practical weight as described in Table 3.  
14.5.6 Toxicities
Include nausea, vomiting, and diarrhea.

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14.6 FILGRASTIM
Note:  Filgrastim or its biosimilar may be used interchangeably on this protocol. 
14.6.1 Other Names
Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen
14.6.2 How supplied
Filgrastim will be obtained commercially by the Clinical Center Pharmacy Department and is 
supplied in 300 ug/mL and 480 ug/1.6mL vials.  
14.6.3 Storage
G-CSF should be refrigerated and not allowed to freeze.  The product bears the expiration date.  
The product should not be shaken. 
14.6.4 Stability
It is generally stable for at least 10 months when refrigerated. 
14.6.5 Administration
The appropriate dose is drawn up into a syringe.  G-CSF will be given as a daily subcutaneous 
injection.  
14.6.6 Toxicities
The side effects of G-CSF are skin rash, myalgia, and bone pain, an increase of pre-existing 
inflammatory conditions, enlarged spleen with occasional associated low platelet counts, 
alopecia (with prolonged use) elevated blood chemistry levels.
14.7 TRIMETHOPRIM AND SULFAMETHOXAZOLE DOUBLE STRENGTH (TMP/SMX DS)
14.7.1 How supplied 
TMP/SMX DS will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  
It may be used for the prevention of PCP pneumonia.  
14.7.2 Administration
The oral dose is 1 tablet PO daily 3 times a week (MUST be on non-consecutive days) beginning 
at or near the time of discharge from the hospital and continuing for at least 6 months and until 
the CD4 count is greater than 200 on 2 consecutive lab studies. 
14.7.3 Toxicities 
Like other sulfa drugs, TMP/SMX DS can cause allergies, fever, photosensitivity, nausea, and 
vomiting.  Allergies typically develop as a widespread itchy red rash with fever 8 to 14 days after 
beginning the standard dose.  Neutropenia, a reduction in the number of neutrophils, can also 
occur.
14.8 AEROSOLIZED PENTAMIDINE IN PLACE OF TMP/SMX DS
Patients with sulfa allergies may receive aerosolized Pentamidine 300 mg per nebulizer at or 
around the time of discharge from the hospital and continued monthly until the CD4 count is 

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above 200 on 2 consecutive follow up lab studies and for at least 6 months post chemotherapy.  
Pentamidine Isethionate will be obtained by the Clinical Center Pharmacy Department from 
commercial sources.  It will be used to prevent the occurrence of PCP infections.  It is supplied 
in 300 mg vials of lyophilized powder and will be administered via nebulizer.  Toxicities 
reported with the use of Pentamidine include metallic taste, coughing, bronchospasm in heavy 
smokers and asthmatics; increased incidence of spontaneous pneumothorax in patients with 
previous PCP infection or pneumatoceles, or hypoglycemia.
14.9
 HERPES VIRUS PROPHYLAXIS
14.9.1  Valacyclovir (Valtrex)
Valacyclovir will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It may be used orally to prevent the occurrence of herpes virus infections in patients 
with positive HSV serology.  It is supplied in 500 mg tablets.  Valacyclovir will be started the 
day after the last dose of fludarabine at a dose of 500 mg orally daily if the patient is able to 
tolerate oral intake.  See package insert for dosing adjustments in patients with renal impairment.  
Common side effects include headache, upset stomach, nausea, vomiting, diarrhea, or 
constipation.  Rare serious side effects include hemolytic uremic syndrome and thrombotic 
thrombocytopenic purpura.
14.9.2  Acyclovir
Acyclovir will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It may be used to prevent the occurrence of herpes virus infections in patients who 
cannot take oral medications.  It is supplied as powder for injection in 500 mg/vials.  
Reconstitute in 10 mL of sterile water for injection to a concentration of 50 mg/mL.  
Reconstituted solutions should be used within 12 hours.  IV solutions should be diluted to a 
concentration of 7 mg/mL or less and used within 12 hours.  IV solutions should be diluted to a 
concentration of 7 mg/mL or less and infused over 1 hour to avoid renal damage.  Reversible 
renal insufficiency has been reported with IV but not oral acyclovir.  Neurologic toxicity 
including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs have been 
reported with higher doses of acyclovir.  Should this occur, a dosage adjustment will be made or 
the drug will be discontinued.  Stomach upset, headache or nausea, rash or hives; peripheral 
edema; pain, elevated liver function tests; and leukopenia, diarrhea, lymphadenopathy, myalgias, 
visual abnormalities and elevated creatinine have been reported.  Hair loss from prolonged use 
has been reported.  Acyclovir will not be used concomitantly with other nucleoside analogs that 
interfere with DNA synthesis, e.g. ganciclovir.  In renal disease, the dose is adjusted as per 
product labeling.
14.10  FUNGAL PROPHYLAXIS
14.10.1 Fluconazole
Fluconazole will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It can be used as prophylaxis against fungal infections.  It is available in 200 mg tablets.  
It can cause headache, nausea, vomiting, diarrhea, or abdominal pain, and liver damage which 
may be irreversible.  It can cause rashes and itching, which in rare cases has caused Stevens 
Johnson Syndrome.  It has several significant drug interactions.  The package insert should be 
consulted prior to prescribing.  For IV administration in patients who cannot tolerate the oral 
preparation, Fluconazole comes in 2 mg/mL solution for injection, and prepared according to 

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Clinical Center Pharmacy standard procedures.  It should be administered at a maximum IV rate 
of 200 mg/hr.
14.11  SUPPORT MEDICATIONS
14.11.1 Ondansetron hydrochloride
Ondansetron hydrochloride will be obtained by the Clinical Center Pharmacy Department from 
commercial sources.  It will be used to control nausea and vomiting during the chemotherapy 
preparative regimen.  It can cause headache, dizziness, myalgias, drowsiness, malaise, and 
weakness.  Less common side effects include chest pain, hypotension, pruritus, constipation and 
urinary retention.  Consult the package insert for specific dosing instructions.
14.11.2 Furosemide
Furosemide will be obtained by the Clinical Center Pharmacy Department from commercial 
sources.  It will be used to enhance urine output during the chemotherapy preparative regimen 
with cyclophosphamide.  Adverse effects include dizziness, vertigo, paresthesias, weakness, 
orthostatic hypotension, photosensitivity, rash, and pruritus.  Consult the package insert for a 
complete list of all side effects. 

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15 REFERENCES
1.
Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy 
for cancer. Immunol Rev. 2014;257(1):56-71.
2.
Hinrichs CS, Restifo NP. Reassessing target antigens for adoptive T-cell therapy. Nat 
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Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human 
papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 
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prevention of noncervical cancers in both men and women. Cancer. 2008;113(10 Suppl):3036-
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Burden of potentially human papillomavirus-associated cancers of the oropharynx and oral 
cavity in the US, 1998-2003. Cancer. 2008;113(10 Suppl):2901-9.
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Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine 
cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23(21):4626-33.
8.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-
based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 
2008;359(11):1116-27.
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16 APPENDICES
16.1 APPENDIX A:  PARTICIPATING SITE ROLES AND OVERSIGHT PLAN
The study will also be conducted at a participating site under a reliance agreement.  The role of 
the participating site is generally limited to sample and data analysis as described in Section 
5.1.5.  Enrollment and routine follow up per protocol will not be conducted at participating site. 
Data will be collected from the sites as outlined in Section 6.1 and expedited reporting will be 
per Section 7.4. Protocol and regulatory compliance will be ensured as described in Section 7.6.1 
and 13.2.
IRB determinations will be forwarded to the participating site PI/study coordinator by a member 
of the study team.

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16.2 APPENDIX B: ADVERSE EVENTS OCCURRING IN ≥10% OF PATIENTS TREATED WITH 
ALDESLEUKIN (N=525)1
Body System
% Patients 
Body System
  
 % Patients
Body as a Whole 
Metabolic and Nutritional Disorders
Chills 
52 
Bilirubinemia 
40
Fever 
29 
Creatinine increase 
33
Malaise 
27 
Peripheral edema 
28
Asthenia 
23
SGOT increase 
23
Infection 
13 
Weight gain 
16
Pain 
12 
Edema 
15
Abdominal pain 
11 
Acidosis 
12
Abdomen enlarged 
10 
Hypomagnesemia 
12
Cardiovascular 
Hypocalcemia 
11
Hypotension 
71 
Alkaline phosphatase incr
10
Tachycardia 
23
Nervous
Vasodilation 
13 
Confusion 
34
Supraventricular tachycardia
12 
Somnolence 
22
Cardiovascular disordera 
11 
Anxiety 
12
Arrhythmia 
10 
Dizziness 
11
Digestive 
Respiratory
Diarrhea 
67 
Dyspnea 
43
Vomiting 
50 
Lung disorderb 
24
Nausea 
35 
Respiratory disorderc 
11
Stomatitis 
22 
Cough increase 
11
Anorexia 
20 
Rhinitis 
10
Nausea and vomiting 
19 
Skin and Appendages
Hemic and Lymphatic 
Rash 
42
Thrombocytopenia 
37
Pruritus 
24
Anemia 
29 
Exfoliative dermatitis 
18
Leukopenia
16 
Urogenital
Oliguria 
63
a Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF.
b Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi.
c Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes.
1Source: Proleukin® Prescribing Information – June 2007

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16.3 APPENDIX C: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT
Toxicity
Grade
Supportive Medications
Stop Cycle*
Stop 
Treatment**
Chills
3
IV Meperidine 25-50mg IV 
q1hr, prn
No 
No
Fever
3
Acetaminophen 650mg po 
q4hr; Indomethacin 50-75mg 
po q8h
No
No
Pruritus
3
Hydroxyzine HCl 10-20mg po 
q6h, prn; Diphenhydramine 
HCl 25-50mg po q4h prn
No 
No
Nausea/Vomiting/A
norexia
3
Ondansetron 10mg IV q8hr 
prn, Granisetron 0.01 mg/kg 
IV qday prn, Droperidol 1mg 
IV a4-6h prn; Prochlorperazine 
25mg PR prn or 10mg IV q6hr 
prn
No
No
Diarrhea
3
Loperamide 2mg po q3h prn; 
Diphenoxylate HCl 2.5mg and 
Atropine sulfate 25mcg po q3h 
prn; Codeine sulfate 30-60mg 
po q4h prn
If uncontrolled 
after 24h despite 
all supportive 
measures
No
Malaise
3 or 4
Bedrest
If other toxicities 
occur 
simultaneously
No
Hyperbilirubinemia
3 or 4
Observation
If other toxicities 
occur 
simultaneously
No
Anemia
3 or 4 
Transfusion with PRBCs
If uncontrolled 
despite all 
supportive 
measures
No
Thrombocytopenia
3 or 4 
Transfusion with platelets
If uncontrolled 
despite all 
supportive 
measures
No

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Toxicity
Grade
Supportive Medications
Stop Cycle*
Stop 
Treatment**
Edema/Weight gain
3
Diuretics prn
No 
No
Hypotension
3
Fluid resuscitation, 
Vasopressor support
If uncontrolled 
despite all 
supportive 
measures
No
Dyspnea
3 or 4 
Oxygen or ventilator support
If requires 
ventilator 
support
No
Oliguria
3 or 4 
Fluid boluses or dopamine at 
renal doses
If uncontrolled 
despite all 
supportive 
measures
No
Increased Creatinine
3 or 4
Observation
Yes (Grade 4)
No
Renal Failure
3 or 4 
Dialysis/CVVH
Yes
Yes
Pleural Effusion
3
Thoracentesis
If uncontrolled 
despite all 
supportive 
measures
No
Bowel Perforation
3
Surgical intervention
Yes
Yes
Confusion
3
Observation
Yes
No
Somnolence
3 or 4 
Intubation for airway 
protection
Yes
Yes
Arrhythmia
3
Correction of fluid and 
electrolyte imbalances; 
chemical conversion or 
electrical conversion therapy
If uncontrolled 
despite all 
supportive 
measures
No
Elevated Troponin 
Levels
3 or 4 
Observation
Yes
If changes in 
LV function 
have not 
improved to 
baseline by 
next dose

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Toxicity
Grade
Supportive Medications
Stop Cycle*
Stop 
Treatment**
Myocardial 
Infarction
4
Supportive care
Yes
Yes
Elevated 
Transaminases
3 or 4
Observation
For Grade 4 
without liver 
metastases
If changes 
have not 
improved to 
baseline by 
next dose
Hyperbilirubinemia
3 or 4 
Observation
For Grade 4 
without liver 
metastases
If changes 
have not 
improved to 
baseline by 
next dose
Electrolyte 
Imbalances
3 or 4
Electrolyte replacement
If uncontrolled 
despite all 
supportive 
measures
No
Neutropenia
4
Observation
No
No
*Unless the toxicity is not reversed within 12 hours.
**Unless the toxicity is not reversed to Grade 2 or less by next treatment.

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16.4 APPENDIX D: INTERLEUKIN-2 TOXICITIES OBSERVED IN PATIENTS TREATED AT THE 
NIH CLINICAL CENTER

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16.5 APPENDIX E: ECOG PERFORMANCE STATUS SCALE
ECOG Performance Status Scale*
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time.  Ambulatory and capable of all self-
care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., 
Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.