Clinical trial NCT03318900
Conditions: COL6A3 Positive HLA-A*0201 Positive Cells Present PRAME Positive Recurrent Ovarian Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-09-04; Completion date: 2023-12-20
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/Ib trial studies the side effects and best dose of utomilumab and how well it works with CD8-positive T-lymphocyte (T-cell infusion) and aldesleukin in treating patients with ovarian cancer that has come back. Aldesleukin may stimulate white blood cells to kill ovarian cancer cells. Giving white blood cells (T-cells) that have been activated by a vaccine with aldesleukin may kill more tumor cells. Immunotherapy with utomilumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving T-cell infusion with aldesleukin and utomilumab may work better in treating patients with ovarian cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. Assess the safety and toxicity of adoptively transferred central memory-type CTL targeting ovarian cancer antigens administered alone, and in combination with, utomilumab, an agonistic anti-CD137 antibody, in patients with platinum-resistant ovarian cancer.

II. Evaluate the functional and numeric in vivo persistence of adoptively transferred central memory-type CTL with and without utomilumab.

SECONDARY OBJECTIVES:

I. Evaluate the anti tumor effect of adoptively transferred central memory-type CTL targeting ovarian cancer antigens as measured by best overall response rate (BORR) and progression free survival (PFS).

OUTLINE: This is a dose escalation study of utomilumab.

Patients undergo leukapheresis. Patients then receive cyclophosphamide intravenously (IV) on day -2, CD8-positive T-lymphocyte via infusion on day 0, and aldesleukin subcutaneously (SC) every 12 hours for 14 days. Beginning 24 hours after CD8-positive T-lymphocyte, patients also receive utomilumab IV over 90 minutes on days 1, 29, 57, 85, 113, and 141 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 3, 7, 14, 22, 28, 35, 43, 49, 56, 64, 70, 77, 84, 112, and 140.

Arms: arm 1: Patients undergo leukapheresis. Patients then receive cyclophosphamide IV on day -2, CD8-positive T-lymphocyte via infusion on day 0, and aldesleukin SC every 12 hours for 14 days. Beginning 24 hours after CD8-positive T-lymphocyte, patients also receive utomilumab IV over 90 minutes on days 1, 29, 57, 85, 113, and 141 in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Aldesleukin intervention 2: CD8-Positive T-Lymphocyte intervention 3: Cyclophosphamide intervention 4: Leukapheresis intervention 5: Utomilumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Undergo leukapheresis intervention 5: Given IV

Protocol documents:
Prot_SAP_001.pdf: 
T Cells for Ovarian Cancer Treatment 
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2016-0400 
Phase I/Ib Study of Adoptive Cellular Therapy Using 
Autologous IL-21-Primed CD8+ Tumor Antigen-Specific T 
Cells in Combination with Utomilumab (PF-05082566) in 
Patients with Platinum Resistant Ovarian Cancer 
 
 
 
 
 
Principal Investigator 
Amir A. Jazaeri MD 
 
Co-Principal Investigator 
Cassian Yee, MD 
 
 
Co-Investigators 
Karen Lu, MD 
Robert Coleman, MD 
Shannon Westin, MD 
 
 
Statistician 
Ying Yuan, PhD 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................................... 3 
1. 
INTRODUCTION ........................................................................................................................... 5 
2. 
OBJECTIVES ................................................................................................................................. 6 
2.1. 
Primary ............................................................................................................................................................. 6 
2.2. 
Secondary ......................................................................................................................................................... 6 
3. 
RATIONALE .................................................................................................................................. 6 
3.1. 
Immunotherapy for Ovarian Cancer ................................................................................................................. 6 
3.2. 
Tumor Antigens Relevant to Ovarian Cancer ................................................................................................... 7 
3.2.1. 
Tumor Associated Antigens in Ovarian Cancer Targeted in this Study ....................................................... 7 
3.2.2. 
COL6A3 ....................................................................................................................................................... 7 
3.2.3. 
PRAME ........................................................................................................................................................ 8 
3.2.4. 
Targeting PRAME, COL6A3, or both ......................................................................................................... 8 
3.3. 
Adoptive T cell Therapy: Rationale as a Treatment Modality .......................................................................... 8 
3.4. 
Antigen-loss variants and antigen-spreading .................................................................................................... 9 
3.5. 
CD137 and cancer ............................................................................................................................................ 9 
3.6. 
Regulatory T Cells .......................................................................................................................................... 10 
3.7. 
The Use of Interleukin-2 in Adoptive T Cell Therapy ................................................................................... 10 
3.8. 
Adoptive T Cell Therapy using antigen-specific CD8+ T Cells in Lymphodepleted Recipients ................... 10 
3.9. 
IL-21 exposure leads to generation of CD28hi helper-independent CD8 T cells in vitro .............................. 11 
3.10. Safety Considerations ..................................................................................................................................... 11 
3.11. Rationale and Proposed Study of Adoptive T Cell Therapy using IL-21 Modulated CD8 CTL for the 
Treatment of Patients with Advanced Ovarian Cancer .............................................................................................. 12 
3.12. Generation of PRAME and COL6A-specific CTL ......................................................................................... 12 
4. 
STUDY DESIGN ........................................................................................................................... 13 
4.1. 
Target Population ........................................................................................................................................... 13 
4.2. 
Study Design .................................................................................................................................................. 13 
4.3. 
Endpoints ........................................................................................................................................................ 14 
4.3.1. 
Primary ....................................................................................................................................................... 14 
4.3.2. 
Secondary ................................................................................................................................................... 14 
5. 
PATIENT ELIGIBILITY ............................................................................................................ 14 
5.1. 
Inclusion Criteria for Enrollment and Leukapheresis (Turnstile 1) ................................................................ 15 
5.2. 
Inclusion Criteria for Treatment (Turnstile 2) ................................................................................................ 15 
5.3. 
Exclusion Criteria for Enrollment .................................................................................................................. 16 
6. 
STUDY AGENTS .......................................................................................................................... 17 
6.1. 
Antigen-specific CD8+ T cells ........................................................................................................................ 17 
6.2. 
Cyclophosphamide ......................................................................................................................................... 17 
6.3. 
Interleukin-2 ................................................................................................................................................... 17 
6.4. 
Utomilumab administration ............................................................................................................................ 17 
7. 
PLAN OF TREATMENT/STUDY SCHEDULE ....................................................................... 17 
8. 
SCHEDULE OF EVALUATIONS .............................................................................................. 20 
8.1. 
General Toxicity Assessment ......................................................................................................................... 20 
8.2. 
Efficacy Assessment ....................................................................................................................................... 20 


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8.2.1. 
Clinical Response ....................................................................................................................................... 20 
8.2.2. 
Immune Related Response Evaluation ....................................................................................................... 20 
8.2.3. 
Best Overall Response Rate (BORR) ......................................................................................................... 21 
8.2.4. 
Duration of Response ................................................................................................................................. 21 
8.2.5. 
Progression Free Survival (PFS) ................................................................................................................ 21 
8.3. 
Immune Monitoring ........................................................................................................................................ 21 
8.4. 
Tumor Immunophenotyping ........................................................................................................................... 22 
9. 
MANAGEMENT OF TOXICITIES AND COMPLICATIONS .............................................. 22 
9.1. 
Dose Limiting Toxicity (DLT) ....................................................................................................................... 22 
9.2. 
Exceptions ...................................................................................................................................................... 22 
9.3. 
Criteria for Discontinuation of Therapy ......................................................................................................... 23 
9.4. 
Trial Stopping Criteria .................................................................................................................................... 23 
9.5. 
Management of Symptoms during T Cell Infusion ........................................................................................ 23 
9.6. 
Toxicities Warranting Ablation of Adoptively Transferred T Cells ............................................................... 24 
10. 
REPORTING SERIOUS ADVERSE EVENTS ......................................................................... 24 
10.1. Definition of Adverse Events ......................................................................................................................... 24 
10.2. Reporting to the FDA ..................................................................................................................................... 26 
10.3. Reporting to Pfizer ......................................................................................................................................... 26 
10.3.1. 
Hy’s Law ............................................................................................................................................... 27 
10.3.2. 
Exposure or Lack of Effect .................................................................................................................... 27 
11. 
STATISTICAL CONSIDERATIONS ........................................................................................ 27 
11.1. Trial Design .................................................................................................................................................... 27 
11.2. Operating Characteristics ............................................................................................................................... 28 
11.3. Analysis Plan .................................................................................................................................................. 29 
12. 
DATA ENTRY AND PROTOCOL MANAGEMENT .............................................................. 29 
13. 
ADMINISTRATIVE CONSIDERATIONS ............................................................................... 29 
13.1. Protocol Monitoring ....................................................................................................................................... 29 
13.2. Changes to the Protocol .................................................................................................................................. 29 
14. 
REFERENCES .............................................................................................................................. 30 
 
 
 


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1. 
INTRODUCTION 
This protocol proposes to examine the safety and duration of in vivo persistence and anti-tumor efficacy 
of adoptively transferred autologous tumor-reactive ovarian cancer antigen-specific CD8+ T cells with or 
without utomilumab (PF-05082566), an agonistic anti-CD137 therapy in patients with advanced ovarian, 
fallopian tube, or primary peritoneal cancer. 
Adoptive T cell therapy (ACT) is one form of personalized immune therapy involving the ex vivo 
selection and expansion of antigen-specific T cells for infusion into patients 1. This approach overcomes 
many of the obstacles that can limit vaccine-elicited responses and provides rigorous control over the 
magnitude, specificity, avidity and phenotype of the effector T cells1-5. Studies using adoptively 
transferred antigen-specific T cells performed by our lab have demonstrated clinical benefit in time to 
progression and in some cases durable partial to complete responses for patients with metastatic 
melanoma 2,5. Analysis of these previous clinical studies reveals that improved efficacy can be achieved 
by: 1) extending the in vivo persistence of transferred T cells, 2) broadening the repertoire of the immune 
response to limit the outgrowth of antigen-loss tumor variants, and 3) addressing mechanisms of tumor 
immune evasion 2,5. 
We recently established a robust protocol for generating long-lasting central memory type T cells against 
a panel of cancer-testis antigens as well as several other shared tumor-associated antigens that will now 
allow us to target non-melanoma solid tumor malignancies, including ovarian cancer. 6-9 While the 
addition of immune checkpoint inhibitors to adoptive cellular therapy has been productive, the availability 
of agonist antibodies to costimulatory receptors such as CD137 provides an additional means of 
extending in vivo persistence and overcoming mechanism of immune evasion by recruiting endogenous T 
cell and NK cell responses to non-targeted tumor associated antigens.  
CD137 (also known as 4-1BB) is a molecule that is up regulated on activated T cells and functions as a 
costimulatory receptor. When engaged to its ligand (CD137L/ 4-1BBL), CD137 delivers positive 
costimulatory signals that enhance TCR signaling, IL-2 transcription, and T cell survival. The use of anti-
CD137 antibody can increase T-cell recruitment into tumor sites, enhance their cytotoxic activity, and 
protect T cells from activation-induced cell death (AICD)10. 
We propose a combined biologic strategy involving the use of adoptively transferred ovarian cancer 
antigen-specific CD8 T cells and the concomitant administration of anti-CD137 as a means of enhancing 
the transferred T cell response and promoting the generation of endogenous T cell responses against a 
broader panel of tumor-associated antigens that are released in a pro-inflammatory environment following 
lysis of ovarian antigen+ tumors by transferred T cells. 
This phase I/Ib study will evaluate the safety, in vivo persistence, and anti-tumor efficacy of adoptively 
transferred antigen-specific CTL alone and in combination with utomilumab (PF-05082566) in patients 
with advanced ovarian cancer. A maximum of 18 evaluable patients will be enrolled- in a dose escalation 
study of utomilumab. (Please note that throughout the protocol utomilumab, anti-CD137 and PF-05082566 
will be used interchangeably and all refer to the same drug). 
 
 


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2. 
OBJECTIVES 
2.1. 
PRIMARY 
1. Assess the safety and toxicity of adoptively transferred central memory-type CTL targeting ovarian 
cancer antigens administered alone, and in combination with, utomilumab, an agonistic anti-CD137 
antibody, in patients with platinum resistant ovarian cancer 
2. Evaluate the functional and numeric in vivo persistence of adoptively transferred central memory-
type CTL with and without utomilumab.  
2.2. 
SECONDARY 
Evaluate the anti tumor effect of adoptively transferred central memory-type CTL targeting ovarian 
cancer antigens as measured by best overall response rate (BORR) and progression free survival (PFS). 
3. 
RATIONALE 
3.1. 
IMMUNOTHERAPY FOR OVARIAN CANCER 
Despite high rates of complete response to the combination of tumor reductive surgery and adjuvant 
platinum-taxane based chemotherapy, the vast majority of patients with stage III/IV epithelial ovarian 
cancer (EOC) recur with a median progression free survival of approximately 18 months11. With rare 
exceptions, relapsed ovarian cancer is considered incurable, and patients who progress on, or recur less 
than 6 months from the completion of platinum-based chemotherapy, are deemed “platinum resistant,” 
and constitute a very poor prognostic group. Despite decades of clinical investigations, most therapies are 
associated with only modest response rates and a typical median progression free survival of 3-4 months 
across a wide variety of cytotoxic and biological agents12. Thus, development of new strategies that will 
ultimately improve the overall survival of patients with EOC represents a crucial unmet need. 
The landmark success of immune checkpoint inhibitor drugs such as Ipilimumab and Nivolumab has 
rejuvenated the field of immune-oncology and has led to intense focus on other co-stimulatory and co-
inhibitory immune pathways13. Immunogenicity of EOC has been well documented, and there is extensive 
literature demonstrating the presence of clonally activated CD3+CD8+ TCRαβ+ T-cells in ovarian tumors 
and their prognostic significance 14-20. TIL derived from EOC patients demonstrate tumor specificity and 
killing of autologous EOC tumor cells20. A meta-analysis of studies investigating the prognostic 
significance of TIL in ovarian cancer revealed an independent positive effect on survival associated with 
the presence of TIL21. There is strong evidence that EOC harbors an immune-suppressive environment 
that includes T-regs, CTLA4-and PD-1 expressing TILs, monocyte/macrophages, and elevated 
intratumoral and plasma levels of immunosuppressive cytokines such as IL10, IL6 and TGFβ22-28. Hence, 
the immune system represents a potentially paradigm changing and under explored area of therapeutic 
intervention for ovarian cancer. 
 
 


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3.2. 
TUMOR ANTIGENS RELEVANT TO OVARIAN CANCER 
A primary obstacle to the development of antigen-specific T cell therapy for ovarian cancer has been the 
difficulty in identifying appropriate target antigens. The most well-defined ovarian tumor associated 
antigen (TAA), the HER2/neu proto-oncogene, is overexpressed in 10-15% of ovarian cancers, and has 
been targeted in vaccine trials for the treatment of patients with breast and ovarian cancers. Although 
HER2/neu-specific responses can be generated in vivo following repeated peptide or protein 
immunizations, such responses have not been particularly robust and HER2/neu-specific T cells generated 
in vitro using the predicted immunogenic peptides or HER2/neu proteins generally fail to recognize 
tumors expressing physiological levels of antigen. Efforts underway to augment HER2/neu specific 
responses in vivo through various immunization strategies (DNA vaccines, novel adjuvants) and the 
identification of additional potentially more immunogenic epitopes presented by Class I and Class II 
MHC may lead to the generation of more vigorous, high affinity HER2/neu-specific cellular responses in 
the future. Currently, however, the in vitro generation of HER2/neu-specific T cells is not sufficiently 
mature for clinical trials of adoptive T cell therapy.  
In recent years, several groups, using methods to screen tumor-derived expression libraries with 
autologous tumor-reactive T cells or the sera of patients with cancer, have identified a number of novel 
immunogenic tumor proteins29,30. The identification of these antigens, and the mapping of specific 
epitopes recognized by CD4+ and CD8+ T cells, has facilitated the development of strategies designed to 
augment antigen-specific T-cell responses. 
3.2.1. TUMOR ASSOCIATED ANTIGENS IN OVARIAN CANCER TARGETED IN THIS 
STUDY 
Successful immunotherapy requires the characterization of TAA that are commonly expressed in ovarian 
tumors, but not in normal tissues. Moreover, the ideal antigen should exhibit a high frequency of 
expression in cancer and evidence of immunogenicity. We have evaluated two tumor antigens 
overexpressed or uniquely in ovarian cancer: PRAME and COL6A3, both of which have been extensively 
analyzed for prevalence of expression tumor and normal tissues and immunogenicity. 
3.2.2. COL6A3 
COL6A3 encodes the alpha-3 chain of type VI collagen, and facilitates cell anchoring by interacting with 
integrins, decorins, hyalurnon and proteoglycans. The antigen and the HLA-A*0201-restricted peptide is 
overexpressed on several solid tumor malignancies, including ovarian cancer (> 35%) and is up regulated 
in platinum-resistant ovarian cancer lines 31. Among 280 normal tissue samples (including brain, heart, 
liver, cartilage, skin,) peptide presentation was detected in placenta only and 115 of 475 tumor samples, 
including 9/20 ovarian cancers. According to the TCGA database, exon 6 expression of COL6A3 is 
specifically higher in tumor samples compared to very low levels in normal tissue. Immunogenicity 
assays and function T cell data in our lab have demonstrated the ability to generate responses in 14/25 
healthy donor PBMCs (56%); responses in COL6A3+ patients may be significantly higher. We have 
chosen to target COL6A3 because it likely represents not only a cancer cell target, but also a tumor-
associated stromal/ fibroblast antigen and addresses the possibility that co-targeting of this compartment 
may enhance anti-tumor efficacy both directly and indirectly32. Immunogenicity assays and function T 


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cell data in our lab have demonstrated the ability to generate responses in 3.11 of 19 donors (unpublished 
data).  
3.2.3. PRAME 
PRAME, also known as preferentially expressed antigen in melanoma, is a germinal tissue-specific gene 
expressed in placenta and endometrium, and both hematological and solid tumor malignancies. Several 
HLA-A*0201 restricted epitopes have been identified, one of which, PRAME-004, has been shown to be 
presented in ovarian cancer of high immunogenicity33. This epitope has been found only on tumor 
samples, and not normal tissues. In the TCGA database, it is expressed at very high levels in melanoma, 
ovarian and uterine/endometrial cancers (> 40 RPKM) with no expression in normal tissues except at very 
low levels in adrenal gland. Its prevalence of expression in ovarian cancer is > 80%.  
3.2.4. TARGETING PRAME, COL6A3, OR BOTH 
When targeting two antigens, that do not appear to be linked in expression, we calculated the prevalence 
of both antigens being expressed. Among 262 high-grade ovarian cancers, COL6A3 was expressed in 
50% of samples; PRAME being expressed 82%, yielding a combined targeting prevalence of 32%. Given 
the prevalence of HLA-A*0201 of 40-50%, we expect that approximately two-thirds of the potential 
subjects will have at least one targetable antigen, while 12-15% will be positive for both antigens. In this 
investigation a total of 10 billion CTL per meter squared, targeting either a single or both antigens, will be 
administered. 
3.3. 
ADOPTIVE T CELL THERAPY: RATIONALE AS A TREATMENT MODALITY 
In contrast to tumor vaccination strategies, adoptive T cell therapy allows more rigorous control over the 
magnitude and avidity of the targeted response by appropriate manipulation and selection in vitro of the T 
cells used for therapy34,35. Tumor-reactive effector cells of a desired specificity and phenotype can be 
identified in vitro, exposed to cytokines and immune-modulators that influence differentiation during 
priming and expanded to very large numbers – greater than 1010 T cells - producing frequencies of 
antigen-specific T cells in the peripheral blood that are over ten-fold higher than that possible by current 
immunization regimens alone. 
Effector cells that have been used in adoptive therapy are generally represented by:  
1. Tumor-infiltrating lymphocytes (TIL) that are harvested from tumor sites and expanded using 
supraphysiologic doses of IL-2 for adoptive transfer, 
2. Antigen-specific T cells (CTL) generated from peripheral blood following cyclic in vitro stimulation 
with the antigenic epitope and expanded for adoptive transfer 
Historically, TIL have been more commonly used for adoptive therapy due to their relatively lower labor- 
and resource- intensive requirements; however, their use is limited to patients with accessible tumor of 
sufficient cell yield from whom TIL cultures can be generated. The generation of antigen-specific CTL 
from the peripheral blood is technically more demanding and its use is restricted to a few specialized 
centers; however, for targeting PRAME, COL6A3 and other tumor-associated antigens, antigen-specific 
CTL can be routinely generated from HLA-A2+ patients using a strategy pioneered in our lab we have 
coined “ endogenous T cell therapy (ETC), a form of adoptive cellular therapy involving the isolation and 


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expansion of tumor-reactive T cells from the peripheral blood. By developing enabling technologies using 
IL-21 priming to enrich for a long lasting central memory population of T cells and the use of a clinical 
grade cell sorter, we have been able to render this a feasible and broadly applicable strategy for patients 
not only with melanoma, but also patients with other solid tumor malignancies for which other forms of 
immune-based therapies, including other forms of adoptive cellular therapy has been limiting. Strategies 
to streamline the production of antigen-specific CTL and yield a product in 7 weeks from time of 
peripheral blood cell collection have been developed and conditioning regimens and associated toxicities 
have been minimized while maintaining similar anti-tumor efficacy1-3,7,36.  
3.4. 
ANTIGEN-LOSS VARIANTS AND ANTIGEN-SPREADING 
Both murine and human studies have demonstrated tumor regression following immunologic targeting of 
only a single antigen or epitope in settings in which the antigen is known to be heterogeneously 
expressed4,37-41. In a vaccine study of melanoma patients, anti-tumor CTL recognizing non-targeted 
antigens MAGE-C2 and gp100 expanded several-fold in vivo after MAGE-3 vaccination, exceeded the 
frequency of anti-MAGE-3 CTL, and were associated with complete tumor regression. Using CD4+ T cell 
clones to the single tumor-associated antigen, NY-ESO-1, we demonstrated the induction of a broader 
multivalent response appearing in a patient who developed a complete regression of his tumor42. Recent 
studies using CTL targeting MART-1 in combination with anti-CTLA4 demonstrate induction of 
endogenous T cell responses to non-targeted tumor-associated antigens, NY-ESO-1, gp100, MAGE-A1 
and tyrosinase accompanied by tumor regression and in 2 of 10 patients a complete response suggesting a 
correlation between antigen-spreading and tumor regression2. 
3.5. 
CD137 AND CANCER 
The expression of CD137 on tumor-reactive T cells and its ability to increase T-cell recruitment into 
tumor sites, protect T cells from activation-induced cell death, and enhance their cytotoxic activity make 
the use of agonistic antibodies against CD-137 an attractive strategy for cancer immunotherapy43,44. 
Utomilumab that will be used in this study is currently in several clinical trials and results of the phase I 
monotherapy study were reported at ASCO in 2014 (Abstract #3007). This study was an open-label, dose 
escalation conducted in patients with advanced malignancies for which no curative therapy was available. 
Cohorts of 3-6 patients were enrolled initially using a 3+3 design (0.006 to 0.3 mg/kg), then a Time-To-
Event CRM design for higher doses (0.6 to 5 mg/kg). Among 27 treated patients, the best clinical 
response was disease stabilization, in 6 patients (22%). Importantly, there were no dose-limiting toxicities 
and all discontinuations were due to disease progression, not adverse events.  
Furthermore, recently the preliminary results of the phase I study of the combination of utomilumab and 
Pembrolizumab in 23 patients with a range of advanced or metastatic solid cancers (ASCO Abstract 
#3002, 2016). Six patients achieved an objective response to utomilumab plus pembrolizumab, including 
two complete responses in small cell lung cancer and RCC. Treatment emergent adverse events were 
mostly grade 1-2 and no subject discontinued study medication due to treatment-related adverse events. 
The study demonstrated the safety and efficacy profile of utomilumab in doses up to 5.0 mg/kg in 
combination with pembrolizumab supports further investigation in patients with advanced solid tumors. 
In a preclinical translational investigation of ovarian cancer-derived TIL, our group has shown that the 
use of anti-CD137 ex vivo results in higher success rates and proportion of CD8+ TIL (Sakellarious-
Thompson et al., SITC 2015 Abstract). 


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3.6. 
REGULATORY T CELLS 
CD4+ regulatory T cells (Treg) comprise 5-10% of CD4+ cells in human peripheral blood and have been 
phenotypically characterized as CD4+ cells constitutively expressing surface CD25. Treg CD4+ cells, in 
contrast to recently activated CD4+ T cells that are CD25med or resting CD4+ T cells that are CD25lo, can 
be isolated based on being phenotypically CD25hi, and further distinguished by expression of the forkhead 
transcription factor, Foxp3. Cyclophosphamide has been shown to deplete Treg cells, and in murine 
studies cyclophosphamide-mediated Treg depletion enhanced anti-tumor immunity45-48, suggesting this 
may in part be the basis for the immuno-potentiating effect of cyclophosphamide in tumor therapy 
models. In patients, circumstantial evidence suggests that the levels of Treg cells may correlate with 
disease stage and prognosis49, and selective depletion of CD25+ cells using an IL-2-diphtheria-toxin 
conjugate is the subject of several ongoing clinical trials50,51.  
3.7. 
THE USE OF INTERLEUKIN-2 IN ADOPTIVE T CELL THERAPY 
In our clinical studies, adoptively transferred CTL clones had a median survival of 6.6 +/- 0.8 days in the 
absence of IL-2. The addition of a 14-day course of low-dose IL-2 (250,000 U/m2 twice daily) following 
T cell infusion significantly prolonged median CTL survival to 16.8 +/- 1.6 days without associated 
toxicity 4. The frequency of transferred CTL in vivo began to fall before the end of the 14-day course, 
suggesting limited benefit might be expected with continued administration of IL-2 at this dose beyond 14 
days.  
High-dose IL-2 (720,000 U/kg three times daily) has been administered following adoptive transfer of 
CD8+ T cells52,53. In one study, clonal T cells were promulgated to very high numbers and clinical 
responses were observed; however, due to the design of the study, no conclusions could be drawn as to 
whether high-dose IL-2 was required for the in vivo survival or expansion of transferred T cells. In 
addition to a direct effect on T cell expansion, it could be speculated that increase vascular permeability 
induced by high-dose IL-2 provides improved tissue access to tumor sites. Additionally, our own studies 
and that of others54 have shown that exposure to high-dose IL-2 (1000 U/ml) leads to rapid, antigen-
independent expansion of CTL clones in vitro (in a manner similar to IL-15) while exposure to low-dose 
IL-2 had little effect. Of note, responses to high-dose IL-2 were only observed with antigen-specific CTL 
clones generated by cyclical re-stimulation using PBMCs of vaccine-naïve donors. CTL clones generated 
from G209M-vaccinated donors and exposed to high doses of IL-2 in vitro failed to respond to either 
high-dose IL-2 or IL-15, thus concurring with the hypothesis that the manner and source from which T 
cells are generated can influence their in vivo behavior.  
3.8. 
ADOPTIVE T CELL THERAPY USING ANTIGEN-SPECIFIC CD8+ T CELLS IN 
LYMPHODEPLETED RECIPIENTS  
We initially evaluated the use fludarabine alone as a lymphodepleting-conditioning reagent due to its 
predictable kinetics and relatively low toxicity. By comparing an infusion of T cell clones given first 
without, and then a second infusion given following fludarabine lymphodepletion we could directly 
evaluate the influence of fludarabine lymphodepletion on a uniform CD8+ T cell population. Following 
fludarabine lymphodepletion, induction of lymphopenia led to an increase in serum levels of homeostatic 
cytokines, IL-7 and IL-15, and an average 3-fold increase in the median T cell survival compared to that 
achieved by an infusion of the identical T cell clone infused without prior lymphodepletion55. In this 


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study, we also determined that apart from the extrinsic influence of prior conditioning, the duration of in 
vivo persistence was associated with an intrinsic property of a given T cell clone – this property being the 
proliferative capacity of a T cell clone as measured in vitro by the number of cell divisions (CFSE 
dilution) or absolute cell number following exposure to low-dose IL-15.  
One insight borne out of the clinical studies performed by the NCI and our above studies of adoptive 
cellular therapy is that the in vivo clinical response is related to in vivo persistence and that methods to 
modulate and/or identify tumor-reactive T cells with enhanced replicative potential would lead to more 
effective therapy. Indeed, work in murine models demonstrate the superior anti-tumor effect of “early 
effector” T cells and in non-human primates, it was recently demonstrated that methods to enrich for T 
cells harboring a central memory program are more likely to experience an extended period of in vivo 
persistence even when driven along an effector pathway. However, the endogenous frequency of tumor 
antigen-specific T cells with central memory properties is relatively rare. To this end, we explored an 
alternative approach to generating a population of tumor-antigen-specific CD8 T cells with enhanced self-
renewal capacity.  
3.9. 
IL-21 EXPOSURE LEADS TO GENERATION OF CD28HI HELPER-INDEPENDENT 
CD8 T CELLS IN VITRO 
We discovered that among the γ-chain receptor cytokines, IL-21 alone, was unique in not only increasing 
the frequency of antigen-specific CTL recognizing a tumor-associated antigens that could be generated 
but also in arresting differentiation at a stage that conferred helper-independence to the population of 
tumor-reactive CTL. Antigen-specific CTL exposed to IL-21 during priming expressed CD45RO, very 
little CCR7 or CD62L, but retained high levels of CD28, which is rarely expressed by memory effector 
tumor-reactive T cells following in vitro stimulation. This unique phenotype was stable for several weeks 
during in vitro expansion without the requirement for further IL-21 exposure suggesting that imprinting 
occurred during priming. Engagement of these CTL with the tumor ligand alone mediated IL-2 
production-which was blocked with CTLA4-Ig, demonstrating that IL-2 production/helper-independence 
was mediated through CD288,56. In subsequent studies, we demonstrated that pretreating the T cell culture 
by CD25 depletion, led to elimination of 50% of FoxP3+ Treg cells and enhancement of antigen-specific 
CTL frequency by ten-fold. However, combined CD25 depletion, and IL-21 exposure during in vitro 
stimulation, led to elimination of > 99.9% of Treg cells (more than one log- greater decrease in Treg 
frequency than what could previously be achievable by non-invasive means), and a greater than 200-fold 
increase in the numbers of tumor-reactive antigen-specific CTL that could be elicited 8,56. When expanded 
for adoptive therapy, 25-65% of the total T cell culture was represented by tumor antigen-specific CTL, 
while retaining CD28 expression.  
3.10. SAFETY CONSIDERATIONS 
When targeting tumor-associated antigens that are also self proteins, transferred T cells may mediate 
autoimmune toxicity. In some cases, the target antigen is expressed by normal tissues without significant 
physiologic consequence. However, unexpected toxicities due to adoptive T cell therapy will be 
addressed by therapy with steroids, which provide a lympholytic and anti-inflammatory effect. We have 
conducted in vitro studies demonstrating that a concentration of methylprednisolone at levels about one-
log below that attained in vivo (100 ng/ml) is sufficient to induce apoptosis in our T cell clones resulting 


T Cells for Ovarian Cancer Treatment 
A. Jazaeri 
January 15, 2020 
12 
in >90% cell death within 48 hours. Steroids may additionally suppress nonspecific inflammatory 
mediators (such as macrophages) that may be precipitated by T cell activation57,58. 
Our experience in patients receiving T cell infusions who were started on steroid therapy for reasons not 
related to treatment-related toxicity, have demonstrated that the administration of steroids is effective in 
eliminating infused clones from the peripheral blood. Two patients in the initial study receiving 
melanoma-specific T cell clones were given emergent steroid therapy for an impending obstruction of the 
superior vena cava by enlarging tumor mass. Analysis of the peripheral blood in these patients 
demonstrated rapid decrease in circulating T cell clones from a frequency of > 1/750 PBMCs to 
undetectable levels within 48 hours after beginning steroid therapy consistent with in vitro findings. In 
another ongoing clinical trial of adoptive therapy, we are conducting to evaluate reconstitution of CMV 
immunity post marrow transplantation, two patients received infusions of CMV-specific CD4+ T cell 
clones similarly demonstrated rapid disappearance of the infused clones following steroid therapy for 
graft-versus-host disease. 
3.11. RATIONALE AND PROPOSED STUDY OF ADOPTIVE T CELL THERAPY USING 
IL-21 MODULATED CD8 CTL FOR THE TREATMENT OF PATIENTS WITH 
ADVANCED OVARIAN CANCER 
Current strategies that we and others have evaluated to extend the in vivo persistence of transferred T 
cells include the administration of IL-2 and the use of pre-infusion conditioning regimens to inhibit the 
influence of regulatory cells limiting expansion and to induce lymphopenia and up regulation of 
homeostatic cytokines such as IL-7 and IL-15. These extrinsic approaches have proven effective; 
however, the development of methods to isolate early stage effector CTL with superior self-renewal 
capacity would be highly desirable in light of animal studies demonstrating enhanced anti-tumor efficacy.  
We recently developed, for the first time, a strategy to generate, helper-independent early effector human 
CD8 T cells which exhibit enhanced self-renewal capacity and high affinity for tumor-associated antigen 
targets. In vitro priming in the presence of the gamma-chain receptor cytokine, IL-21 and rapamycin, 
yielded CTL with an optimal balance of high replicative capacity and enhanced effector function. In 
murine studies evaluating the use of early effector/central memory T cells, a T cell dose that was 100 fold 
less than the standard dose was sufficient to mediate tumor eradication and in some cases, long term 
survival59,60. For this reason, we plan a starting dose approximately 10 to 100 fold less than that used in 
TIL studies (up to 200 billion cells) where no selection or enrichment was made to generate helper-
independent CTL. 
In this study, we propose a first-in-human study evaluating the use of IL-21 modulated antigen-specific 
CTL for the treatment of patients with advanced ovarian cancer following cyclophosphamide 
conditioning. 
3.12. GENERATION OF PRAME AND COL6A-SPECIFIC CTL 
We will use the A2-restricted epitope of PRAME and COL6A3 to generate autologous antigen specific, 
CTL from the PBMCs of leukapheresis products. Dendritic cells will be pulsed with the A2-restricted 
epitope peptide of PRAME or COL6A3, and individually co-cultivated with autologous PBMC in 48-well 
cultures supplemented with IL-21 according to results of preclinical studies; restimulation after 7 days 
will be supplemented with IL-2 and IL-7. Following 1-2 cycles of in vitro stimulation, individual wells 


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13 
will be screened with the respective tetramer and wells with highest frequency of ovarian cancer antigen- 
specific CTL will be pooled, stained with tetramer and sorted using a clinical grade cell sorter. We have 
routinely achieved sort enrichment of antigen-specific CTL to 80% purity starting with a population 
containing as low as 0.3% tetramer+ T cells. In vitro expansion of these cells achieves 3000 to 5000-fold 
expansion, reaching numbers sufficient for adoptive transfer (1010 cells/m2) within 6-8 weeks from 
leukapheresis. 
4. 
STUDY DESIGN 
All patients will receive low-dose cyclophosphamide conditioning (300 mg/m2) 2 days prior to infusion, 
and low dose IL-2 (250,000 U/m2 s.c. q12h for 14 days) after infusion. For Dose Level 1 cohorts, an 
infusion of ovarian cancer antigen-specific CTL will be administered on Day 0 at a total dose of 1 x 
1010/m2 total, if both antigens are present (0.5 x 1010 for each antigen); if only one antigen is present then 
CTL will be administered on Day 0 at a total dose of 1 x 1010. In the absence of any dose-limiting 
toxicity, the subsequent cohorts will be treated with the same number of ovarian cancer antigen -specific 
CTL in combination with two dose levels of utomilumab as described in Section 4.2. Utomilumab will be 
administered within 24 hours of T cell infusion and continued for a total of 6 doses 4 weeks apart. 
Subjects for whom at least 10 billion/m2 antigen specific T cells cannot be generated will be deemed 
inappropriate candidates for treatment and will be removed from the study and replaced. If Dose Level 1 
is found to be too toxic, de-escalation to Dose Level -1 consisting of a total of 2X109/m2 (1 billion T 
cells/m2 per each antigen if both antigens present). 
4.1. 
TARGET POPULATION 
Patients with platinum resistant recurrent or persistent high grade ovarian, fallopian tube, or primary 
peritoneal cancer and measurable disease by radiographic criteria, expressing HLA-A*0201 and whose 
tumor expresses either or both of the target antigens PRAME and COL6A3 will be eligible. We anticipate 
that patient accrual will be achieved within 18 months, with treatment, follow-up and analysis completed 
after an additional 6 months. 
4.2. 
STUDY DESIGN 
A maximum of 18 evaluable patients will be enrolled. Patients will be enrolled in cohorts of 3 patients to 
evaluate the safety of using ovarian cancer antigen specific TCM without (Dose Level 1) and with 
escalating doses of utomilumab (Dose Level 2 and 3 at 0.3 and 1.2 mg/kg, respectively). Subjects are 
considered evaluable for response based on treatment cohort.  For the cohort assigned to T-cells alone, 
subjects must have received outpatient cyclophosphamide and T-cell infusion to be considered 
evaluable.  For cohorts assigned to T-cell plus Utomilumab, subjects are considered evaluable for 
response if they receive T-cells plus at least one dose of Utomilumab. Additional details including the 
dose escalation rule is provided in Section 11. Subjects who receive T cells alone will serve as a baseline 
comparison for the immunobiological effect of utomilumab on the transferred ovarian cancer antigen-
specific CTL, which can be tracked and analyzed directly ex vivo.  
 
 


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14 
4.3. 
ENDPOINTS 
4.3.1. PRIMARY 
1. Safety and toxicity will be assessed using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. Patients will be monitored closely following therapy as described in the 
Schedule of Treatment and Evaluation (Table 1). Dose limiting toxicities are defined in Section 9. 
We have not observed any serious adverse events related to ovarian cancer antigen specific T cell 
therapy in our patients with leukemia nor have there been any reported serious toxicities in clinical 
trials targeting PRAME and COL6A3 to our knowledge. However, the combination with anti-CD137 
warrants closer monitoring in light of potential immune-related AEs. Patients with pre-existing lung 
disease and autoimmune disease will be excluded.  
2. Duration of in vivo persistence. Transferred antigen-specific T cells will be tracked by tetramer 
analysis as well as by TCR tracking (Immunoseq assay, Adaptive Biotech), both assays, have been 
established in our lab as reliable measures of T cell persistence. Duration of in vivo persistence will 
be defined as the time between T cell infusion and last time point at which the transferred T cell DNA 
signature is detectable in peripheral blood. Multiparameter analysis can be performed on the 
tetramer+ T cells to evaluate expression of memory/differentiation and exhaustion/coinhibitory 
markers in vivo following adoptive transfer.  
4.3.2. SECONDARY 
PFS and BORR. Patients with recurrent ovarian cancer experience progressively shorter periods of 
disease control.  
5. 
PATIENT ELIGIBILITY 
Patients with recurrent or persistent platinum resistant high grade epithelial ovarian cancer will be 
considered for this study. Patients with platinum resistant constitute a very poor prognostic group12. 
Despite decades of clinical investigations targeting this population, most cytotoxic and biological agents 
result in only modest rates of response and have a typical median PFS of 3-4 months across a wide variety 
of cytotoxic and biological agents12,61. Given the timeline for screening and T cell manufacturing, 
subjects are eligible for enrollment and leukapheresis while still platinum-sensitive. However, they 
must have developed platinum resistant disease (progression on a platinum-containing regimen or 
recurrence within 180 days of last dose of platinum-containing chemotherapy) prior to treatment. 
Eligibility will also require a tumor biopsy to determine the expression of COL6A3 and/or PRAME by 
quantifiable RT-PCR as performed by Immatics Inc. (CLIA-certified conditions – already established). 
Peripheral blood mononuclear cells for T cell culture will be collected from these patients by 
leukapheresis. Leukocyte collection can occur at any point in their disease course and will be at least three 
weeks after previous course of chemotherapy to allow for recovery of leucocytes. Approximately 2-3 
months are required to isolate, expand and complete quality control testing on T cells for infusion. Once 
isolated, T cells can be cryopreserved for later use. In this interval patient may proceed with other 
clinically used chemotherapy regimens. 


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15 
5.1. 
INCLUSION CRITERIA FOR ENROLLMENT AND LEUKAPHERESIS 
(TURNSTILE 1) 
 
a. Histopathologic documentation (must be performed or reviewed at MD Anderson) of recurrent 
high grade epithelial ovarian cancer. 
b. At least one prior line of platinum-based chemotherapy (subjects are eligible for enrollment and 
leukapheresis while still platinum-sensitive, however, they must have developed platinum 
resistant disease for treatment (turnstile 2)). 
c. 18 to 75 years of age. 
d. Tumor biopsy reveals expression PRAME and/or COL6A3 by Immatics assay. 
e. Expression of HLA-A*0201. 
f. ECOG performance status of 0-1 (Appendix G) and an expected survival of greater than 16 
weeks. 
g. Willing and able to give informed consent. 
h. Adequate normal organ and marrow function as defined below:  
• 
Hemoglobin ≥ 9.0 g/dL, 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L (> 1000 per mm3), 
• 
Platelet count ≥ 75 x 109/L (>100,000 per mm3), 
• 
Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless diagnosed with 
Gilbert’s syndrome, 
• 
AST/ALT ≤ 2.5 x institutional upper limit of normal unless liver metastases are present, in 
which case it must be ≤ 5x ULN, and 
• 
Serum creatinine CL >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 
1976) or by 24-hour urine collection for determination of creatinine clearance: 
Creatinine CL (mL/min) 
= Weight (kg) x (140 – Age) x 0.85 
72 x serum creatinine (mg/dL) 
i. 
Subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥50 years 
old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, 
OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a 
negative serum pregnancy test upon study entry.  
j. 
Women of childbearing potential (WOCBP) must be using an adequate method of contraception 
to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is 
minimized. Suggested precautions should be used to minimize the risk or pregnancy for at least 1 
month before start of therapy, and while women are on study for up to 3 months after T cell 
infusion, and at least 8 weeks after the study drug is stopped. 
 
5.2. 
INCLUSION CRITERIA FOR TREATMENT (TURNSTILE 2) 
Note: Evaluate within one week of planned start of cyclophosphamide pre-infusion.  
a. ECOG performance status of ‘0-1’ (Appendix G).  
b. Subjects must have platinum resistant disease (progression on a platinum-containing regimen or 
recurrence within 180 days of last dose of platinum-containing chemotherapy).  Subjects that are 


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January 15, 2020 
16 
not platinum resistant but are deemed not to be candidates for platinum-based chemotherapy due 
to prior significant allergic reaction may participate with PI approval. 
c. Bi-dimensionally measurable disease by radiographic imaging (MRI or CT scan).  
d. At least 4 Weeks must have elapsed since the last chemotherapy, immunotherapy, radiotherapy or 
major surgery. At least 6 Weeks for bevacizumab. 
e. Toxicity related to prior therapy must either have returned to ≤ grade 1, baseline, or been deemed 
irreversible.  
f. Persons of reproductive potential must agree to use and utilize an adequate method of 
contraception throughout treatment and for at least 8 weeks after study drug is stopped. 
g. Willing and able to give informed consent. 
 
5.3. 
EXCLUSION CRITERIA FOR ENROLLMENT 
Note: Exclusion criteria must be met by all subjects prior to proceeding with leukapheresis. 
Exclusion criteria will be reassessed and confirmed within one week of planned start of 
cyclophosphamide infusion.  Complete pulmonary function test and/or dobutamine stress 
echocardiography may be repeated at this time if deemed necessary by the Principal Investigator: 
a. Clinically significant pulmonary dysfunction, as determined by medical history and physical 
exam. All patients will undergo pulmonary functions testing. Results of this evaluation will be 
considered before excluding patients, and all patients with FEV1 < 60% of normal or DLco (corr 
for Hgb) < 55% will be excluded. 
b. Significant cardiovascular abnormalities including any one of the following: 
i. 
Congestive heart failure,  
ii. 
Clinically significant hypotension,  
iii. 
Symptoms of coronary artery disease,  
iv. 
Presence of cardiac arrhythmias on EKG requiring drug therapy, or 
v. 
Patients with a history of cardiovascular disease. 
All patients will have a dobutamine stress echocardiography before beginning treatment. Results 
of this evaluation will be considered before excluding patients on the basis of cardiovascular 
abnormalities. Subjects with evidence of stress-induced cardiac ischemia or ejection fraction less 
than 55% will be excluded. 
c. History of central nervous system (CNS) metastasis.  
d. Autoimmune disease: Patients with a history of Inflammatory Bowel Disease are excluded from 
this study, as are patients with a history of autoimmune disease (e.g. Systemic Lupus 
Erythematous, vasculitis, infiltrating lung disease) whose possible progression during treatment 
would be considered by the Investigator to be unacceptable. 
e. Participation in another clinical study with an investigational product administered during the last 
28 days. 
f. Receipt of the last dose of previous chemotherapy, hormonal, or biologic treatment for ovarian, 
fallopian tube, or primary peritoneal cancer in the last 28 days (in the last 6 weeks for 
bevacizumab). 


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17 
g. Current or prior use of immunosuppressive medication within 28 days before enrollment, with the 
exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological 
doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. 
h. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous 
immunotherapy agent, or any unresolved irAE >Grade 1. 
i. 
History of allogeneic organ transplant. 
j. 
Unresolved partial or complete small or large bowel obstruction. 
k. Receipt of live attenuated vaccination within 30 days prior to enrollment or within 30 days of 
planned lymphodepletion 
l. 
Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will 
make the administration of study drug hazardous or obscure the interpretation of adverse events. 
m. Active viral hepatitis. 
n. Confirmed HIV infection. 
o. Confirmed diagnosis of Ehler-Danlos Syndrome. 
6. 
STUDY AGENTS 
6.1. 
ANTIGEN-SPECIFIC CD8+ T CELLS 
All T cells administered will be autologous T cells derived from the subject’s peripheral blood 
lymphocytes. Methods employed to generate and qualify CD8+ antigen-specific T cells for infusions are 
detailed in Appendix I Briefly, T cells demonstrating antigen-specific cytolytic function will be tested for: 
• 
CD3+, 8+ surface phenotype, 
• 
Class I MHC restricted lysis of antigen-expressing target cells, and 
• 
Mycoplasma, fungal and bacterial sterility. 
T cells will be infused intravenously at a rate of not more than 500cc/hour through a peripheral vein or 
central catheter. The infusion bag will be gently mixed every 5 minutes during the infusion. 
6.2. 
CYCLOPHOSPHAMIDE 
Cyclophosphamide (CY) at 300 mg/m2 will be administered intravenously (IV) as an outpatient 
procedure. CY administration will be scheduled 2 days prior to prior to T cell infusion (Day -2).  
6.3. 
INTERLEUKIN-2 
IL-2 will be initiated within 6 hours of T cell infusion. Low-dose IL-2 will be administered at 250,000 
U/m2 s.c. q12h x 14 days. Patients will receive at least their first dose while inpatient. Prior to discharge, 
patients or their caregiver will be instructed on s.c. self-administration. 
6.4. 
UTOMILUMAB ADMINISTRATION 
Utomilumab will be administered per manufacturer’s instructions (Pfizer).  
7. 
PLAN OF TREATMENT/STUDY SCHEDULE  
 


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18 
Table 1. Schedule of Treatment and Evaluation 
Visit 
Screen 
Leuka-
pheresis 
Pre-
infusion 
CY 
T 
Cells 
On Treatment 
EOT
a 
Visit Day 
-28 to -1 
before 
Leu-
kapheresis 
Variable 
-28 to -2 
-2 
0b 
1c 
3 
7 
14 
21 
28 
35 
42 
56 
70 
84 
112 
140 
168d 
Visit Window  
- 
- 
- 
- 
±3 Days 
Written Informed Consent 
Xe 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
 
X 
Xm 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examg 
X 
X 
X 
Xm 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsh 
X 
Xi 
X 
Xm 
Xj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
O2 Saturation 
X 
 
X 
Xm 
Xj 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
 
X 
Xm 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff and platelets 
X 
Xk 
Xl 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry Paneln 
X 
X 
Xm 
Xm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid functionp 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
ß-HCG Serum Pregnancy Testq 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typingr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dobutamine Stress Echocardiography 
X 
 
Xs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function Test 
X 
 
Xs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infection testingt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapharesis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
 
 
X 
 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Staging for measurable diseasev 
 
 
X 
 
 
 
 
 
 
 
 
Xw 
 
 
 
 
X 
 
Xx 
CA125 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Xy 
Tumor Biopsyz 
Xaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamidebb 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T Cellscc 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low Dose IL-2 
 
 
 
 
Xdd 
 
 
 
 
 
 
 
 
 
 
 
Anti-CD137ee 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Immune Monitoringff 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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19 
 
a If a subject leaves the study prior to reaching Day 168, the End-of-treatment visit is defined as the last visit where the decision is made to discontinue protocol directed treatment. 
b Subject to be admitted to in-patient service ahead of T cell infusion. 
c Subject to be discharged from in-patient service after Anti-CD137 treatment and when they clinically meet discharge criteria. 
d Patients who have detectable transferred cells >0.5% of CD8+ T cells at the end of monitoring, show tumor response (refer to Section 8.2 for definitions) or show antigen spreading, will continue to be 
monitored on study with visits every 8 weeks or as often as clinically indicated unless the disease gets worse, patients start another therapy, or patient is taken off study. 
e Turnstile 1/Leukapheresis Consent 
f Turnstile 2/Treatment Consent. Eligibility Criteria must be met. Steroids are not permitted 3 days prior to T cell infusion and concurrently during therapy. Patients may not be on any other treatments for their 
cancer aside from those included in the protocol. Patients may not undergo another form of treatment concurrently with this study. If patients agree to proceed with T cell therapy and all criteria are met, then a 
cyclophosphamide infusion visit (outpatient) and T cell infusion visit (inpatient) appointment will be scheduled.   
g Full physical examination is required at screening. Targeted physical examinations are to be performed at all other time points. 
h Vital signs will include temperature, pulse, breathing, and blood pressure. See Section 8.1. 
i Leukapheresis may be deferred for patients with active infections or oral temperature > 38.2° C within 72 hours prior to planned Leukapheresis. 
j Performed before infusion, every 15 minutes during infusion, every 30 minutes for 2 hours after completion of infusion, and then every 6 hours over night. 
k Leukapheresis may be deferred for patients with Hct < 28%, lymphocytes <1000/uL and platelets <50,000 immediately prior to Leukapheresis. 
l Patients will be excluded from treatment if CBC and Chemistry profile prior to cyclophosphamide and T cell infusion includes any of the following: WBC ≤ 2000/uL, Hct ≤ 24% or Hb ≤ 8 g/dL, ANC ≤ 1000, 
Platelets ≤ 50,000, Creatinine ≥ 3.0 x ULN, AST/ALT ≥ 2.5 x ULN, and Bilirubin ≥ 3 x ULN. 
m If not performed within previous 7 days. Confirmation that subjects meet the Turnstile 2 inclusion and exclusion criteria must be performed within one week of planned start of Cyclophosphamide pre-
infusion. 
n Comprehensive chemistry panel to include electrolytes, BUN, Cr, Liver function tests (AST, alkaline phosphatase, total bilirubin, and direct bilirubin), and LDH. .  
o Coagulation testing to include PT, PTT, and INR and will be checked prior to biopsy and as clinically indicated (e.g. prior to a planned procedure, if taking anti-coagulation medication or if evidence of 
coagulation disorder). 
p Thyroid function tests are  required prior to start of outpatient visits of utomilumab administration, unless abnormal in which case they are followed as clinically indicated. 
q Only for subjects of child-bearing potential. 
r HLA typing will only be performed if HLA status is unknown. 
s Only will be repeated at the discretion of the Investigator. 
t Patients will be screened for Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Virus Antibody, and HIV 1/HIV 2 Antibody.  Positive screenings will not be enrolled. 
u If not performed within the previous 30 days. 
v Patients must have bi-dimensional measureable disease by radiographic imaging (MRI or CT scan). 
w To be performed between Day 35 and 42. 
x Not required if the assessment has been performed within 6 weeks. 
y Not required if the assessment has been performed within 6 weeks. 
z Subjects are required to have a biopsy at screening to determine the expression of COL6A3 and/or PRAME. As an optional procedure, subjects may provide extra tissue at the time of clinically-indicated 
biopsies (on treatment or at the time of progression). 
aa To be transferred to Immatics for COL6A3 and PRAME expression determination. 
bb Cyclophosphamide will be administered at 300 mg/m2 intravenously 2 days prior to T cell infusion as an outpatient procedure. 
cc Administer T cells at a dose of 1010 cells/m2. T cells from in vitro cultures will be washed three times with RPMI-Hepes solution and re-suspended in 250-500 ml of 0.9% NaCl in preparation for infusion. 
dd Low-dose IL-2 (250,000 U/m2 s.c. q12h) will begin within 6 hours of T cell infusion and continue for a total of 14 days (28 doses). 
ee Dose level 1 patients will receive no anti-CD137.  Dose level 2 and 3 patients will receive intravenous anti-CD137 at 0.3mg/kg and 1.2 mg/kg, respectively, within 24 hours of T cell infusion. 
ff 60 ml in tubes containing heparin (green top) and 5 ml in a tube containing Potassium Oxalate/Sodium Fluoride (gray top). See Section 8.3. 
 


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20 
8. 
SCHEDULE OF EVALUATIONS  
8.1. 
GENERAL TOXICITY ASSESSMENT 
Vital signs (temperature, pulse, breathing, blood pressure), Physical exams, oxygen saturation, 
Comprehensive chemistry panel, Complete blood counts, differentials and platelet counts will be 
completed according to the schedule as outlined in Table 1. Of note, the dates listed on the study calendar 
are approximate as many patients reside out of the area and cannot always follow the time points as 
dictated by the protocol.  
8.2. 
EFFICACY ASSESSMENT 
8.2.1. CLINICAL RESPONSE 
Radiographic imaging and clinical assessment of residual disease will be compared with pre-infusion 
baseline assessment according to modified RECIST 1.1 (see Section 8.2.2). A complete response (CR) 
will be defined as total regression of all tumor, a partial response (PR) as 30% or greater decrease in the 
sum of the longest diameter of target lesions and progressive disease (PD) as 20% increase in the sum of 
the longest diameter of target lesions (modified world health organization criteria or mWHO). This 
assessment will be performed at 6 and 12 weeks following T cell infusion and then every 8 weeks (± 1 
week) until disease progression or intervening therapy. The overall response rate (OR) will be after 1 
cycle (12) weeks. 
8.2.2. IMMUNE RELATED RESPONSE EVALUATION 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 
chemotherapy including the following62,63: 
• 
Response to immunotherapy may be delayed, 
• 
Response to immunotherapy may occur after PD by conventional criteria, 
• 
The appearance of new lesions may not represent PD with immunotherapy, and 
• 
SD while on immunotherapy may be durable and represent clinical benefit. 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of anti-cancer 
medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating anti-cancer 
compounds, this study will include the following in addition to standard RECIST 1.1 criteria: 
RECIST will be modified so that PD must be confirmed with a second radiologic assessment, preferably 
at least 5 weeks (+/- 7 days) after the initial assessment of PD in the absence of clinically significant 
deterioration. Treatment with utomilumab should continue between the initial assessment of progression 
and confirmation of progression at outlined in the protocol. 
Modification of RECIST as described is meant to discourage the early discontinuation of the study 
regimen and provide a more complete evaluation of its anti-tumor activity than would be seen with 
conventional response criteria. Nonetheless, the efficacy analysis will be conducted by programmatically 
deriving each efficacy endpoint based on the first evidence of progression (by modified RECIST 1.1 
criteria described below) when progression is confirmed by a second scan. 


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21 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that necessitates 
treatment with anti-cancer therapy other than the study regimen or other symptomatic progression that 
requires urgent medical intervention (e.g., central nervous system metastasis, respiratory failure due to 
increasing malignant pleural effusion, or development of mechanical bowel obstruction due to 
carcinomatosis or tumor compression). 
8.2.3. BEST OVERALL RESPONSE RATE (BORR)  
BORR is defined as the total number of patients who’s BOR is CR or PR, divided by the total number of 
patients. 
8.2.4. DURATION OF RESPONSE  
A patient’s Duration of Response is defined as the time between the date measurement criteria are first 
met for subsequently-confirmed PR or CR (whichever status is recorded first) and the date of disease 
progression or death. Duration of Response will be calculated for all patients with CR or PR using the 
Kaplan-Meier product limit method. For those patients who remain alive and have not progressed, 
Duration of Response will be censored on the date of last tumor assessment.  
8.2.5. PROGRESSION FREE SURVIVAL (PFS)  
PFS is defined as the time between T cell infusion date and the date of progression or death. A patient 
who dies without reported prior progression will be considered to have progressed on the date of death. 
For those who remain alive and have not progressed, PFS will be censored on the date of last tumor 
assessment. For patients who have PD prior to Week 12 and a subsequent assessment of SD, PR or CR, 
the date of PD following response (where available) will be used in the analysis of PFS; otherwise these 
patients will be censored on the date of their last tumor assessment. PFS is estimated for each arm using 
the Kaplan-Meier product limit method. 
8.3. 
IMMUNE MONITORING 
Patients will have 60 mL of heparinized blood (green top tube) drawn at the pre-T cell infusion visit, 
immediately prior to the CD8+ T cell infusion, and on days +1, +3 and +7 and then weekly through week 
6, then every 2 weeks through week 12, and then followed by every 4 weeks until the patient comes off 
the protocol. 
Patients will also have 5 mL gray top tube drawn at the pre-infusion visit, immediately prior to the CD8+ 
T cell infusion, and on day +1, +7, +14, +28, +42, +56, +84, +112, +140 and +168 after the T cell 
infusion.  
Samples will be used to evaluate the duration of in vivo persistence and function of infused T cells as well 
as antigen spreading. 
Immune monitoring will be carried out in the Yee Laboratory, with the support of the Core Immune 
Monitoring Lab. 
For the primary translational endpoint, the numeric and functional persistence of transferred CTL will be 
performed on peripheral blood obtained from patients prior to T cell infusion (baseline sample) on Days 
+1, +3, +7, and weekly thereafter. To prevent inter-test bias, all samples will be cryo-preserved, and then 


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thawed and assayed simultaneously. The numeric frequency of transferred T cells will be determined 
using peptide MHC-tetramer analysis or specific CDR3 TCR quantitative PCR of transferred CTL if 
necessary. The function of transferred CTL will be determined by intracellular cytokine staining of 
tetramer+ CD8+ cells following in vitro stimulation as previously described.  
8.4. 
TUMOR IMMUNOPHENOTYPING  
Patients undergoing clinically indicated biopsies (on treatment or at the time of progression) will be asked 
to provide consent for optional additional biopsy cores for research purposes at the time of the clinically 
indicated biopsy. These biopsies will be used to assess the outgrowth of antigen or MHC-loss tumor 
variants. 
In addition, when possible biopsies will be used to investigate localization of transferred antigen-specific 
CTL to tumor sites will be evaluated. Single cell suspensions will be prepared and stained to identify 
antigen-specific CTL by tetramer analysis. Tetramer positive cells will be sorted and analyzed for identity 
to the original infused CTL by PCR of a cell-specific CDR3 region of the T cell receptor. Where possible, 
these results will be compared with a pre-infusion tumor sample and the peripheral blood. A T cell 
frequency at least five-fold higher than that found in the peripheral blood or pre-infusion sample will be 
considered evidence of T cell localization/accumulation in disease sites.  
9. 
MANAGEMENT OF TOXICITIES AND COMPLICATIONS 
9.1. 
DOSE LIMITING TOXICITY (DLT) 
• 
Toxicities will be counted as a DLT only if deemed to be at least possibly related to the 
experiment therapy. 
• 
Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction; 
• 
Any adverse event, laboratory abnormality or inter current illness which, in the judgment of the 
clinical team, presents a substantial clinical risk to the patient with continued dosing 
• 
Any other ≥ Grade 3 non-skin related adverse event that does not return to baseline levels within 
7 days, with the exception of events listed below in Section 9.2. 
9.2. 
EXCEPTIONS 
• 
Grade 1-2 Cytokine Release Syndrome (CRS) that, in the opinion of the investigators, is 
attributable to T cell infusions: Including but not limited to asthenia, flu-like symptoms, myalgia, 
lymphopenia, neutropenia that returns to a Grade 2 toxicity on 7 days from day of onset. 
• 
Hospitalization for ≤ Grade 2 adverse events where the primary reason for hospitalization is to 
expedite the clinical work-up. 
• 
Patients with the following conditions where in the Investigator’s opinion continuing study drug 
administration is justified: 
o Ocular toxicity that has responded to topical therapy. 
o Endocrinopathies where clinical symptoms are controlled with appropriate hormone 
replacement therapy. Note: Utomilumab may not be restarted while the patient is being 
treated with systemic corticosteroids except for patients on stable doses of hormone 
replacement therapy such as hydrocortisone. 
• 
Fever > 40C for less than 24 hours. 
• 
WBC < 1000 for less than 7 days. 


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• 
Platelets < 50,000 for less than 7 days. 
• 
ANC < 500 for less than 7 days. 
9.3. 
CRITERIA FOR DISCONTINUATION OF THERAPY 
• 
Permanent discontinuation of utomilumab, T cell infusion and IL-2 will be required for any 
patient experiencing a dose-limiting toxicity (9.1) with exceptions as noted in 9.2. 
• 
Withdrawal of informed consent (subject’s decision to withdraw from the study for any reason). 
• 
Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the opinion of 
the Investigator, indicates that continued treatment with study therapy is not in the best interest of 
the subject. 
• 
Pregnancy: all WOCBP should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation and therapy will be discontinued.  
• 
Imprisonment or the compulsory detention for treatment of either a psychiatric or physical (e.g., 
infectious disease) illness.  
9.4. 
TRIAL STOPPING CRITERIA  
We will early stop the trial if at the lowest dose level (i.e., dose -1), (i) there is one or more death within 
30 days after the investigational treatment at least possibly related to the study agent; or/and (ii) the 
number of patients experienced DLT reach the following stopping boundary, where the definition of DLT 
is provided in Section 9.1. 
Table 2. Stopping Criteria  
The number of patients 
treated at dose level -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 
15 
16 17 18 
Stop the trial if # of 
DLT >=  
NA NA 
2 
3 
3 
4 
4 
4 
5 
5 
6 
6 
6 
7 
7 
8 
8 
8 
 
9.5. 
MANAGEMENT OF SYMPTOMS DURING T CELL INFUSION 
Mild transient symptoms have been observed with tumor infiltrating lymphocytes (TIL); lymphokine 
activated killer (LAK) therapy and antigen-specific T cell infusions. The management of these symptoms 
is outlined below: 
• 
Fever, chills and temperature elevations > 101°F will be managed with acetaminophen 650 mg 
p.o. q 4-6 hrs. All subjects that develop fever or chills will have a blood culture drawn. Naproxen 
250 mg po q 12 hours prior to and during IL-2 will be administered prophylactically per standard 
practice guidelines for IL-2 administration.  
• 
Headaches may be managed with acetaminophen following a neurologic examination. 
• 
Nausea, vomiting will be treated with a non-steroidal anti-emetic of choice.  
• 
Hypotension will initially be managed by intravenous fluid administration and further measures 
as dictated by standard medical practice. 


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• 
Hypoxemia will initially be managed with supplemental oxygen and further measures as dictated 
by standard medical practice. 
• 
Management of cytokine release syndrome (CRS) is an evolving field and hence will be 
conducted according to the most up to date institutional guidelines. Management will include 
transfer to ICU and use of Tocilizumab as clinically indicated. Patients who do not respond to 
Tocilizumab and other supportive measures will undergo ablation of adoptively transferred T 
cells as described in Section 9.5. 
 
9.6. 
TOXICITIES WARRANTING ABLATION OF ADOPTIVELY TRANSFERRED T 
CELLS 
Severe toxicity occurring after CD8+ T cell infusions and, in the best judgment of the investigator, are 
related to CD8+ T cells toxicity as opposed to a transient albeit severe cytokine release syndrome, may 
warrant ablation. Patients that receive ablation must be discontinued from the study. 
Examples of such scenarios include: 
• 
Hypotension (systolic BP <90 mmHg and > 20 mmHg below baseline), tachycardia (HR > 130), 
tachypnea (RR > 32) and/or hypoxemia (arterial O2 saturation < 90%), not responsive to 
supportive care. 
• 
Grade 2 or greater allergic reaction, consisting of bronchospasm or generalized urticaria.  
• 
Grade 3 or greater toxicity occurring in any other organ system following administration of 
antigen-specific cytotoxic T cells, and not attributable to a different cause. Exceptions to this are: 
o Fever of >40˚C which lasts less than 48 hours following infusions  
o Lymphopenia of Grade 3 that does not revert to Grade 2 within 96 hours 
• 
Cytokine Release Syndrome (grade 3-4) unresponsive to Tocilizumab and other non-steroid 
interventions. 
Patients will receive corticosteroids if treatment-related toxicity warranting ablation of T cells is observed 
and the following dose schedule is suggested however may be modified according to institutional 
guidelines:  
• 
Day 1 Intravenous Solu-Medrol at 2 mg/kg  
• 
Day 2 Intravenous Solu-Medrol at 2 mg/kg  
• 
Day 3-4 Prednisone at 30 mg po b.i.d.  
• 
Day 5-6 Prednisone at 15 mg po b.i.d.  
• 
Day 7-8 Prednisone at 10 mg po b.i.d.  
• 
Day 9-10 Prednisone at 10 mg po q.d  
• 
Day11-12 Prednisone at 5 mg po q.d.  
 
10. 
REPORTING SERIOUS ADVERSE EVENTS 
10.1. DEFINITION OF ADVERSE EVENTS 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 


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• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. 
It does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. 
• 
A 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. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
Important medical events as defined above, may also be considered serious adverse events. Any important 
medical event can and should be reported as an SAE if deemed appropriate by the Principal Investigator 
or the IND Sponsor, IND Office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Unanticipated Adverse Events for Drugs and Devices”. Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, regardless of attribution (within 5 working 
days of knowledge of the event). 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office. 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the 
IND Office and WIRB.  
Serious adverse events will be captured from the time of the first protocol-specific intervention until 30 
days after the last study treatment/intervention, unless the participant withdraws consent. Serious adverse 
events must be followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event.  
Additionally, any serious adverse events that occur after the 30 day time period that are related to the 
study treatment must be reported to the IND Office. This may include development of a secondary 
malignancy.  
 


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10.2. REPORTING TO THE FDA 
Serious adverse events will be forwarded to the FDA by the IND sponsor (Safety Project Manager IND 
Office) according to 21 CFR 321.32 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines and Institutional Review Board policy. 
All related grade 2 and all Grade 3 or higher adverse events, regardless of the attribution, will be captured 
and entered into the CRF. Unrelated grade 1 and grade 2 will not be entered into the CRF. Adverse events 
will be captured from the time of the first protocol-specific intervention until 30 days after the last dose of 
study drug, with the following exception: For all subjects (whether or not intervening therapy is used), the 
reporting window for AEs will start from the time of the first protocol-specific intervention  to 7 days 
after protocol-directed apheresis or until the start of intervening therapy, whichever occurs first, except in 
the case of a Serious Adverse Event, which must be captured, regardless of grade. . Adverse events will 
also be captured from the time of the first protocol-specific intervention after the patient is enrolled in 
Turnstile 2 until 30 days after the last dose of study drug.  
Table 3. Capturing Adverse Events 
Grade and Attribution 
Capture in CRF? 
1 and Unrelated 
No 
1 and Related 
No 
2 and Unrelated 
No 
2 and Related 
Yes 
3 or higher and Unrelated 
Yes 
3 or higher and Related 
Yes 
 
All adverse events will be noted and graded according to the NCI CTCAE version 5.0. The Investigator 
or physician designee is responsible for verifying and providing source documentation for all adverse 
events and assigning the attribution for each event for all subjects enrolled on the trial. 
10.3. REPORTING TO PFIZER 
Once patients receive utomilumab, the study staff will forward to Pfizer the AE or SAE reports at the 
same time they are sent to the FDA. These submissions to Pfizer will include the MD Anderson AE 
reporting form and the Pfizer “Reportable Event Fax Cover Sheet (US).” These reports should be sent to 
Pfizer via facsimile at 1-866-997-8322. 
 


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10.3.1. HY’S LAW 
Cases of potential drug-induced liver injury as assessed by laboratory test values ("Hy's Law Cases") are 
also reportable to Pfizer. If a Study subject develops abnormal values in aspartate aminotransferase (AST) 
or alanine aminotransferase (ALT) or both, concurrent with abnormal elevations in total bilirubin and no 
other known cause of liver injury, that event would be classified as a Hy's Law Case. As such, the term 
SAE will be understood to also include Hy's Law Cases. 
10.3.2. EXPOSURE OR LACK OF EFFECT 
Even though there may not be an associated SAE, exposure to the Pfizer Product during pregnancy, 
exposure to the Pfizer Product during lactation, and occupational exposure to the Pfizer Product are 
reportable, and lack of effect of the Pfizer Product may also be reportable. As such, the term SAE will be 
understood to include exposure during pregnancy, exposure during lactation, occupational exposure, and 
reportable instances of lack of effect. Reports submitted to Pfizer should include the “Exposure During 
Pregnancy (EDP) Supplemental Form.” 
11. 
STATISTICAL CONSIDERATIONS 
11.1. TRIAL DESIGN 
We will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015) to find the MTD. The 
BOIN design is implemented in a simple way similar to the traditional 3+3 design, but is more flexible 
and possesses superior operating characteristics that are comparable to those of the more complex model-
based designs, such as the continual reassessment method (CRM).  
The target toxicity rate for the MTD is 0.3 and the maximum sample size is 18. We will enroll and treat 
patients in cohorts of size 3. For the goal of determining the MTD, the dose-limiting toxicity (DLT) 
assessment periods are 6 weeks for T cells (i.e., dose 1 and dose -1) and 8 weeks for T cells + utomilumab 
(i.e., doses 2 and 3), respectively. The trial design is described as follows: 
1. Patients in the first cohort are treated at dose level 1. 
2. To assign a dose to the next cohort of patients, we conduct dose escalation/de-escalation 
according to the rule displayed in Table 4. When using Table 4, please note the following  
a. “Eliminate” means that we eliminate the current and higher doses from the trial to prevent 
treating any future patients at these doses because they are overly toxic.  
b. When we eliminate a dose, we automatically de-escalate the dose to the next lower level. 
When the lowest dose is eliminated, we stop the trial for safety. In this case, no dose should 
be selected as the MTD.  
c. If none of the actions (i.e., escalation, de-escalation or elimination) is triggered, we treat the 
new patients at the current dose.  
d. If the current dose is the lowest dose and the rule indicates dose de-escalation, we will treat 
the new patients at the lowest dose unless the number of DLTs reaches the elimination 
boundary, at which point we will terminate the trial for safety.  
e. If the current dose is the highest dose and the rule indicates dose escalation, we will treat the 
new patients at the highest dose.  
3. Repeat step 2 until the maximum sample size of 18 is reached or the trial is stopped.  


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Table 4. Dose escalation/de-escalation rule for the BOIN design 
 
The number of patients treated at the current dose 
Actions 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Escalate if # 
of DLT <=  
0 
0 
0 
0 
1 
1 
1 
1 
2 
2 
2 
2 
3 
3 
3 
3 
4 
4 
De-escalate if 
# of DLT >= 
1 
1 
2 
2 
2 
3 
3 
3 
4 
4 
4 
5 
5 
6 
6 
6 
7 
7 
Eliminate if # 
of DLT >= 
NA 
NA 
3 
3 
4 
4 
5 
5 
5 
6 
6 
7 
7 
8 
8 
8 
9 
9 
To safeguard patients from the case that the lowest dose (i.e., dose -1) is overly toxic, we will early stop 
the trial if at the lowest dose level, (i) there is one or more death within 30 days after the investigational 
treatment at least possibly related to the study agent; or/and (ii) the number of patients experienced DLT 
reach the following stopping boundary, where the definition of DLT is provided in Section 9.1. 
Table 5. Stopping rule for the BOIN design 
Action 
The number of patients treated at dose level -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Stop the trial if 
# of DLT >=  
NA 
NA 
2 
3 
3 
4 
4 
4 
5 
5 
6 
6 
6 
7 
7 
8 
8 
8 
 
After the trial is completed, we select the MTD based on isotonic regression as specified by Liu and Yuan 
64. Specifically, we select as the MTD the dose for which the isotonic estimate of the toxicity rate is 
closest to the target toxicity rate. If there are ties, we select the higher dose level when the isotonic 
estimate is lower than the target toxicity rate; and we select the lower dose level when the isotonic 
estimate is greater than the target toxicity rate. 
11.2. OPERATING CHARACTERISTICS 
Table 6 shows the operating characteristics of the trial design based on 1000 simulations of the trial. The 
operating characteristics show that the design selects the true MTD with high probabilities and allocates 
more patients to the dose levels with the DLT rate closest to the target of 0.3. 
Table 6. Operating Characteristics of the BOIN design 
 
Dose Level 
Number of 
Patients 
% Early 
Stopping 
 
-1 
1 
2 
3 
Scenario 1 
 
True DLT rate 
0.03 
0.10 
0.30 
0.45 
18.0 
0.0 
Selection % 
0.2 
18.3 
57.9 
23.6 
# Pts Treated 
0.2 
6.3 
8.0 
3.6 
Scenario 2 
 
True DLT rate 
0.02 
0.06 
0.13 
0.30 
18.0 
0.0 
Selection % 
0.0 
1.1 
27.2 
71.7 


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# Pts Treated 
0.0 
3.9 
5.9 
8.1 
Scenario_3 
 
True DLT rate 
0.01 
0.02 
0.08 
0.15 
18.0 
0.0 
Selection % 
0.0 
0.1 
4.3 
95.6 
# Pts Treated 
0.0 
3.3 
4.2 
10.5 
Scenario_4 
 
True DLT rate 
0.50 
0.70 
0.80 
0.90 
11.4 
75.3 
Selection % 
23.9 
0.8 
0.0 
0.0 
# Pts Treated 
7.0 
4.2 
0.1 
0.0 
 
11.3. ANALYSIS PLAN 
The vivo persistence of adoptively transferred central memory-type CTL will be summarized using the 
Kaplan-Meier curve at each dose level. Summary statistics, including mean, standard deviation and 95% 
confidence interval, will be used to describe the response rate. Kaplan-Meier curve will be used to 
describe the PFS and duration of the response.  
A toxicity summary will be submitted to the IND Office Medical Monitor and Safety Group, after the first 
3 evaluable subjects complete 6 weeks of T-Cell only treatment, or 8 weeks of T-Cell plus Utomilumab 
combination treatment, and every 3 evaluable subjects thereafter. Reviewer’s approval must be obtained 
prior to advancing/changing dose levels. An efficacy summary will be submitted to the IND Medical 
Monitor and Safety Group,after every six evaluable subjects have completed 12 weeks of treatment. 
12. 
DATA ENTRY AND PROTOCOL MANAGEMENT  
For the purposes of this study at M. D. Anderson Cancer Center, the Prometheus data management 
system will be employed. All patients will be registered in CORe before any study specific tests are 
performed. 
13. 
ADMINISTRATIVE CONSIDERATIONS  
13.1. PROTOCOL MONITORING  
The study will be monitored by the M.D. Anderson IND office and a protocol specific monitoring plan 
will be followed. 
The principal investigator will monitor the data and toxicities to identify trends. The principal investigator 
will be responsible for revising the protocol as needed to maintain safety. The principal investigator will 
also review serious adverse events and evaluate trends. Whenever a trend is identified, the principal 
investigator will determine an appropriate follow up plan. 
The investigator will submit toxicity data summary for each set of 3 evaluable patients enrolled to the 
IND Office Medical Monitor and the EDSMB.  
13.2. CHANGES TO THE PROTOCOL 
Any change or addition to this protocol requires a written protocol amendment that must be approved by 
the IND Office and the WIRB. A copy of the written approval of the WIRB must be received by the IND 


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30 
Office and the principal investigator before implementation of any changes. The WIRB must review and 
approve all amendments to the protocol. 
14. 
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