Clinical trial NCT02500576
Conditions: Metastatic Melanoma Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-08-07; Completion date: 2022-10-12
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well giving pembrolizumab with standard chemotherapy, tumor infiltrating lymphocytes (TIL), and aldesleukin works in treating patients with melanoma that has spread to other areas of the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving an infusion of TIL, or white blood cells, may help stimulate the immune system to help kill more cells. Aldesleukin may also stimulate the white blood cells to kill melanoma cells. Giving pembrolizumab together with standard chemotherapy, TIL, and high- or low-dose aldesleukin may help stop the melanoma from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. Evaluate the overall response rates of pembrolizumab (MK-3475) combined with lymphodepletion, TIL and high or low dose aldesleukin (interleukin-2) therapy in patients with metastatic melanoma.

SECONDARY OBJECTIVES:

I. Comparison of progression free survival between the treatment arms. II. Comparison of overall survival between the treatment arms. III. Comparison of deep tumor responses (defined as over 60% reduction in tumor burden) between the treatment arms as per Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

IV. Number of complete responses in both treatment arms. V. Safety evaluations by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.

EXPLORATORY OBJECTIVES:

I. Identification of biomarkers predictive of treatment response or failure through immunohistochemistry, flow cytometry, gene expression changes as assessed by NanoString codeset, neo-antigen identification and complementary determining region (CDR)3 sequencing from blood and tumor samples acquired from baseline and on-treatment samples.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard lymphodepleting chemotherapy comprising of cyclophosphamide intravenously (IV) over 2 hours on days -7 and -6 followed by fludarabine phosphate IV piggyback (IVPB) over 15-30 minutes on days -5 to -1. Patients also receive therapeutic tumor infiltrating lymphocytes IV over 15-60 minutes on day 0 followed by high-dose aldesleukin IV over 15 minutes every 8-16 hours for up to 15 doses on days 1-5. Beginning between 21-28 days after TIL infusion, patients receive maintenance therapy comprising of pembrolizumab IV over 30 minutes every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard lymphodepleting chemotherapy comprising of cyclophosphamide, fludarabine phosphate, and therapeutic tumor infiltrating lymphocytes as in Arm I, followed approximately 6 hours later by low-dose aldesleukin subcutaneously (SC) once per day (QD) for 14 days. Patients also receive pembrolizumab as in Arm I.

After completion of study treatment, patients are followed up every 3 months.

Arms: arm 1: Patients receive standard lymphodepleting chemotherapy comprising cyclophosphamide IV over 2 hours on days -7 and -6 followed by fludarabine phosphate IVPB over 15-30 minutes on days -5 to -1. Patients also receive therapeutic tumor infiltrating lymphocytes IV over 15-60 minutes on day 0 followed by high-dose aldesleukin IV over 15 minutes every 8-16 hours for up to 15 doses on days 1-5. Beginning between 21-28 days after TIL infusion, patients receive maintenance therapy comprising pembrolizumab IV over 30 minutes every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive standard lymphodepleting chemotherapy comprising cyclophosphamide and fludarabine phosphate and therapeutic tumor infiltrating lymphocytes as in Arm I, followed approximately 6 hours later by low-dose aldesleukin SC for 14 days. Patients also receive pembrolizumab as in Arm I.
Interventions: intervention 1: Aldesleukin intervention 2: Cyclophosphamide intervention 3: Fludarabine Phosphate intervention 4: Laboratory Biomarker Analysis intervention 5: Pembrolizumab intervention 6: Quality-of-Life Assessment intervention 7: Therapeutic Tumor Infiltrating Lymphocytes
Intervention descriptions: intervention 1: Given IV or SC intervention 2: Given IV intervention 3: Given IVPB intervention 4: Correlative studies intervention 5: Given IV intervention 6: Ancillary studies intervention 7: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
TITLE: Phase II study of MK-3475 in conjunction with lymphodepletion, TIL, and high or 
low dose IL-2 in patients with metastatic melanoma 
IND NUMBER: 16480 
EudraCT NUMBER: 
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Table of Contents 
1.0 Trial Summary 
3 
2.0 Trial Design 
3 
3.0 Objectives and Hypotheses 
4 
4.0 Background and Rationale 
5 
5.0 Methodology 
18 
6.0 Trial Flow Chart 
35 
7.0 Trial Procedures 
37 
8.0 Statistical Analysis Plan 
53 
9.0 Labeling, Packaging, Storage and Return of Clinical Supplies 
54 
10.0 Administrative and Regulatory Details 
55 
11.0 References 
56 
12.0 Appendices 
61 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
TIL with MK-3475 
Trial Phase 
II 
Clinical Indication 
Stage IIIc unresectable and stage IV melanoma 
Trial Type 
Treatment 
Type of control 
n/a 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups 
Arm 1: high dose IL-2 Arm 2: low dose IL-2 
Number of trial subjects 
36 
Estimated duration of trial 
3 years 
Duration of Participation 
3-5 years
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a randomized phase II study of treating patients with lymphodepletion, ex-vivo 
expanded melanoma specific tumor infiltrating lymphocytes (TIL) followed by high dose 
(Arm 1) or low dose (Arm 2) IL-2. All patients will have had prior surgical excision of a 
melanoma tumor deposit to isolate the TIL and amplify to over a billion cells. Once patients 
have completed and passed extensive pre-treatment screening evaluations, they will be 
randomized to one of two treatment groups. Arm 1 will consist of 18 patients who receive 
standard high dose IL-2 after TIL infusion. Arm 2 will consist of 18 patients who will receive 
low dose IL-2. Patients will be randomized based on tumor stage (stage IIIc/M1a vs. M1b/M1c 
and LDH (elevated or normal). All patients will receive standard lymphodepletion consisting 
of fludarabine and cyclophosphamide chemotherapy. This will be followed by melanoma 
specific tumor infiltrating lymphocyte infusion and IL-2 will be administered starting 
approximately 12-16 hours post completion of the T cell infusion. Approximately 21 days 
after T cell infusion, all patients will initiate on the anti PD-1 antibody MK-3475 200mg IV 
flat dosing every three weeks for up to 2 years. 
In addition to clinical endpoints of overall response rate, progression free survival and overall 
survival, this trial emphasizes correlative research with built-in research blood collection and 
biopsies to facilitate identification of biomarkers of response or failure to therapy (see section 
4.2.2.2). 
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2.2 Trial Diagram 
3.0 OBJECTIVES & HYPOTHESES 
3.1 Primary Objectives 
Objectives: Evaluate the overall response rates of MK-3475 combined with lymphodepletion, 
TIL and high or low dose interleukin-2 therapy in patients with metastatic melanoma. 
Secondary Objectives 
Objectives: 
(1) Comparison of progression free survival between the treatment arms
(2) Comparison of overall survival between the treatment arms
(3) Comparison of deep tumor responses (defined as over 60% reduction in tumor burden)
between the treatment arms as per RECIST criteria
(4) Number of complete responses in both treatment arms
 
Day +21  
(+7 days), then every 21 days (± 7 days) for up to a total of 31 doses 
(2 years of therapy). 
Day +21  
(+7 days), then every 21 days (± 7 days) for up to a total of 31 doses 
(2 years of therapy). 
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(5) Safety evaluations by CTCAE v
4.0
3.2 Exploratory 
Objective 
Objective: Identification of biomarkers predictive of treatment response or failure 
through immunohistochemistry, flow cytometry, gene expression changes as assessed 
by NanoString codeset, neo-antigen identification and CDR3 sequencing from blood 
and tumor samples acquired from baseline and on-treatment samples. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Adoptive Cell Therapy (ACT) for Melanoma 
ACT using expanded TIL has shown great promise for the treatment of Stage IV melanoma 
patients failing all other types of therapy [1-3]. ACT clinical trials reported by the NCI 
(Bethesda) using a lymphodepleting pre-conditioning regimen before TIL and IL-2 infusion 
have had clinical response (CR) rates of up to 51% [1-3]. A number of immune-related 
mechanisms account for this improved persistence and better clinical response [2, 4, 5]. The 
current methodology for ACT requires a two-phase process. The first phase involves the 
expansion of TIL, isolated from surgically-resected tumor fragments, ex vivo with IL-2 
in small scale over a period of 4-5 weeks [4, 6]. TIL cultures from patients exhibiting 
a minimal rate of expansion are then expanded in large-scale using a Rapid Expansion 
Protocol (REP) in a GMP facility [6, 7]. A typical post-REP TIL product for infusion consists 
of 25 to 150 billion T-cells, with increased numbers of infused CD8+ TIL correlating to better 
clinical response (Fig. 2 and Fig. 3A). We have established a comprehensive and successful 
immunotherapy program at the MDACC aimed at further enhancing the efficacy of ACT 
by improving TIL expansion protocols and developing synergistic therapies. MDACC is 
the largest center for ACT of melanoma outside of the NCI. At present, we are conducting 
a Phase II clinical trial assessing the efficacy of ACT using expanded TIL ex vivo using 
the classical REP described above together with 
lymphodepletion before TIL infusion [2, 3]. 
Since starting our program in 2006, we have 
cultured melanoma tumor fragments from 
over 600 patients with Stage IV melanoma 
and have successfully expanded minimal 
numbers of TIL (at least 4 x 107) needed for 
the large-scale REP from approximately 60% 
of patients. So far we have treated over 70 
patients with their expanded TIL with the 
pace of treatment accelerating to 2-3 patients 
per month. 
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Fig. 2 shows some examples of the significant 
tumor regressions that have occurred in patients responding to TIL in our ACT program; 
these patients were refractory to all other therapies. The clinical response rate in our ACT 
program so far has been very encouraging (Table 1) with 45% of the 71 patients evaluated 
post-infusion so far (32/71) exhibiting a clinical response (PR/CR) according to RECIST 
criteria after CT scans of target lesions starting at 6 weeks after treatment. Duration of 
responses has varied with some patients achieving years of clinical benefit (Table 1). 
Immunocorrelative studies have revealed that CD8+ T-cells are critical in mediating anti- 
tumor responses and that higher numbers of infused CD8+ TIL correlates with greater objective 
tumor regression (Fig. 3A, and data not shown). 
Table 1: updated progression free and overall survival for 71 TIL treated patients as of 
September 2013. 
During REP anti-tumor CD8+ TIL not only greatly increase in number, but also further 
differentiate and acquire more potent anti-tumor killing function [7]. This is needed for anti- 
tumor CTL activity, but is also associated with an acquisition of a terminally differentiated 
CTL phenotype and a loss of effector-memory (EM) CD8+ T-cells (CD27+CD28+) capable of 
long-term persistence and expansion in the host after adoptive transfer [5, 7, 8]. However, 
maintenance of CD28 expression in particular has been shown to be critical for TIL to 
respond to further antigenic stimulation, long-term cell division and persistence in vivo, as 
found by studies at the NCI as well as data from our group [5, 7, 9]. We have tracked the 
persistence of specific TIL clonotypes after ACT using TCR Vβ sequencing of isolated 
PBMC post-infusion, and found that the persistence for over 1 month of one or more major 
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Total CD8+ TILs infused 
Vβ clonotypes in blood (%) 
Vβ clonotypes in blood (%) 
TCR clonotypes in the TIL correlates with clinical response (Fig. 3B). 
Our laboratory has been actively engaged in identifying biomarkers which correlate with 
clinical response in TIL treated patients. We have found that patients who achieve responses 
to TIL tend to have higher absolute numbers of TIL infused. Additionally, patients with 
higher  proportions  of  CD8+  T  cells  in  their  infusion  product  also  tend  to  have  better 
responses. An unexpected finding was that the negative co-stimulatory markers PD-1, BTLA 
and TIM3 on infused TIL correlated with improved patient responses. Indeed, patient TIL 
with higher frequencies of BTLA + T cells seemed to have improved clinical responses [10]. 
Much work is required to validate the significance of these potential biomarkers. 
A 
B
80 
PR/CR 
SD/PD 
80 
150 
100 
50 
p=0.05 
60 
40 
20 
0 
0 
1 
3 
5 
80 
60 
60 
40 
20 
0 
0 
1 
3 
5 
80 
60 
0 
PR/CR 
PD/SD 
Response type 
40 
20 
0 
0 
1 
3 
5 
Months post-infusion 
40 
20 
0 
0 
1 
3 
5 
Months post-infusion
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Fig. 3. Persistence of major TIL TCR clonotypes and total CD8+ TIL infused is associated with clinical 
response to ACT. A. Higher number of infused CD8+ TIL correlates with clinical response. B. Vβ TCR 
clonotype analysis of post-infusion PBMC following infusion in lymphodepleted patients showing persistence of 
major TIL Vβ clonotypes in two representative patients with a PR/CR. In contrast, the major TCR clonotypes 
rapidly disappear by 1 month in non-responding patients (SD/PD). 
4.1.2 Impact on IL-2 Dosing in Adoptive Cell Therapy 
Use of high dose intravenous IL-2 beginning approximately 12 hours after TIL infusion has 
been utilized as a mechanism to promote survival and enhanced efficacy of transferred T 
cells [10-13]. However, HD-IL2 is associated with significant toxicities including grade 3 
capillary leak syndrome, hypotension, diarrhea, nausea, vomiting, skin changes, anorexia, 
mucositis, dysphagia, constitutional symptoms, and laboratory changes. Rarely, grade 4 
toxicities and death have been seen with the HD-IL2 regimen. Due to expected high level 
adverse effects associated with HD-IL2, we do not offer this regimen to patients over the age 
of 65 or to patients with significant cardiovascular or pulmonary compromise at baseline 
which thus limits our ability to offer ACT to a significant portion of melanoma patients. 
However, we do not yet know how much addition of HD-IL2 to the TIL treatment protocol 
really adds to the induction of clinical responses associated with this regimen and it is 
possible that similar efficacy could be appreciated by using lower doses of IL-2. Multiple 
prior studies have investigated use of ACT with low doses of IL-2 [1, 14, 15] and while it 
seems that better response rates are seen with the high dose regimen, low dose IL-2 
administered IV or SC has also produced durable responses with much better tolerance to 
therapy. A groundbreaking study in 2002 treated patients with four infusions of autologous 
CD8+ T cell clones against MART1, Melan -A and gp100 tumor associated antigens to 10 
patients with metastatic melanoma. Very low doses of IL-2 were used (0.25, 0.50 and 1.0 x 
106 units/m2 twice daily for the second, third and fourth infusions, respectively). These 
autologous T cells were found to persist in vivo, localized to the tumor sites and led to 
clinical responses in eight of ten treated patients with responses seen for up to 21 months. 
This regimen was very well tolerated and there were no AEs attributed to the administered 
SC LD-IL2 [14]. 
In an early study phase I study of adoptive cell therapy, patients with metastatic melanoma 
were treated with non-myeloablative lymphodepleting chemotherapy consisting of 
cyclophosphamide and fludarabine and were then infused with in vitro expanded, tumor 
reactive autologous T cell clones selected for high avidity recognition of melanoma antigens. 
There were three cohorts of patients who then went on to receive either no interleukin 2, low 
dose IL-2 (72,000 IU/kg IV three times a day to a maximum of 15 doses) or high dose IL-2 
(720,000 IU/kg intravenously three times a day for a maximum of 12 doses). Although there 
were no durable responses in this clinical trial, this was thought to be more due to need for 
additional manipulations of the transferred T cell population as transient responses were seen 
in both the low dose and high dose IL-2 treated patients [1]. 
In a more recent pilot study using low dose IL-2, six patients with metastatic melanoma 
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refractory to prior therapies were treated with standard non-myeloablative lymphodepletion 
and TIL infusion followed by low dose IL-2 administered as 2 million IU daily for 14 days. 
Two of the six patients had ongoing complete responses at the time of publication (+10 and 
+30 months), 2 patients had stable disease of 4 and 5 month duration and two patients
progressed shortly after treatment. The median time to progression was 8.2 months and
overall survival was 12 months [15].
4.1.3 PD1 blockade with ACT is synergistic in preclinical models 
An important pre-clinical tool utilized by our laboratory has been the development of an 
adoptive T cell therapy model in mice. In these studies, B16 tumors were inoculated into 
mice and allowed to grow for 7 days prior to treatment with adoptively transferred pmel T 
cells expressing a T cell receptor recognizing a specific B16 tumor antigen restricted epitope 
of gp100. This was then followed by a gp100 peptide-pulsed vaccine and interleukin-2. 
Sacrifice of mice approximately 6 days post infusion showed accumulation of PD-1 positive 
endogenous and transferred T cells in the tumor site compared to T cells localized in the 
spleen. These T cells were not fully functional when interferon-gamma production in response 
to re-stimulation with gp100 pulsed cells was assessed, thus indicating potential limited 
therapeutic efficacy of these cells [16]. 
For the next set of experiments, MC38/gp100 tumor-inoculated mice were treated with anti 
PD-1 antibody on day of and two and four days post adoptive transfer of luciferase- expressing 
T cells. Six days after adoptive transfer of the T cells, luciferase activity scoring was 
performed showing approximately 3 fold more transferred T cells at the tumor site 
compared with mice receiving the control antibody (Figure 4A, B, C) [16]. 
Additionally, use of anti PD-1 antibody in both MC38/gp100 and B16 tumor inoculated mice 
after adoptive transfer of T cells lead to statistically significant shrinkage of tumor compared 
to mice treated with T cells or anti PD-1 antibody alone (Figure 4 D and E) with little evident 
toxicity. Further work was done to characterize the mechanism of this apparent synergy and 
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it was found that ACT combined with PD-1 blockade did not reduce the number of 
immunosuppressive regulatory T cells or myeloid derived suppressor cells. However, there 
was evidence of increased expression of the interferon gamma inducible (INF-γ) chemokine 
CXCL10 within the tumor micro-environment. This was verified by finding increased INF-γ 
levels within the tumors of mice undergoing combination ACT with anti PD-1 antibody 
compared with mice treated with ACT alone. There was no significant difference in the 
expression of other cytokines such as IL-10, transforming growth factor-beta and IL-17 [16]. 
4.1.4 Anti PD-1 Antibody: Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [17]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies [18-29]. In particular, the presence of CD8+ T-cells and 
the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with 
improved prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
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T-cells under healthy conditions, is to down-modulate unwanted or excessive immune
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig
superfamily member related to CD28 and CTLA-4 which has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2)
[30, 31]. The structure of murine PD-1 has been resolved [32]. PD-1 and family members are
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs,
an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine- 
based switch motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved
in the CD3 T cell signaling cascade [31, 33-35]. The mechanism by which PD-1 down
modulates T cell responses is similar to, but distinct from that of CTLA-4 as both
molecules regulate an overlapping set of signaling proteins [36]. PD-1 was shown to be
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B cells, T
regs and Natural Killer cells [37, 38].Expression has also been shown during thymic
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and
dendritic cells [39]. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or
can be induced in a variety of cell types, including non-hematopoietic tissues as well as in
various tumors [40-43]. Both ligands are type I transmembrane receptors containing both
IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions
with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T cell
activation triggered through the T cell receptor. PD-L1 is expressed at low levels on various
nonhematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic
inflammatory environments. PD-L2 is thought to control immune T cell activation in
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T cell function in peripheral
tissues [43]. Although healthy organs express little (if any) PD-L1, a variety of cancers were
demonstrated to express abundant levels of this T cell inhibitor. PD-1 has been suggested to
regulate tumor-specific T-cell expansion in subjects with melanoma. This suggests that the
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be
considered as an attractive target for therapeutic intervention.
A recent study of TIL from fresh melanoma tumors showed that expression of inhibitory 
receptors including PD-1 on CD8+ TIL identified and selected for a diverse repertoire of 
autologous tumor-reactive cells. Additionally TCR deep sequencing showed that the most 
highly expanded clonotypes were the ones which had the ability to recognize autologous 
tumor. These data suggest that PD-1 identifies clonally expanded CD8+ tumor-reactive 
populations and suggests that expression of PD-1 on CD8+ TIL could function as a potential 
predictive biomarker of response to checkpoint inhibition [44]. 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
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4.1.5 Preclinical and Clinical Trial Data on MK-3475 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Trial Rationale 
ACT using TIL has consistently shown response rates over 40% with a substantial proportion 
of patients achieving durable responses over 12 months in over 60% of responding patients 
[10]. The most widely adopted TIL protocol utilizes high dose IL-2 after TIL infusion to 
produce an environment conducive to the survival and proliferation of transferred cells. 
However, HD-IL2 is associated with significant grade 3 toxicities that contribute to lack of 
widespread use of this regimen. Recent advancements in checkpoint blockade in melanoma 
have shown response rates of approximately 40% with the anti PD-1 antibody MK-3475 and 
early data indicates durable responses although data need to continue to mature [45]. It has 
been shown that PD-1 + T cells increase in the tumor microenvironment after adoptive cell 
therapy in patients as well as in mouse models. Preclinical data from MDACC demonstrates 
solid pre-clinical proof that addition of anti PD-1 antibody improves the therapeutic efficacy 
of adoptive cell therapy and also demonstrates a potential mechanism of these improved 
responses in mice. We hypothesize that addition of MK-3475 to lymphodepletion, TIL infusion 
and IL-2 will be synergistic leading to improved response rates, improved progression free 
and overall survival. Additionally, we believe that addition of MK-3475 to this regimen will 
produce enough synergy with the adoptively transferred cells that the use of high dose IL-2 
would not be required and treatment with LD-IL2 may be non-inferior to results seen with 
historical controls. This protocol provides us with the ability to combine two of the most 
effective therapies for melanoma and thus gives us the chance to potentially cure more patients 
and positively impact on the lives of our patients and enhance our understanding of the 
immune system. 
4.2.1 Rationale for Dose Selection/Regimen 
4.2.1.1 Interleukin-2 (Aldesleukin, Proleukin) 
Interleukin-2 (IL-2) will be manufactured and supplied by Prometheus and will be purchased 
by the M.D. Anderson pharmacy from commercial sources. IL-2 is a 133 amino acid-long 
peptide primarily secreted by T-cells in response to various antigenic stimuli. The cytokine 
acts through a specific IL-2 receptor consisting of α, β, γ subunits. In addition to T-cell 
proliferation, IL-2 leads to activation and proliferation of natural killer (NK) cells, increasing 
their tumoricidal activity. Other actions of IL-2 include augmentation of B-cell growth and 
immunoglobulin production, enhancement of interferon (IFN)-γ and tumor necrosis factor 
(TNF)-β production from T-cells, IL-6 production by monocytes, modulation of histamine 
release by basophils, and upregulation of IL-2 receptors. This triggers the release of various 
other cytokines leading to the total immune/ inflammatory reaction and resultant toxicity. 
In this study, there will be two arms of patients that differ based on the dosage of IL-2 that is 
administered after adoptive cell therapy. Arm 1 will receive the classical high dose IL-2 
regimen which is administered as an inpatient treatment.  Initial studies using high dose IL-2 
for the treatment of metastatic melanoma and renal cell carcinoma have demonstrated 
responses in 3 - 24% of patients with durable remissions in approximately 6% of treated 
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patients [46]. Grade III toxicities common to IL-2 include diarrhea, nausea, vomiting, 
hypotension, skin changes, anorexia, mucositis, dysphagia, constitutional symptoms, and 
laboratory changes. Additional Grade IV and V toxicities have been seen with IL-2 (See 
Appendix H). 
Arm 2 will receive low dose IL2 after completion of adoptive cell therapy. While such doses 
have seldom resulted in clinical response, doses as low as 100,000 U have been demonstrated 
to induce cellular immunologic effects in vivo while doses greater than 106 U/m2 were 
associated with systemic symptoms of malaise and myalgias. Following subcutaneous (s.c.) 
administration, IL-2 exhibits a half-life of between 3 to 12 hours, sustained serum levels of 
10- 25 U/ml, and receptor saturating serum concentrations of 22 pM after an injection of
250,000 U/m2 [46-48]. Administration of 3 x 106 U/m2 of IL-2 for up to 21 days for the
treatment of melanoma results in response rates of 0 to 9% [49]. Therefore, patients receiving
low-dose IL-2 in this trial, (2 million IU SC daily x 14 days), are unlikely to receive
significant benefit from the IL-2 alone, rather, the IL-2 is administered in a manner designed
to promote persistence of infused T cells in vivo. Patients treated with low dose IL-2 do not
experience significant toxicity [50-52] and it is rare to have CTCAE grade 3-4 events which
is directly in contrast to what is expected with patients treated with high dose IL-2.
4.2.1.2 Fludarabine 
Fludarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine, 9- 
β-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination. Fludarabine is 
a purine antagonist antimetabolite. Fludarabine phosphate is rapidly dephosphorylated to 2-
fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active 
triphosphate, 2-fluoro-ara-ATP. This metabolite appears to act by inhibiting DNA 
polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA 
synthesis. The mechanism of action of this antimetabolite is not completely characterized 
and may be multi-faceted. 
Fludarabine will be purchased by the M.D. Anderson pharmacy from commercial sources. 
Fludarabine is supplied as a fludarabine phosphate powder in the form of a white, lyophilized 
solid cake. The fludarabine powder is stable for at least 18 months at 2 – 8 degrees C; when 
reconstituted, fludarabine is stable for at least 16 days at room temperature. Specialized 
references should be consulted for specific compatibility information. Fludarabine is 
dephosphorylated in serum, transported intracellularly and converted to the nucleotide 
fludarabine triphosphate; this 2-fluoro-ara-ATP molecule is thought to be required for the 
drug’s cytotoxic effects. Fludarabine inhibits DNA polymerase, ribonucleotide reductase, 
DNA primase, and may interfere with chain elongation, and RNA and protein synthesis. 
Fludarabine is administered as an I.V. infusion in 100 ml 0.9% sodium chloride, USP over 
approximately 15-30 minutes. At doses of 25 mg/m2/day for 5 days, the primary side effect 
is myelosuppression. However, thrombocytopenia is responsible for most cases of severe 
and life-threatening hematologic toxicity.  Hemolytic anemia has been reported after one or 
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more courses of fludarabine with or without a prior history of a positive Coomb’s test; fatal 
hemolytic anemia has been reported. In addition, bone marrow fibrosis has been observed 
after fludarabine therapy. Other common adverse effects include malaise, fatigue, anorexia, 
and weakness. Irreversible and potentially fatal central nervous system toxicity in the form 
of progressive encephalopathy, blindness, and coma is rare at the currently administered 
doses. More common neurologic side effects at the current doses of fludarabine include 
weakness, pain, malaise, fatigue, paresthesia, visual or hearing disturbances, and sleep 
disorders. Adverse respiratory effects of fludarabine include cough, dyspnea, and allergic or 
idiopathic interstitial pneumonitis. Tumor lysis syndrome has been rarely observed in 
fludarabine treatment of Chronic Lymphocytic Leukemia (CLL). 
4.2.1.3 Cyclophosphamide (Cytoxan) 
Cyclophosphamide is a synthetic anti-neoplastic drug chemically related to the nitrogen 
mustards. It is biotransformed principally in the liver to active alkylating metabolites by a 
mixed function microsomal oxidase system. These metabolites interfere with the growth of 
susceptible rapidly proliferating malignant T-cells. The mechanism of action is thought to 
involve cross-linking of tumor cell DNA. 
Cyclophosphamide is well absorbed after oral administration with a bioavailability greater 
than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated 
primarily in the form of metabolites, but from 5% to 25% of the dose is excreted in urine as 
unchanged drug. Several cytotoxic and non-cytotoxic metabolites have been identified in 
urine and in plasma. Concentrations of metabolites reach a maximum in plasma 2 to 3 hours 
after an intravenous dose. Plasma protein binding of unchanged drug is low but some 
metabolites are bound to an extent greater than 60%. It has not been demonstrated than any 
single metabolite is responsible for either the therapeutic or toxic effects of 
cyclophosphamide. Although elevated levels of metabolites of cyclophosphamide have been 
observed in patients with renal failure, increased clinical toxicity in such patients has not 
been demonstrated. 
Following conversion to active metabolites in the liver, cyclophosphamide functions as an 
alkylating agent and possesses potent immunosuppressive activity. The serum half-life after 
intravenous administration ranges from 3 to 12 hours; the drug and/or its metabolites can be 
detected in the serum for up to 72 hours after administration. 
Cyclophosphamide will be obtained from commercially available sources by the M. D. 
Anderson pharmacy. It will be diluted in 250 ml NS and infused over approximately two 
hours. The dose will be based on the patient’s body weight, but to prevent undue toxicity, it 
will not exceed a dose greater than 140% of the maximum ideal body weight per 
Metropolitan Life Insurance Company, Height and Weight Tables (Appendix K). 
Hematologic toxicity occurring with cyclophosphamide usually includes leukopenia and 
thrombocytopenia. Anorexia, nausea, and vomiting may occur, especially after high-doses. 
Diarrhea, hemorrhagic colitis, and mucosal and oral ulceration have been reported in patients. 
Sterile hemorrhagic cystitis occurs in about 20% of patients; severity can range from 
microscopic hematuria to extensive cystitis with bladder fibrosis. Although the incidence of 
hemorrhagic cystitis associated with cyclophosphamide appears to be lower than 
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that associated with ifosfamide, mesna (sodium 2-mercaptoethanesulfonate) has been used 
prophylactically as an uroprotective agent Mesna may not be effective in all patients. 
Patients who receive high dose cyclophosphamide may develop interstitial pulmonary 
fibrosis, which can be fatal. Hyperuricemia due to rapid cellular destruction may occur, 
particularly in patients with hematologic malignancy. Hyperuricemia may be minimized by 
adequate hydration, alkalinization of the urine, and/or administration of allopurinol. If 
allopurinol is administered, patients should be watched closely for cyclophosphamide 
toxicity due to allopurinol induction of hepatic microsomal enzymes. At high doses, 
cyclophosphamide can also result in a syndrome of inappropriate antidiuretic hormone 
secretion; hyponatremia with progressive weight gain without edema occurs. Cardiotoxicity 
has been observed at high doses of cyclophosphamide. Deaths have occurred from diffuse 
hemorrhagic myocardial necrosis and from acute myopericarditis; in such cases, congestive 
heart failure may occur within a few days of the first dose. Other consequences of 
cyclophosphamide 
cardiotoxicity 
include 
arrhythmias, 
potentially 
irreversible 
cardiomyopathy, and pericarditis. Other reported adverse effects of cyclophosphamide include 
headache, dizziness, and myxedema; faintness, facial flushing, and diaphoresis. 
4.2.1.4 Mesna (Sodium 2-mercaptoethanesulfonate, Mesnum, Mesnex, NSC-113891) 
Mesna (sodium 2-mercaptoethanesulphonate; given by IV injection) is a synthetic sulfhydryl 
compound that can chemically interact with urotoxic metabolites of cyclophosphamide 
(acrolein and 4-hydroxycyclophosphamide) to decrease the incidence and severity of 
hemorrhagic cystitis. 
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis. 
Analogous to the physiological cysteine-cystine, mesna is rapidly oxidized to its major 
metabolite, mesna disulfide (dimesna). Mesna disulfide remains in the intravascular 
compartment and is rapidly eliminated by the kidneys. In the kidney, the mesna disulfide is 
reduced to the free thiol compound, mesna, which reacts chemically with the urotoxic 
metabolites, resulting in their detoxification. 
Mesna will be obtained commercially and is supplied as a 100 mg/ml solution. Intact 
ampules are stored at room temperature. Diluted solutions (1 to 20 mg/dl) are physically and 
chemically stable for at least 24 hours under refrigeration. Mesna is chemically stable at 
room temperature for 48-72 hours in D5W, 48-72 hour in D5W/0.45% normal saline, or 24 
hours in normal saline. It will be diluted up to 20 mg Mesna/ml fluid in D5W or normal 
saline and will be administered intravenously as a continuous infusion. Toxicities include 
nausea, vomiting and diarrhea. 
4.2.1.5 G-CSF (Granulocyte Colony-Stimulating Factor) 
G-CSF may be given in the form of Filgrastim or PEG-Filgrastim at the appropriate doses.
The side effects of G-CSF are skin rash, myalgia and bone pain, an increase of preexisting
inflammatory conditions, enlarged spleen with occasional associated low platelet counts,
alopecia (with prolonged use) elevated blood chemistry levels.
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4.2.1.6 Antimicrobials 
Antimicrobials will be instituted as per standard of care to prevent bacterial, fungal and viral 
infections typically encountered during the period of immunosuppression post 
lymphodepletion. 
4.2.1.7 T-cell preparation 
The procedures and reagents for expanding the human TIL cells and the Certificates of 
Analysis are contained in the CMC located in the IND office. 
4.2.1.8 MK-3475 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose- 
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL- 
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for a Q2W and Q3W 
dosing schedule. 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication. The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no
significant impact of tumor burden on exposure. In addition, exposure was similar between
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in
exposure between different indication settings and the dose of 200mg IV every 3 weeks is the
dose chosen by Merck in future clinical trials.
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4.2.2 Rationale for Endpoints 
4.2.2.1 Efficacy Endpoints 
The primary endpoint is RR to demonstrate the anti-tumor activity of MK-3475 in both study 
groups. The primary measure for assessment of tumor response is based on RECIST 1.1 by 
investigator review. Secondary endpoints will include assessment of PFS, OS, number of 
deep responses, number of complete responses and safety analyses. 
4.2.2.2 Biomarker Research 
Biomarker research is heavily emphasized in this clinical trial. We will have access to stored 
tumor and blood for the time of TIL harvest. Research blood and tumor biopsy 
(specifications detailed in Section 7.2.8) will also be collected prior to hospital admission 
for lymphodepletion. Blood will be collected at day +7 (+/-2 days). Blood and tumor (tumor 
biopsy if feasible) will be repeated on day +21 (+/-7 days) which is prior to the first dose of 
MK-3475 to assess changes by the two different IL-2 dosing schemas utilized in this protocol. 
Blood collection and tumor biopsy is also mandatory (tumor biopsy if feasible) on day +42 
(+/-7 days) just prior to the second dose of MK-3475 to assess changes in circulating T cells 
and tumor microenvironment from exposure to MK-3475. Research blood and biopsy of 
residual disease if feasible will be performed at week 9 with the first restaging scan and 
then at every subsequent restaging scan every 12 weeks. 
Planned biomarker research includes: 
1. Phenotypic analysis of TIL infusion product by flow cytometry: Panels of antibodies
will be designed to answer specific questions about phenotype and function of the T
cells. State of differentiation can be determined (CD3, CD4, CD8, CD45RA,
CD45RO, CCR7, CD27, CD28) in combination with functional type by intracellular
staining for various cytokines and mediators of CTL activity (IL-2, IL-4, IL-10, IL-8,
IFN-γ, IL-9, IL-17, Granzyme B, perforin) or transcription factors associated with
commitments to different functional paths (Eomes, Tbet).
2. Immune 
analysis 
of 
tumors 
will 
be 
performed 
using 
our 
customized
immunohistochemistry panel to evaluate immune cell phenotype (CD3, CD4, CD8,
FoxP3, CD68, CD56, CD20, CD45RO) and markers of functionality (granzyme B,
perforin) as well as determinants of immune modulation (PD-1, LAG3, TIM3, ,
BTLA, and proliferative status (e.g. TUNEL, Ki-67). Using this panel, we will be
able to perform correlative studies between response to therapy and immune cell
subtype numbers and function or the presence of immunodulatory molecules in the
tumor microenvironment. We expect to see high expression of PD-L1 within the
tumor due to IFN-γ expression triggered by the homing of activated T cells into the
tumor post treatment. We also expect to see increased proliferation and markers of
functionality on the T cells in the tumor post treatment as compared to the baseline
tumor sample. Samples will be shared with Merck specifically for PD-L1 testing
using their proprietary assay.
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3. CDR3 sequencing: We will track the fate of bulk CD8+, CD4+ or sorted tumor
specific TIL clones after infusion and monitor if tumor specific clones migrate
preferentially to the tumor or not. We will also determine which sorted subpopulations
persist longer post-infusion and determine if persistence of the infused TIL correlate
with response to TIL + MK-3475 therapy.
4. Assessment of gene expression changes from baseline to on-treatment samples and
correlation with clinical response is planed through use of our validated NanoString
code-set of 788 pertinent signaling and immune-related genes.
5. Neoantigen discovery will be performed on patients with excellent clinical response
to allow us to ascertain novel antigens involved in development of immune responses
to this therapy. At MDACC, we have devised an in-house neo-antigen discovery
platform that combines whole exome sequencing of the tumor tissue to define
mutations existing in the patient’s tumor, algorithm-based prediction of epitope
binding affinity of the predicted peptides to the different HLA molecules, and TIL
screening of the identified peptides to identify reactive T cells. Our group has
optimized a system whereby the MHC class I bound peptides are eluted off of the
patient’s own tumor tissue and analyzed using tandem mass spectrometry (MS/MS).
In addition, part of the tumor tissue is sent for whole exome sequencing and
immunogenic peptides are predicted based on the patients’ own unique HLA type.
5.0 
METHODOLOGY 
5.1 
Entry Criteria 
Patient evaluation for eligibility and registration will occur utilizing a two-turnstile design. 
5.1.1 Turnstile I – Screening – Initiation of TIL Expansion/TIL Harvests 
Entry Criteria 
1. Patients must have metastatic melanoma or stage III in-transit, subcutaneous,
or regional nodal disease.
2. Patients must have a lesion amenable to resection for the generation of TIL on
MD Anderson protocol 2004-0069.
3. Patients must receive an MRI/CT/PET of the brain within 6 months of signing
informed consent. If new CNS lesions are present, patient must have definitive
treatment (including surgery or radiation). PI or his designee should make final
determination regarding enrollment.
4. Age greater than or equal to 18 years.
5. Clinical performance status of ECOG 0 – 1 within 30 days of signing
informed consent.
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6. Patients previously treated with immunotherapy, targeted therapy, or no
therapy (treatment naïve) will be eligible.
7. Patients receiving cytotoxic agents will be evaluated by the PI or his designee
for eligibility suitability.
8. Patients with a negative pregnancy test (urine or serum) must be documented within
14 days of screening for women of childbearing potential (WOCBP). A WOCBP has
not undergone a hysterectomy or who has not been naturally postmenopausal for at
least 12 consecutive months (i.e. who has not had menses at any time in the
preceding 12 consecutive months).
5.1.2 Turnstile II-- Treatment – Chemotherapy/Cell Infusion Entry Criteria 
1. Patients must sign the treatment consent document before Turnstile II screening
procedures. Patients must fulfill all of the following criteria to be eligible for Turnstile
II of the study.
2. Patients   must   have   adequate   TIL   that   were   previously   harvested   and
then cryopreserved on MDACC protocol 2004-0069.
3. Patients who have had prior therapy (BRAF inhibitors, ipilimumab, anti PD-1
antibody or anti PD-L1 antibody) or treatment naïve patients are eligible as long
as toxicity from therapy is ≤ grade 1 or at baseline.
4. Patients must have at least one biopsiable measurable metastatic melanoma, lesion >
1cm and must be amenable to undergoing serial biopsies through the course  of therapy
(see Section 7.2.7). This lesion must not be documented as one of the target lesions
5. Patients may have CNS metastases which have been treated and are radiographically
stable for at least 4 weeks
6. Patients of both genders must practice birth control for four months after receiving
the preparative regimen (lymphodepletion) and continue to practice birth control
throughout the study. Patients must have a documented negative pregnancy test
(urine or serum) for women who have menstruated in the past 12 months and without
sterilization surgery.
7. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s) or if the
patient is post-menopausal, the patient agrees to use 2 methods of contraception
throughout the study such as: condom, diaphragm, hormonal, IUD, or sponge plus
spermicide.  Abstinence is an acceptable form of birth control.
8. Pregnancy testing will be performed within 14 days of screening for women of
childbearing potential (WOCBP). A WOCBP has not undergone a hysterectomy or
who has not been naturally postmenopausal for at least 12 consecutive months (i.e. who
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has not had menses at any time in the preceding 12 consecutive months). . 
9. Clinical performance status of ECOG 0-1 within 30 days of signing informed consent. .
10. A stress cardiac test (stress thallium, stress MUGA, dobutamine echocardiogram or
other stress test that will rule out cardiac ischemia) within 1 month of
lymphodepletion.
11. 12-lead EKG showing no active ischemia and QTc interval less than 480 msec
12. Pulmonary function tests (FEV1>65% or FVC>65% of predicted) within 1 month of
lymphodepletion.
13. Have measurable disease based on RECIST 1.1 and irRC criteria (Appendix D).
14. Demonstrate adequate organ function as defined in Table 2, all screening labs should
be performed within 30 days of admission to the hospital for initiation of
lymphodepletion.
Table 2 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
(GFR can also be used in place of 
creatinine or CrCl) 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy  
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
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5.2 
Subject Exclusion Criteria 
5.2.1 Turnstile I – Screening – Initiation of TIL Expansion/TIL Harvests 
Exclusion Criteria 
1. Active systemic infections requiring intravenous antibiotics, coagulation disorders or
other major medical illnesses of the cardiovascular, respiratory or immune system.
PI or his designee shall make the final determination regarding appropriateness of
enrollment
2. Primary immunodeficiency and need for chronic steroid therapy, Exception: Patients
on chronic physiologic dose of steroid equivalent to prednisone < 10 mg/day is
allowed.
3. Patients who are pregnant or nursing.
4. Presence of a significant psychiatric disease, which in the opinion of the
principal investigator or his designee, would prevent adequate informed consent.
5. Presence of an active autoimmune disease requiring systemic treatment within the
past 3 months or a documented history of clinically severe autoimmune disease.
Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to
this rule. Subjects that require intermittent use of bronchodilators or local steroid
injections would not be excluded. Subjects with hypothyroidism stable on hormone
replacement or Sjorgen’s syndrome will not be excluded. Subjects with hypophysitis
stable on physiologic dose steroid will not be excluded from the study.
5.2.2 Turnstile II-- Treatment – Chemotherapy/Cell Infusion Exclusion Criteria 
1. Is currently participating in or has participated in a study of an investigational agent
or using an investigational device within 4 weeks of lymphodepletion (with the
exception of MD Anderson protocol 2004-0069).
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to initiation of
lymphodepletion. Exception: Patients on chronic physiologic dose of steroid equivalent
to prednisone < 10 mg/day is allowed.
3. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to
investigational or standard agents administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to lymphodepletion or who has not recovered (i.e., ≤ Grade 1 or
at baseline) from adverse events due to a previously administered agent.
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-
Note: Subjects with ≤ Grade 2 neuropathy, alopecia, hypophysitis stable on
physiologic dose of steroid equivalent to prednisone < 10 mg/day,
hypothyroidism stable on hormone replacement are an exception to this
criterion and may qualify for the study.
-
Note: If subject received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
5. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at least four
weeks prior to the first dose of trial treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
not using steroids for at least 7 days prior to initiation of lymphodepletion.
7. Has an active autoimmune disease requiring systemic treatment within the past 3
months or a documented history of clinically severe autoimmune disease. Subjects
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Subjects that require intermittent use of bronchodilators or local steroid injections
would not be excluded from the study. Subjects with hypothyroidism stable on
hormone replacement or Sjorgen’s syndrome will not be excluded from the study.
Subjects with hypophysitis stable on physiologic dose of steroid will not be excluded
from the study.
8. Has evidence of interstitial lung disease or has a history of non-infectious pneumonitis
that required steroids or current pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
11. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit through
120 days after the last dose of trial treatment.
12. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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13. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
14. Has received a live vaccine within 30 days prior to the initiation of lymphodepletion.
15. Any active systemic infections requiring intravenous antibiotics, coagulation disorders
or other major medical illnesses of the cardiovascular, respiratory or immune system,
such as abnormal stress thallium or comparable test, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease. PI or his designee shall make
the final determination regarding appropriateness of enrollment.
5.3    Trial Treatments 
5.3.1 Treatment Plan 
36 patients will be treated in two separate arms. Both arms will receive standard 
lymphodepleting chemotherapy and TIL infusion. Arm 1 will receive high dose IL2 after 
lymphodepletion and TIL infusion. Arm 2 will receive low dose IL2 after lymphodepleion 
and TIL infusion. If patients develop stable or partially responding disease, up to 31 doses (2 
years) of MK-3475 will be administered, with the first dose beginning approximately 21 (+7 
days) after TIL infusion. Patients who have a CR to therapy can discontinue MK-3475 if CR 
is appreciated for six months or longer. 
5.3.1.1 T Cell Growth 
T-cells will be expanded in a state-of-the-art GMP facility that will allow compliance with all
FDA regulations regarding investigational cell transfer products. We have demonstrated that
we can successfully expand TIL on the majority of patients and have treated patients with up
to 150 billion TIL. The procedures and reagents for expanding the human TIL cells and the
Certificates of Analysis are contained in the CMC located in the IND office.
5.3.1.2 Lymphodepletion 
All patients will receive lymphodepleting chemotherapy with cytoxan and fludarabine to 
enhance T cell persistence and effectiveness in vivo. Cytoxan will be administered at 60 
mg/kg/day I.V. in 250 ml NS over approximately 2 hours on Days –7 and –6. Mesna 60 
mg/kg with D5W or NS at 125 ml/hr infused intravenously over 24 hours on Days -7 and -6. 
The dose will be based on the patient’s body weight, but to prevent undue toxicity, it will not 
exceed a dose greater than 140% of the maximum ideal body weight per Metropolitan Life 
Insurance Company, Height and Weight Tables (Appendix K). Fludarabine will then be 
infused at 25 mg/m2 IVPB daily over approximately 15-30 minutes on Days –5 to –1. To 
prevent undue toxicity with fludarabine, the dose will be based on body surface area (BSA), 
but will not exceed a dose calculated on surface areas based on body weights greater than 
140% of the maximum ideal body weight per Metropolitan Life Insurance Company, Height 
and Weight Tables (Appendix K). 
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Variations from the lymphodepletion (e.g. infusion times; schedule of treatments, etc) prior 
to day 0 will be documented in the medical record but will not be considered protocol 
violations/deviations. 
5.3.1.3 TIL Infusion 
On day 0, TIL will be infused as an inpatient by I.V. over approximately 15-60 minutes 
depending on the volume of cells to be infused. Up to 150 billion cells will be infused. Tylenol 
(acetaminophen) will be given by mouth before the T-cell infusion to decrease the risk of these 
side effects. 
5.3.1.4 IL-2 Administration 
After completing the T cell infusion, patients will begin treatment with either high or low 
dose interleukin-2 (IL-2) depending on their treatment assignment. 
Patients randomized to receive high dose IL-2 in arm 1 will receive therapy on an inpatient 
basis at the standard dose of 720,000 IU/kg as an intravenous bolus over an approximate 15 
minute period every 8-16 hours for up to 15 doses starting 12-16 hours after T cell infusion. 
Doses will be skipped if patients reach Grade III or IV toxicity due to high dose IL-2, except 
for the reversible Grade III toxicities common to high dose IL-2 such as diarrhea, nausea, 
vomiting, hypotension, skin changes, anorexia, mucositis, dysphagia, or constitutional 
symptoms and laboratory changes (i.e. platelets, creatinine, total bilirubin) as detailed in 
Appendix H. If the toxicity is easily reversed by supportive measures, then additional doses 
may be continued. 
Patients randomized to receive low dose IL-2 in arm 2 will initiate this therapy 
approximately 6 hours after completion of T cell infusion. Therapy will be administered as a 
subcutaneous injection for 14 days. Patients will be allowed to leave the hospital prior to 14 
days as long as their blood counts have recovered adequately (ANC >500, hemoglobin >8, 
platelets >30,000) and they have received educating on injecting the IL-2 while out of the 
hospital. 
5.3.1.5 MK-3475 Administration 
On day +21 (+7 days), patients will receive their first dose of MK-3475 200mg IV over 30 
minutes (- 5 minutes/ + 10 minutes). MK-3475 will be administered every 21 (+/-7) days. 
Patients will receive up to 31 doses (2 years of therapy). 
5.3.2 Dose Selection/Modification 
5.3.2.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.2.1 
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5.3.2.2 Dose Modification 
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities, non- 
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or 
life- threatening AEs as per Table 3 below. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Restarting 
Treatment 
Dose/Schedule for 
Restarting Treatment 
Discontinue 
Subject 
Hematological 
Toxicity 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding Grade
3 neutropenia, 
anemia, and 
thrombocytopenia 
Yes 
Toxicity resolves 
to Grade 0-1 or 
baseline 
May increase the dosing 
interval by 1 week 
Toxicity does 
not resolve within 
12 weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
4 
Yes 
Toxicity resolves 
to Grade 0-1 or 
baseline 
May increase the dosing 
interval by 1 week 
Non-
hematological 
Toxicity 
Note: Exception to be 
treated similar to grade 
1 toxicity 
•
Grade 2 
alopecia
•
Grade 2 fatigue
For additional 
information regarding 
Adverse Events with a 
potential Immune- 
Etiology reference 
Section 5.6.1.1. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity resolves 
to Grade 0-1 or 
baseline 
Clinical AE resolves 
within 4 weeks: Same 
dose and schedule 
(reference Section 
5.7.2.2 for 
recommendations 
regarding pneumonitis) 
Clinical AE does not 
resolve within 4 weeks: 
May increase the dosing 
interval by 1 week for 
each occurrence 
Toxicity does not 
resolve within 12 
weeks of last 
infusion 
3, 4 
Yes 
Toxicity resolves 
to Grade 0-1 or 
baseline 
May increase the dosing 
interval by 1 week for 
each occurrence 
Toxicity does not 
resolve within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or life-
threatening event 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial 
treatment should be discontinued after consultation with the principle investigator. With 
investigator agreement, subjects with a laboratory adverse event still at Grade 2 after 12 
weeks may continue treatment in the trial only if asymptomatic and controlled. For 
information on the management of adverse events, see Section 5.7.2 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 should be discontinued from trial treatment. 
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5.3.3 Timing of Dose Administration 
Administration of lymphodepletion, TIL and IL-2 should be as specified in section 5.3.1.1- 
5.3.1.4. 
Administration of MK-3475 will be as a 30 minute (- 5 mi nut es / + 10 m inut es) 
IV infusion (treatment cycle intervals may be increased due to toxicity as described in Table 
3). 
5.3.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
5.4 
Randomization or Treatment Allocation 
Subjects will be approved for treatment after fulfilling the screening evaluations as specified 
by Turnstile 1 and Turnstile 2 (sections 5.1.1 and 5.1.2). Subjects will then be assigned a 
subject number and will be eligible for randomization. Subject randomization will be 
implemented by MD Anderson Cancer Center’s Clinical Oncology Research System (CORe) 
. Once a subject number has been assigned, it cannot be reassigned to any other patient. 
If the subject is prematurely discontinued from the study without having received the 
prescribed treatment, an additional subject may be enrolled as a replacement subject. 
5.5 
Stratificatio
n 
Patients will be stratified based on tumor stage (stage IIIc/M1a vs. M1b/M1c) and LDH 
(elevated or normal). 
5.6 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. 
5.6.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be documented in the medical record but will 
not be captured in  the case report form (CRF) including all prescription, over-the-counter 
(OTC), herbal supplements, IV medications, supporting prophylactic medication, and fluids. 
Concomitant medications administered during the trial and 30 days after the last dose of trial 
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treatment should be recorded for SAEs and ECIs as defined in Section 7.4.8.1. 
5.6.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than MK-3475
•
Radiation therapy
o
Note:  Radiation therapy to asymptomatic solitary lesion or to the brain may
be allowed
•
Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed..
•
Glucocorticoids for any purpose other than to modulate symptoms from an event of
clinical interest of suspected immunologic etiology. Exception: Patients on chronic
dose of steroid equivalent to Prednisone < 10 mg/day is allowed. Patients requiring
glucocorticoids prior to CT scans are allowed for patients who are sensitive to CT
scans contrast.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.7 
Rescue Medications & Supportive Care 
5.7.1 Prophylaxis 
Patients treated with lymphodepletion are subject to opportunistic infections and appropriate 
infectious agent prophylaxis is required. 
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5.7.1.1 Infection Prevention and Pneumocystis carinii Pneumonia (PCP) Prophylaxis 
Patients will receive levofloxacin at 500 mg daily (or an equivalent antibiotic) until ANC 
recovers to greater than 500/mm3 and the fixed combination of trimethoprim (TMP) and 
sulfamethoxazole (SMX) as double strength (DS) tablet [DS tabs = TMP 160 mg/tab and 
SMX 800 mg/tab] p.o. b.i.d. twice a week. TMP/SMX-DS will be taken by patients beginning 
on Day -7 and continuing for a minimum of 6 months post chemotherapy. Patients with sulfa 
allergies, Pentamidine 300 mg IV will be given starting Day -1 and will be administered every 
21 days for six months after lymphodepletion. If IV Pentamidine is not feasible after discharge, 
Pneumocystis Jirovecii Pneumonia (PCP) prophylaxis can be substituted with oral 
antimicrobials such as Atovaquone as per standard of care for 6 months after 
lymphodepletion.Patients will be given prophylactic antibiotics intravenously during high 
dose IL-2 therapy. 
5.7.1.2 Herpes Virus Prophylaxis 
At the time of the T cell infusion, patients will be administered valtrex 500 mg p.o. daily 
for 6 months after lymphodepletion, if the patient is able to take oral medications. If patient 
needs intravenous medication give acyclovir 5 mg/kg IVPB every 8 hours, which is continued 
until absolute neutrophil count is greater than 1000/ml. Reversible renal insufficiency has 
been reported with IV administered acyclovir but not with oral acyclovir. Neurologic 
toxicity including delirium, tremors, coma, acute psychiatric disturbances, and abnormal 
EEGs has been reported with higher doses of acyclovir. If symptoms occur, a dosage 
adjustment will be made or the drug be discontinued. Acyclovir will not be used 
concomitantly with other nucleoside analogs (e.g. ganciclovir), which interfere with DNA 
synthesis. In patients with renal disease, the dose is adjusted as per product labeling. 
5.7.1.3 Fungal Prophylaxis 
Patients will begin Fluconazole 200 mg p.o. daily with the T cell infusion (Day 0) and 
Continue for 6 months after lymphodepletion.. 
5.7.1.4 Ondansetron hydrochloride (Zofran) 
It will be used to control nausea and vomiting during the chemotherapy preparative regimen. 
It can cause headache, dizziness, myalgias, drowsiness, malaise, and weakness. Less common 
side effects include chest pain, hypotension, pruritus, constipation and urinary retention. 
Consult the package insert for a complete list of side effects and specific dose instructions. 
5.7.1.5 Furosemide (Lasix) 
It will be used to enhance urine output during the chemotherapy preparative regimen with 
cyclophosphamide. Adverse effects include dizziness, vertigo, paresthesias, weakness, 
orthostatic hypotension, photosensitivity, rash and pruritus. Consult the package insert for a 
complete list of side effects and specific dose instructions. 
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5.7.1.6 Empiric Antibiotics 
Patients will start on broad-spectrum antibiotics, either a 3rd or 4th generation cephalosporin 
or a quinolone for fevers ≥38.5 C with an ANC less than 500/mm3. Aminoglycosides should 
be avoided unless clear evidence of sepsis. Infectious disease consultation will be obtained 
from all patients with unexplained fever or any infectious complications. 
5.7.1.7 Blood Product Support 
In order to reduce neutropenia following chemotherapy and T cell infusion, G-CSF will be 
given at 5 μg/kg/day daily subcutaneously until neutrophil counts reach >500/mm3 Using 
daily CBC’s as a guide, the patient will also receive platelets and packed red blood cells 
(PRBC’s)  as  needed.    Attempts  will  be  made  to  keep  Hb  >8.0  gm/dl,  and  platelets 
>20,000/ml. Leukocyte filters will be utilized for all blood and platelet transfusions to
decrease sensitization to transfused WBC’s and decrease the risk of CMV infection.
Irradiated blood and blood products should be used.
5.7.2 Supportive Care Guidelines for MK-3475 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below. More detailed 
instructions on management of events of clinical interest and immune-related adverse events 
can be found in Appendix G 
•
Diarrhea: Subjects should be carefully monitored for signs and symptoms of
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or
without fever) and of bowel perforation (such as peritoneal signs and ileus). In
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are
persistent and/or severe, endoscopic evaluation should be considered.
o
In subjects with severe enterocolitis (Grade 3), MK-3475 will be permanently
discontinued and treatment with systemic corticosteroids should be initiated at a
dose of 1 to 2 mg/kg/day of prednisone or equivalent. When symptoms improve
to Grade 1 or less, corticosteroid taper should be started and continued over at
least 1 month.
o
In subjects with moderate enterocolitis (Grade 2), MK-3475 should be withheld and
anti-diarrheal treatment should be started. If symptoms are persistent for more than one
week, systemic corticosteroids should be initiated (e.g., 0.5 mg/kg/day of prednisone or
equivalent). When symptoms improve to Grade 1 or less, corticosteroid taper should be
started and continued over atleast 1 month.  Regarding guidelines for continuing
treatment with MK-3475, see Section 5.3.2.2 Table 3.
o
All subjects who experience diarrhea should be advised to drink liberal quantities of
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be
substituted via IV infusion.
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•
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration
should be given in subsequent cycles to the administration of prophylactic antiemetic
therapy according to standard institutional practice. Subjects should be strongly
encouraged to maintain liberal oral fluid intake.
•
Anti-infectives: Subjects with a documented infectious complication should receive oral
or IV antibiotics or other anti-infective agents as considered appropriate by the treating
investigator for a given infectious condition, according to standard institutional practice.
•
Immune-related adverse events: Please see Section 5.7.2.1 below and the separate
guidance document in the administrative binder regarding diagnosis and management of
adverse experiences of a potential immunologic etiology.
•
Management of Infusion Reactions: Acute infusion reactions (which can include
cytokine release syndrome, angioedema, or anaphylaxis) are different from
allergic/hypersensitive reactions, although some of the manifestations are common to
both AEs. Signs and symptoms usually develop during or shortly after drug infusion and
generally resolve completely within 24 hours of completion of infusion. Signs/symptoms
may include: Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint
pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue
(asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle
pain); 
Nausea; 
Pruritus/itching; 
Rash/desquamation; 
Rigors/chills; 
Sweating
(diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to
treatment); Urticaria (hives, welts, wheals); Vomiting.
Table 4 Treatment guidelines for subjects who experience an infusion reaction associated 
with administration of MK-3475. Additional guidance information can be found in Appendix 
G. 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.7.2.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the MK-3475 compound, 
its mechanism of action, and reported experience with immunotherapies that have a similar 
mechanism of action. Special attention should be paid to AEs that may be suggestive of 
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potential irAEs. An irAE can occur shortly after the first dose or several months after the 
last dose of treatment. If an irAE is suspected, efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin or other etiologic causes prior to labeling an adverse event as an 
irAE. Information on how to identify and evaluate irAEs has been developed and is included 
in the Event of Clinical Interest and Immune-Related Adverse Event Guidance Document 
located in the Administrative Binder. 
Further details on management of events of clinic interest and immune related adverse events 
can be found in Appendix G. 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 5. 
Table 5  General Approach to Handling irAEs 
irAE 
Withhold/Discontinue MK- 
3475? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 
Consider  systemic  corticosteroids  in  addition  to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold MK-3475 
Discontinue 
if 
unable 
to 
reduce corticosteroid dose to < 
10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment. May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
5.7.2.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving MK-3475 and 
have an evaluation. The evaluation may include bronchoscopy and pulmonary function tests 
to rule out other causes such as infection. If the subject is determined to have study drug 
associated pneumonitis, the suggested treatment plan is detailed in Table 6. Additional 
guidance information can be found in Appendix G. 
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Table 6 Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue MK- 
3475? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold MK-3475, may 
return to treatment if improves 
to Grade 1 or resolves within 
12 weeks 
Systemic corticosteroids are indicated.  Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue MK-3475 
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Refer to 
the Event of Clinical Interest and Immune-related 
Adverse Event Guidance Document for additional 
recommendations. 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
•
First episode of pneumonitis
o
May increase dosing interval by one week in subsequent cycles
•
Second  episode  of  pneumonitis  –  permanently  discontinue  MK-3475  if  upon
rechallenge subject develops pneumonitis ≥ Grade 2
5.8 
Diet/Activity/Other Considerations 
5.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.8.2 Contraception 
MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm. Non-pregnant, non- 
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study. The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after 
the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
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(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Sections 7.4.3 and 7.4.4. If 
there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
5.8.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on this protocol, the subject will 
immediately be removed from the study. The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the MD Anderson IND office without delay 
and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the MD 
Anderson IND office. If a male subject impregnates his female partner the study personnel 
at the site must be informed immediately and the pregnancy reported to the MD Anderson 
IND office as described above and in Section 7.4.7. 
5.8.4 Use in Nursing Women 
It is unknown whether MK-3475 is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
5.9 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.3.1 – Other Procedures. A subject 
must be discontinued from the trial for any of the following reasons: 
•
The subject or legal representative (such as a parent or legal guardian) withdraws
consent.
•
Confirmed radiographic disease progression
Note: A subject may be granted an exception to continue on treatment with 
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confirmed radiographic progression if clinically stable or clinically improved as 
per the investigator’s discretion 
•
Unacceptable adverse experiences as described in Section 5.7.2.1
•
Intercurrent illness that prevents further administration of treatment
•
Investigator’s decision to withdraw the subject
•
The subject has a confirmed positive serum pregnancy test
•
Noncompliance with trial treatment or procedure requirements
•
The subject is lost to follow-up
•
Administrative reason
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.4 (Visit Requirements). After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.4.3-7.4.4.  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up. After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or 
the end of the study, whichever occurs first. 
5.10 Subject Replacement Strategy 
Subjects on this trial will be replaced if they are unable to receive lymphodepletion, TIL 
infusion, IL-2, or the first dose of MK-3475. 
5.11 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
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6.0 TRIAL FLOW CHART 
Turnstile I 
Screening 
Turnstile II 
Screening 
(-28 to -1 
days) 
Inpatient 
Hospitalization for 
Lymphodepletion, 
TIL and IL-2 
Day +3 
(±24 hours) 
Day +7 
(±2 days) 
Week 3 
Day +21 
(+7 days) 
Week 6 
Day +42 
(±7 days) 
Week 9 
Day +63 
(±7 days) 
Week 12, 15, 
18, 24, 27, 30, 
36, 39, 42, 48, 
51, 54, 60, 63, 
66, 72, 75, 78, 
84, 87, 90 
(±7 days) 
Week 21, 
33, 45, 
57, 69, 
81, 93 
(±7 days) 
End of 
Treatment 
Post 
Treatment 
(every 12 
weeks) 
(±7 days) 
Survivor 
Follow 
Up 
Study Assessments 
Informed consent 
x 
x 
Eligibility Criteria 
x 
x 
Infectious Disease 
Panel a
x 
Demographics 
x 
Medical History 
x 
x 
Concurrent Medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Review Adverse Events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital Signs/ECOG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CBC with Differential
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine or serum B-HCG b
x 
x 
x 
PT/INR, PTT 
x 
Comprehensive Serum 
Chemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
x 
TSH, fT4, T3 
x 
x 
x 
x 
CMV PCR c 
x 
x 
PFTs 
x 
Stress Echocardiogram 
x 
12 Lead EKG 
x 
x 
Tumor Imaging (CT or 
PET) 
x 
x 
x 
x 
x 
x 
CNS Imaging (CT or 
MRI)
x 
x 
x 
x 
x 
x 
Medical Photography d 
x 
x 
x 
x 
x 
FACT-G and FACT-
Melanoma
x 
x 
x 
Tumor Biopsy 
x 
x 
x 
x 
x 
Correlative Studies 
Blood Collection 
x 
x 
x 
x 
x 
x 
x 
x 
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Turnstile I 
Screening 
Turnstile II 
Screening 
(-28 to -1 
days) 
Inpatient 
Hospitalization for 
Lymphodepletion, 
TIL and IL-2 
Day +3 
(±24 hours) 
Day +7 
(±2 days) 
Week 3 
Day +21 
(+7 days) 
Week 6 
Day +42 
(±7 days) 
Week 9 
Day +63 
(±7 days) 
Week 12, 15, 
18, 24, 27, 30, 
36, 39, 42, 48, 
51, 54, 60, 63, 
66, 72, 75, 78, 
84, 87, 90 
(±7 days) 
Week 21, 
33, 45, 
57, 69, 
81, 93 
(±7 days) 
End of 
Treatment 
Post 
Treatment 
(every 12 
weeks) 
(±7 days) 
Survivor 
Follow 
Up 
Study Assessments 
MK-3475 Administration 
x 
x 
x 
x 
x 
Survival Follow-Up 
Review e 
x 
a Infectious disease panel: Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Virus Antibody, HIV 1/HIV 2 Antibody, HTLV I/II Antibody, RPR Qual, CMV Antibody, 
West Nile Virus, Chagas Disease and EBV Panel 
b Screening urine or serum B-HCG must be performed within 14 days of initiating lymphodepletion 
c We will monitor all patients receiving TIL with serum CMV PCR testing at day 3 (+/-24 hours) post TIL infusion and 3 weeks (+/-7 days) after TIL infusion. 
d Medical photography only if the patient has cutaneous disease 
e The patient will be contacted by phone every 3 months. 
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7.0 
TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
Feeder cells will be CMV negative if pre-treatment testing of the patient reveals absence of 
CMV seropositivity. If a patient is CMV positive at baseline, CMV positive feeder cells may 
be utilized. Pools of feeder cells from CMV seropositive patients will be tested by PCR to 
assess for the presence of CMV in the feeder cell population. Those feeder cells that have 
undetectable levels of CMV by PCR will be deemed eligible to be used as feeders in the TIL 
expansion process. We will monitor all patients receiving TIL with serum CMV  PCR testing 
at day 3 (+/-24 hours) post TIL infusion and 3 weeks (+/-7 days) after  TIL infusion. CMV 
PCR blood testing is drawn in a single 10mL purple top tube. The test will be performed at 
MDA through the molecular diagnostics lab. If there is evidence of CMV reactivation as 
evidenced by the CMV pcr, infectious disease specialist will be consulted and further 
management or therapy will be per expert recommendations. 
7.1.2 Administrative Procedures 
7.1.2.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.2.2 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.   The subject or his/her legally acceptable 
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representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and MDA IND office requirements. 
7.1.2.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial. 
7.1.2.4 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
7.1.3 Prior and Concomitant Medications Review 
7.1.3.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial in subject’s medical record.  
7.1.3.2 Concomitant Medications 
The investigator or qualified designee will document  medication in medical record, if any, 
taken by the subject during the trial. All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 7.2. 
7.1.4 Disease Details and Treatments 
7.1.4.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
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7.1.4.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.4.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment. 
7.1.5 Assignment of Screening Number 
Patients will be assigned a screening number which will be determined by the order in which 
the patients initiate screening procedures. For the purposes of this study at M. D. Anderson 
Cancer Center, the Protocol Data Management System (PDMS) will be employed. All 
patients will be registered in MD Anderson Cancer Center’s Clinical Oncology Research 
System (CORe) utilizing a two-turnstile registration before any study specific tests are 
performed. 
7.1.6 Assignment of Randomization Number 
Subjects will be approved for treatment after fulfilling the screening evaluations as specified 
by Turnstile 1 and Turnstile 2 (section 5.1.1 and 5.1.2). Subjects will then be assigned a 
subject number and will be eligible for randomization. Subject randomization will be 
implemented by CORe. Once a subject number has been assigned, it cannot be reassigned 
to any other patient. If the subject is prematurely discontinued from the study without having 
received the prescribed treatment, an additional subject may be enrolled as a replacement 
subject. 
7.1.7 Trial Compliance (Medication/Diet/Activity/Other) 
Assurance of patient trial compliance will be assessed at each clinic visit by the clinical trial 
nurse and treatment staff. 
7.2    Clinical Procedures/Assessments 
7.2.1   Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Appendix A). Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
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determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.7.2.1, Appendix G and the separate guidance document in the 
administrative binder regarding the identification, evaluation and management of AEs of a 
potential immunological etiology. 
Please refer to section 7.4.5 for detailed information regarding the assessment and recording 
of AEs. 
7.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, 
7.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration. 
7.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
During the lymphodepleting chemotherapy regimen and high dose IL-2 therapy, patients will 
be monitored with vital signs at baseline, approximately every 15 minutes (+/- 10 minutes) 
during cell infusion and after cell infusion hourly (+/- 30 minutes) for 4 hours after the 
infusion. 
7.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified 
in the Trial Flow Chart. See Appendix B for ECOG Status definitions. 
7.2.6 12 lead EKG 
12-lead ECG will be obtained as indicated in the Times and Events Tables in Section 6.0.
Each 12-lead ECG will be performed after the subject has rested at least five minutes in a
semi-recumbent or supine position.
Those QTc values greater than 480msec as calculated by the machine must be confirmed 
manually using Bazett’s formula given below: 
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If there are any clinically significant abnormalities including but not limited to a 
QTcB > 500msec, confirm with two additional ECGs taken at least 5 minutes 
apart. 
7.2.7 Tumor Imaging and Assessment of Disease 
Complete evaluation of evaluable lesions with physical examination and appropriate CT 
scans (chest, abdomen, pelvis at least, ct neck if clinically warranted) or whole body PET/CT 
will be performed approximately at 9 weeks (+/- 7 days) after TIL infusion and then at 12 
week intervals (+/- 7 days) for the duration of therapy. After patients have  completed protocol 
therapy, repeat imaging evaluations will continue at 12 week intervals. 
For patients with cutaneous disease, medical photography will be obtained at baseline and 
then at the time of each imaging evaluation. 
Tumor response to therapy in this study will be done using RECIST 1.1 criteria. The immune-
related response criteria (irRC) which is a modified version of WHO criteria will also be 
recorded but determination of the primary endpoint will be via RECIST 1.1 (Appendix D) 
[53]. Patient management will be based on irRC specifications. Tumor measurements for 
determining irRC response will be performed by each patient’s individual attending 
physician. Tumor measurements will be documented in the patient’s research chart and within 
the patient database maintained by the assigned data coordinator. 
Measurable Lesions are lesions that can be accurately measured in two perpendicular 
diameters, with at least one diameter > 10 mm as per irRC and RECIST 1.1 criteria. The 
area will be defined as the product of the largest diameter with its perpendicular. Skin 
lesions can be considered measurable. Cutaneous lesions that are > 5 mm in diameter can be 
considered measurable. 
Non-Measurable (evaluable) Lesions are all other lesions, including unidimensionally 
measurable disease and small lesions. 
7.2.8 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Peripheral blood samples for immune monitoring including flow cytometry and tracking 
persistence of T cell clones will consist of 10cc in a red top tube and up to 50cc in green top 
tubes. These samples will be collected prior to tumor harvest and/or excision, prior to 
lymphodepletion, at day +7 (+/- 2 days) and just prior to first dose (+ 7 days) and second 
dose (+/- 7 days) of MK-3475. These samples will also be collected at the time of each 
restaging scan and at the time of documented progression. 
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Tumor biopsies will be performed during screening for Turnstile 2 and then at day +21 (+/-7 
days) just prior to first dose of anti PD-1 antibody and at day + 42 (+/- 7 days) just prior to 
second dose of anti PD-1 antibody. Biopsy of residual disease will also be performed at week 
9 at the time of restaging scans. Optional biopsies for persistent disease will then be performed 
every 12 weeks at the time of restaging scans. These biopsies will be critical to the 
immunologic correlative studies which are planned (see section 4.2.2.2). Potential biopsy 
types include punch, incisional, excisional or image-guided cores depending on the 
individual patient scenario. 
7.2.9 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below in Table 7. During the preparative regimen and high dose IL-2 therapy, 
patients will have a complete blood count (CBC) and electrolytes every 1 to 2 days of 
treatment. Patients will have CBC, electrolytes and liver function test prior to each MK-3475 
infusion. 
Interval laboratories may be performed at a patient’s local (non-MD Anderson) laboratory if 
this is deemed to be in the patient’s best interest. These laboratory studies must be reviewed 
by the PI/treating MDACC physician to determine clinical significance of these studies.
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Table 7  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity 
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal) 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
(CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
Uric Acid 
Calcium 
Chloride 
Blood for correlative studies 
Glucose 
Phosphorus 
Potassium 
Sodium 
Magnesium 
Total Bilirubin 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
Total protein 
Blood Urea Nitrogen 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
‡ If considered standard of care in your region. 
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7.3 Other Procedures 
7.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.4.5 - Assessing 
and Recording Adverse Events. Subjects who complete 12 months of treatment with MK-
3475 may discontinue treatment. After discontinuing treatment following assessment of CR, 
these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.4.3) and then proceed to the Follow-Up Period of the study (described in Section 7.4.4). 
7.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.4.2.1 Screening 
All patients must sign an informed consent form and a negative pregnancy test (urine or 
serum) must be documented for women of childbearing potential before enrollment in 
Turnstile I and being registered in PDMS. Once enrolled into Turnstile I (2004-0069), patients 
will be screened for Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Virus 
Antibody, HIV 1/HIV 2 Antibody, HTLV I/II Antibody, RPR Qual, CMV Antibody, West 
Nile Virus, Chagas Disease and EBV Panel, within 30 days of signing the informed consent. 
If patient’s tests are found to be positive for prior (inactive) infection with Hepatitis A, 
Hepatitis B, CMV or EBV, patients will still be eligible for treatment on protocol 2014-
0922. If patient’s tests are found to be positive for all other tests, they will not be eligible for 
Turnstile II. If cultures come back positive after TIL Harvest, they will be terminated. These 
infectious disease tests will be drawn per the specifications in protocol 2004-0069 and 
won’t be repeated for this specific treatment protocol. 
While T-cells are being grown (up to 8 weeks), patients may be treated with alternative 
therapies. Investigational agents can be used as long as there is a 4 week wash-out period 
prior to initiation of lymphodepletion. 
Other screening procedures will include: 
1. Full physical exam including vital signs and documentation of ECOG performance
status
2. Measurable disease as defined by irRC RECIST 1.1 on baseline CT chest, abdomen,
pelvis (and neck if clinically indicated) or MRI of disease site
3. MRI brain or CT brain with contrast
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4. Laboratory assessments as depicted in Section 7.2.2 to assess for adequate bone
marrow and organ function
5. Dobutamine stress echocardiogram showing absence of inducible ischemia and LVEF
over 50%
6. Pulmonary function tests with FEV1 > 65%
7. Biopsy of at least one site of metastatic disease that is separate from the target lesion
8. Peripheral blood sample for immune monitoring including flow cytometry and tracking
the persistence of T cell clones will consist of 10cc in a red top tube and 50cc’s in
green top tubes
7.4.1.1 Screening Period 
The screening period will last for up to 28 days after signing the informed consent document. 
7.4.2 Treatment Period 
Patients will be seen in clinic within 1 week of initiation of lymphodepleting chemotherapy 
to review screening evaluations including labs and scans, for updated documentation of 
concurrent medications and baseline AEs and for full physical exam. 
Before the treatment starts and at every 3 month intervals, the patient will be asked to 
complete two quality of life questionnaires. It should take about 15 minutes to complete the 
questionnaires (FACT-G, FACT-Melanoma, Appendix E, F). 
Patients will be admitted to the hospital seven days prior to the planned TIL infusion to 
initiate lymphodepleting chemotherapy. Patients will be seen daily in the hospital throughout 
the course of lymphodepletion, TIL infusion and IL-2 administration. Patients in Arm 1 must 
stay in the hospital throughout the course of HD-IL2 until they have recovered from the 
toxicity of IL-2 and bone marrow function has recovered (neutrophil count is >500/mm3, 
hemoglobin is >8g/dL and platelets are > 30,000/mm3). Patients on Arm 2 will be eligible 
for hospital discharge while still on the 14 days of low dose SC IL-2 if neutrophil count is 
>500/mm3, hemoglobin is >8g/dL and platelets are > 30,000/mm3.
Patients in both arms will initiate MK-3475 on day 21 (+ 7 days) after TIL infusion and 
subsequently will be seen in clinic every 3 weeks prior to each planned dose of MK-3475. 
Complete evaluation of evaluable lesions with physical examination and appropriate CT 
scans (CT chest, abdomen, pelvis) or PET/CT will be performed approximately at 9 weeks 
(+/- 7 days) after TIL infusion and then at 12 week intervals (+/- 7 days) for the duration of 
therapy. After patients have completed protocol therapy, repeat imaging evaluations will 
continue at 12 week intervals. For patients with cutaneous disease, medical photography will 
be obtained at baseline and then at the time of each imaging evaluation. 
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Peripheral blood samples for immune monitoring including flow cytometry and tracking 
persistence of T cell clones will consist of 10cc in a red top tube and up to 50cc in green top 
tubes. These samples will be collected prior to tumor harvest and/or excision, prior to 
lymphodepletion, at day +7 (+/- 2 days) and just prior to first dose (+ 7 days) and second 
dose (+/- 7 days) of MK-3475. These samples will also be collected at the time of each 
restaging scan and at the time of documented progression. 
7.4.3 Post-Treatment Visits 
After completion of the one year duration of therapy, follow up examinations and tests will 
be determined by the treating physician. It is recommended that follow up visits and restaging 
scans be performed approximately every 12 weeks (± 7 days) for three years after completion 
of protocol therapy. 
After that time, we will send the patient a questionnaire (FACT-G, FACT-Melanoma) 
(Appendix E, F) to get information regarding their quality of life for the next five years.  For 
this reason, we will ask the patients to continue to provide us with a current address and 
telephone number, even after completion of this research study. 
7.4.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8-12 weeks by radiologic 
imaging to monitor disease status. Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death or end of the study. Information regarding post-study anti-neoplastic treatment will be 
collected if new treatment is initiated. 
7.4.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
approximately every 3 months to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
7.4.5 Assessing and Recording Adverse Events 
This study will utilize the National Cancer Institute Common Terminology Criteria (CTC) 
for Adverse Events version 4.0 for toxicity and Adverse Event reporting. A copy of the 
CTCAE version 4.0 can be found in Appendix A. All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. 
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 
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MD Anderson IRB will review serious adverse events as they are submitted. 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 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. 
The use of the nonmyeloablative regimen in this protocol is a major procedure, which entails 
serious discomforts and hazards for the patient. Although it is anticipated that this protocol is 
relatively safe because of the expected recovery of the patients’ bone marrow within 2 to 4 
weeks, fatal complications are possible. It is therefore only appropriate to carry out this 
experimental procedure in the context of life threatening metastatic cancer. The major 
hazards are infection and disease progression. The major discomforts are nausea, mucositis, 
anorexia, diarrhea, fever and malaise. Side effects of common drugs used in this 
nonmyeloablative regimen include: 
1. Cyclophosphamide: Marrow suppression, nausea, mucositis, rash, hemorrhagic
cystitis, myocardial damage, alopecia, infertility, nausea and vomiting, SIADH.
2. Fludarabine: Myelosuppression, fever and chills, nausea and vomiting, malaise,
fatigue, anorexia, weakness, neurologic toxicity, and interstitial pneumonitis. Serious
opportunistic infections have occurred in CLL patients treated with fludarabine.
3. Antimicrobials in general: Allergic reactions, renal impairment, nausea, vomiting,
hepatic damage, marrow suppression.
4. High Dose IL-2: A variety of side effects have been associated with high-dose IL-2
administration in our experience at the NCI and a listing of these side effects in 283
patients who received 447 treatment courses are listed in Appendix H.
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol- 
specified procedure, whether or not considered related to the medicinal product or protocol- 
specified procedure. Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
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within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
All adverse events suspected to be due to the combination of TIL with anti pd-1 (for both 
cohorts of patients) and low dose IL-2 (only for patients in Arm B) will be recorded from the 
time the consent form is signed through 90 days following cessation of treatment and at each 
examination on the Adverse Event case report forms/worksheets. Adverse events resulting 
from lymphodepletion and high dose IL-2 will not be recorded. The reporting timeframe for 
adverse events meeting any serious criteria is described in section 7.4.8.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention. If the subject requires a blood draw, fresh tumor 
biopsy etc., the subject is first required to provide consent to the main study and AEs will be 
captured according to guidelines for standard AE reporting. 
7.4.6 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
MDA IND office 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose. No specific information is available on 
the treatment of overdose of MK-3475. In the event of overdose, MK-3475 should be 
discontinued and the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 48 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.4.7 Reporting of Pregnancy and Lactation to the MDA IND office 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
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that occurs during the trial or within 120 days of completing the trial completing the trial, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier. All subjects and female partners of male subjects who become pregnant 
must be followed to the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events (Important 
Medical Events). If the pregnancy continues to term, the outcome (health of infant) must 
also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.4.8 Immediate Reporting of Adverse Events to the MDA IND office 
7.4.8.1 Serious 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:
•
Results in 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.Results in persistent or
significant disability/incapacity;
•
Results in or prolongs an existing inpatient hospitalization;
•
A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions.
•
Is 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
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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 MDACC IRB. 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 90 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 90 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure that 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. 
7.4.8.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 48 hours to the Sponsor and within 2 working days to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 7.4.6 - Definition of an Overdose for
This Protocol and Reporting of Overdose to the IND office, that is not associated with
clinical symptoms or abnormal laboratory results.
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2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper
limit of normal and, at the same time, an alkaline phosphatase lab value that is greater than
2X the upper limit of normal, as determined by way of protocol-specified laboratory testing
or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require
an additional evaluation for an underlying etiology. The trial site guidance for
assessment and follow up of these criteria can be found in the Investigator Trial File
Binder (or equivalent).
3. In the event a subject develops any of the following AEs, a detailed narrative of the event
should be reported as an ECI to the MDA IND office within 48 hours
a. Grade ≥ 3 diarrhea
b. Grade ≥ 2  colitis
c. Grade ≥ 2 pneumonitis
d. Grade ≥ 3 hypo- or hyperthyroidism
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune- 
related event. Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related. 
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the Merck’s product, must be reported within 48 hours to the IND office. 
7.4.9 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0 (Appendix A). Any 
adverse event which changes CTCAE grade over the course of a given episode will have 
each change of grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Table 8  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe  or  medically significant but not immediately life-threatening; hospitalization or  prolongation or  hospitalization indicated; 
disabling; limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
†Results in death; or 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
Is a new cancer; (that is not a condition of the study) or 
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken 
Did the adverse event cause the Merck product to be discontinued? 
Relationship  to 
test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
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Relationship 
to Merck 
product 
(continued) 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
reasonable OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) 
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7.4.10 Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations. 
 
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 “University of Texas 
M. D. Anderson Cancer Center Institutional Review Board Policy on Reporting Serious Adverse 
Events”. 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. 
 
The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for reporting to the IND 
Office. 
 
 
 
8.0 STATISTICAL ANALYSIS PLAN 
 
8.1 
Overview and Sample Size Justification 
 
The primary objective of this trial is to assess the overall response rate (ORR) in each arm. A total of 
36 patients will be randomized in a 1:1 ratio to the HD-IL2 and LD IL-2 arms.  With 18 patients in an 
arm, half the width of a two-sided 95% confidence interval around the ORR will be a maximum of 
23%. Secondary endpoints include safety, OS, PFS, and blood and tumor biomarkers. Secondary 
analyses will consist of comparing secondary endpoints between the treatment arms as well as assessing 
the association between endpoints and clinical and disease covariates of interest. As the trial proceeds, 
the ORR will be monitored separately in each arm to assure that if it is too low, accrual onto the arm 
will stop. 
 
8.2 
Primary Analyses 
 
The ORR will be computed separately by arm and presented with exact 95% confidence intervals. 
 
8.3 
Secondary Analyses 
 
The ORR will be compared between the two treatment arms by using Fisher’s exact test. Safety 
parameters will be compared between the arms by using Wilcoxon rank-sum tests for continuous 
parameters and Fisher’s exact tests for categorical parameters. The method of Kaplan and Meier will be 
used to estimate the distributions of OS and PFS, and distributions will be compared between arms by 
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using the log-rank test.  Cox regression analysis will be used to assess the association between disease 
and clinical covariates of interest and OS and PFS. The association between ORR and the same 
covariates will be assessed by using logistic regression. For the blood and tumor biomarkers collected 
over time, we will use a generalized linear mixed model (GLMM) approach to account for intra-patient 
correlation. 
8.4 
Futility Monitoring 
The primary ORR endpoint in this trial will be monitored using a Bayesian sequential monitoring rule 
(Thall et all, 1995).  If in either arm, there is a high probability that the ORR is less than 40%, accrual 
onto the arm will be stopped.  Patients will be monitored in cohorts of size 3. We will enroll a 
minimum of 6 patients in an arm before stopping. The following stopping rules and boundaries were 
developed using the multc99 application (version 2.0) from the Biostatistics department. Accrual will 
be stopped early in any arm if in that arm 
Pr [100-day ORR < 40% | data] > 0.95 
That is, if we determine that there is a greater than 95% chance that the ORR in an arm is less than 
40%, accrual into the arm will be stopped. We assume a beta (0.8, 1.2) prior distribution for the ORR 
rate (historical prior distribution based on 1000 patients) in each arm, which has a mean of 0.40 
corresponding to the target ORR. Stopping boundaries corresponding to this probability criterion are to 
terminate accrual in an arm if: 
Number of Patients 
Evaluated for ORR 
Stop the arm if 
this many responses 
6 
0 
9 
0-1
12 
0-2
15 
0-2
18 
Always Stop (arm complete) 
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This stopping rule was chosen to assure that the probability that an arm will stop early would be 
between 10% and 15% if the true ORR rate is as low as 40%. The operating characteristics of this rule 
are shown in the table below. 
Table 1. Operating Characteristics for ORR Monitoring Rule 
If the true ORR 
in an arm is… 
Early Stopping 
Probability 
Arm Sample Size 
25th, 50th, 75th percentiles 
20% 
0.605 
6 
12 
18 
30% 
0.305 
12 
18 
18 
40% 
0.119 
18 
18 
18 
50% 
0.035 
18 
18 
18 
60% 
0.008 
18 
18 
18 
The  monitoring  rules  will  be  assessed  by  the  study  team  with  assistance  as  necessary  from  the 
Department of Biostatistics at MD Anderson Cancer Center. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 9. 
Table 9 Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Injection 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, and the trial site personnel are not blinded to treatment. 
Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists 
are not provided. 
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9.4 
Storage and Handling Requirements 
Clinical supplies must be stored  in  a secure, limited-access location under the storage conditions 
specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
The drug product is stored under refrigerated conditions (2ºC- 8ºC). 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining at 
the conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to ar r a n g e 
fo r disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
For All Studies 
By signing this protocol, the investigator recognizes that certain personal identifying information with 
respect to the investigator, and all subinvestigators and study site personnel, may be used and disclosed 
for study management purposes, as part of a regulatory submissions, and as required by law. This 
information may include: 
•
name, address, telephone number, and email address;
•
hospital or clinic address and telephone number;
•
curriculum vitae or other summary of qualifications and credentials; and
•
other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the IND office. 
Additionally, the investigator’s name and business contact information may be included when reporting 
certain serious adverse events to regulatory agencies or to other investigators. By signing this protocol, 
the investigator expressly consents to these uses and disclosures. 
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10.2 Compliance with Financial Disclosure Requirements 
10.3 By signing this protocol, the investigator agrees to provide to MD Anderson accurate 
financial information to allow MD Anderson to submit complete and accurate certification 
and disclosure statements as required by U.S. Food and Drug Administration regulations 
(21 CFR Part 54).Compliance with Law, Audit and Debarment 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 
1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), MD Anderson is solely responsible for determining 
whether the trial and its results are subject to the requirements for submission to the Clinical Trials Data 
Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially 
appropriate trials for their disease conditions and pursue participation by calling a central contact 
number for further information on appropriate trial locations and trial site contact information. 
10.5 Quality Management System 
By signing this protocol, MD Anderson agrees to be responsible for implementing and maintaining 
quality control and quality assurance systems with written SOPs to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations relating to 
the conduct of the clinical study. 
10.6 Data Management 
For the purposes of this study at M. D. Anderson Cancer Center, the Protocol Data Management System 
(PDMS) will be employed. All patients will be registered in CORe utilizing a two-turnstile registration 
before any study specific tests are performed. The continual reassessment method (CRM) used in phase 
I will be implemented using the Biostatistics Department Clinical Trial Conduct Website. 
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52 Caligiuri, M.A., C. Murray, R.J. Soiffer, T.R. Klumpp, M. Seiden, K. Cochran, C. Cameron, C. Ish, 
L. Buchanan, D. Perillo, and et al. Extended continuous infusion low-dose recombinant interleukin-
2 in advanced cancer: prolonged immunomodulation without significant toxicity. J Clin Oncol
1991; 9:2110-2119.
53 Wolchok JD, Hoos A, O’Day S, et al: Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Cancer Res 2009: 15; 7412-20 
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12.0 APPENDICES A-N in PDOL 
APPENDIX O. Events of Clinical Interest 
Colitis (reported as ECI if ≥ Grade 2) 
Bowel Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
GI Perforation 
Necrotizing Colitis 
Diarrhea (report as ECI if ≥ Grade 3 or any grade resulting in dose modification) 
Endocrine (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid Disorder 
Thyroiditis 
Eye 
Uveitis (report as ECI if ≥ Grade 2 or any grade resulting in dose modification) 
Hepatic (reported as ECI if ≥ Grade 2 or any grade requiring dose modification) 
Hepatitis 
Hepatitis, Autoimmune 
Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute Interstitial Pneumonitis 
Interstitial Lung Disease 
Pneumonitis 
Renal (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification) 
Nephritis 
Nephritis Autoimmune 
Renal Failure 
Renal Failure, Acute 
Skin (always reported as ECI regardless of grade) 
Dermatitis Exfoliative 
Erythema Multiforme 
Stevens-Johnson Syndrome 
Toxic Epidermal Necrolysis 
Skin (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Vitiligo 
Other (The following should always be reported as an ECI, regardless of grade) 
Autoimmune Neuropathy 
Demyelinating Polyneuropathy 
Guillain-Barre 
Myasthenia Gravis like syndrome 
Non-infectious myocarditis 
Non-infectious pericarditis 
Pancreatitis 
Rapid onset of Grade 3 fatigue in 
the absence of disease progression 
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REFERENCES 
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nature Reviews
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2. Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint
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3. Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events and
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366:2443-2454.
6. Brahmer JR, Tykodi SS, Chow  LQM,  Hwu  WJ, et al. Safety and Activity of  Anti–PD-L1
Antibody in Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465.
7. Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase
II  study comparing the  tolerability and  efficacy of  ipilimumab administered with or  without
prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res
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8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the
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9. Phan  GQ,  Weber JS,  and  Sondak  VK. 
CTLA-4 Blockade with Monoclonal Antibodies in
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10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse
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http://www.yervoy.com/hcp/rems.aspx
11. Bristol-Myers  Squibb:  YERVOY  (ipilimumab)  prescribing  information  revised  March  2011.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf
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12. Janssen Biotech, Inc.: REMICADE (Infliximab) prescribing information revised September
2011.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_Appr
ovalHistory#labelinfo
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