A Phase I/II Study of the Safety, Tolerability, and Immunoregulatory Activity of Mogamulizumab (KW-0761) in Subjects With Advanced and/or Metastatic Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors, Metastatic Solid Tumors
Sponsor: Memorial Sloan Kettering Cancer Center

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A Phase I/II Study of the Safety, Tolerability, and Immunoregulatory Activity of 
Mogamulizumab (KW-0761) in Subjects with Advanced and/or Metastatic Solid Tumors 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Jedd Wolchok, MD, PhD 
Medicine/ITC 
Co-Principal 
Investigator(s)/Department: 
George Plitas, MD 
Surgery/Breast 
Investigator(s)/Department: 
Alexander Lesokhin, MD  
Neil Segal, MD, PhD 
Margaret Callahan, MD, PhD 
Sandra D’Angelo, MD 
Matthew Hellmann, MD 
Karen Autio, MD 
Dmitriy Zamarin, MD 
Alexandra Snyder Charen, MD 
Michael Postow, MD 
Ruth-Ann Gordon, NP 
Marykate Kasler, NP 
Tiffany DeSadier, NP 
Paul Sabbatini, MD 
Charlotte Ariyan, MD, PhD 
Alex Drilon, MD 
David Hyman, MD 
Mark Bluth, MD 
Stephen Solomon, MD 
Katherine Panageas, PhD 
Travis Hollman, MD, PhD 
Natasha Rekhtman, MD, PhD 
Laura Tang, MD, PhD 
Yong Hannah Wen, MD, PhD 
Mario Lacouture, MD 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Nursing 
Nursing 
Nursing 
Medicine/Gynecologic 
Surgery/GMT 
Medicine/DTC 
Medicine/DTC 
Radiology 
Radiology/Interventional Radiology 
Epidemiology & Biostatistics 
Pathology 
Pathology 
Pathology 
Pathology 
Dermatology 
Consenting 
Professional(s)/Department: 
Jedd Wolchok, MD, PhD 
George Plitas, MD 
Alexander Lesokhin, MD  
Neil Segal, MD, PhD 
Margaret Callahan, MD, PhD 
Sandra D’Angelo, MD 
Matthew Hellmann, MD 
Karen Autio, MD 
Medicine/ITC 
Surgery/Breast 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 

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Dmitriy Zamarin, MD 
Alexandra Snyder Charen, MD 
Michael Postow, MD 
Paul Sabbatini, MD 
Charlotte Ariyan, MD, PhD 
Alex Drilon, MD 
David Hyman, MD 
Marykate Kasler, NP 
Ruth-Ann Gordon, NP 
Tiffany DeSadier, NP 
Medicine/ITC 
Medicine/ITC 
Medicine/ITC 
Medicine/Gynecologic 
Surgery/GMT 
Medicine/DTC 
Medicine/DTC 
Nursing 
Nursing 
Nursing 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ...................................................................... 9 
3.0 
BACKGROUND AND RATIONALE ......................................................................... 9 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................... 17 
4.1 
Design .......................................................................................................................... 17 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................... 24 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................... 31 
6.1 
Subject Inclusion Criteria ........................................................................................... 31 
6.2 
Subject Exclusion Criteria .......................................................................................... 32 
7.0 
RECRUITMENT PLAN ........................................................................................... 33 
8.0 
PRETREATMENT EVALUATION .......................................................................... 35 
9.0 
TREATMENT/INTERVENTION PLAN ...................................................................... 35 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................... 45 
11.0 
TOXICITIES/SIDE EFFECTS .............................................................................. 47 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....... 47 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................... 48 
14.0 
BIOSTATISTICS ................................................................................................. 49 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES ................................................................................................................ 52 
15.1 Research Participant Registration ............................................................................. 52 
16.0 
DATA MANAGEMENT ISSUES ......................................................................... 52 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................ 53 
17.1 Privacy ......................................................................................................................... 53 
17.2 Serious Adverse Event (SAE) Reporting ................................................................... 54 
17.2.1................................................................................................................................... 55 
18.0 
INFORMED CONSENT PROCEDURES ............................................................. 56 
19.0 
REFERENCES .................................................................................................... 58 

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1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Title: 
 
A Phase I/II Study of the Safety, Tolerability, and Immunoregulatory Activity of 
Mogamulizumab (KW-0761) in Subjects with Advanced and/or Metastatic Solid Tumors 
 
Name of Investigational Product: 
 
Mogamulizumab (KW-0761) 
 
Clinical Phase: 
 
Phase I/II 
 
Study Center(s): 
 
Single US center 
 
Study period (months): 
 
Core Study: 18 months (phase I: 6 months; phase II: 12 months) 
Long term follow up for phase II study: 24 months 
Estimated date first subject screened:03/01/2014 
Estimated date last subject completed: 09/01/2015 
Objectives: 
 
Primary: 
 
• 
Determine safety and tolerability profiles, maximum tolerated dose (MTD) if 
achieved, recommended Phase II dose, and dose-limiting toxicity (DLT) of KW- 
0761 (Phase I). 
 
• 
Determine the safety and preliminary efficacy of KW-0761 as determined by 
immune-related response criteria (irRC)  in subjects with triple-negative breast 
cancer, non-small cell lung cancer, and gastric adenocarcinoma (Phase II). 
 
Secondary: 
 
• 
Explore the antitumor activity of KW-0761using measures of activity including Best 
Overall Response Rate (BORR), Disease Control Rate, Duration of Response, 
Time to Response, and Progression Free Survival (PFS) using and RECIST v1.1 
in cohorts of three specific tumor types treated at the MTD. 
• 
Evaluate the effect of KW-0761 on peripheral and intratumoral lymphocyte subset 
composition and function. 
 
• 
Evaluate the effect of KW-0761 on long-term safety. 
Exploratory: 

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• 
Evaluate the impact of KW-0761 on the resident lymphocytes of the skin. 
 
• 
Evaluate the effect of KW-0761 on the fecal microbiota 
 
• 
Evaluate KW-0761 dose-response relationships 
Methodology: 
 
This is a Phase I/II study of KW-0761 in patients with advanced and/or metastatic solid 
organ malignancies. Phase I of the study will be an open label, non-randomized, dose 
escalation, and safety study in adults with histologically confirmed advanced and/or 
metastatic solid tumor malignancies. Subjects who sign an Informed Consent form and 
who meet the eligibility criteria will be enrolled to receive a weekly intravenous (IV) dose of 
KW-0761 ranging from 0.5 mg/kg to 10.0 mg/kg as feasible starting on Day 1 for 4 weeks 
(cycle 1) and a dose every 2 weeks for 4 weeks starting on day 29 (cycle 2). The initial 
treatment course will include Cycle 1 + Cycle 2. Subsequent treatment courses are 
permissible for subjects demonstrating a response or maintaining stable disease and will 
consist of an infusion of KW-0761 every other week. In the absence of toxicity or 
progression of disease, patients may stay on study for up to 12 months. If a subject 
discontinues from the study for reasons other than DLT prior to receiving four complete 
infusions (Week 4), the subject will be replaced. 
 
Treatment Course 1 
Subsequent 
Treatment 
Courses 
Cycle 1 
Cycle 2 
Cycle 
Cycle 
Day 
1 
8 
15 
22 
1 
15 
1 
15 
Study 
Day 
1 
8 
15 
22 
29 
44 
Study 
Week 
1 
2 
3 
4 
5 
7 
 
 
Standard 3+3 cohorts for safety and DLT detection will be utilized. Each cohort will consist 
of at least three evaluable subjects. If DLT is observed in 0/3 subjects, escalation to the 
next dose level will occur. If DLT is detected in 1 of 3 subjects, then three more subjects 
will be added at that dose level. If DLT is demonstrated in an additional subject, dose 
escalation will cease. The dose will depend on the cohort in which they have been 
enrolled. Subjects will be assigned sequentially to a cohort in the order screening is 
completed. No effort will be made to stratify types of subjects into a particular cohort (e.g., 
reserve more severe subjects or tumor distribution patterns for the higher doses).  Cohorts 
will be dosed consecutively by ascending dose amount starting with the lowest dose and 
not in parallel.Telephonic assessments or medical record reviews will occur at Months 6, 

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12, 18, and 24 after last dose is administered. The Investigator can elect to conduct 
additional tests and/or follow-up visits in clinic during this period as needed to evaluate 
and/or treat any adverse event (AEs). 
 
Part 2 of the study (Phase II) will enroll a total of 48 subjects, 16 patients in 3 tumor- 
specific expansion cohorts each treated with the MTD (or highest dose tested) as 
determined in the Phase I part of the study. The 3 tumor-specific expansion cohorts will 
include non-small cell lung cancer, gastric adenocarcinoma, and triple-negative breast 
carcinoma (negative for immunohistochemical expression of the estrogen receptor, 
progesterone receptor, and the Her2 protein). 
 
Number of subjects: 
 
Enrollment of up to 72 subjects is planned. Of the 72 subjects, a maximum of 24 will be 
enrolled in the dose escalation part of this study and the remaining 48 will be enrolled to 3 
tumor-specific expansion cohorts. Depending on the dose escalation cohort, 2 to 5 
additional subjects may be added to a cohort in whom a dose limiting toxicity has been 
observed to confirm results (Toxicity Definitions and Stopping Rules; Section 9.5). 
 
Cohort dose schedule: 
 
In the dose escalation portion, the starting dose will be 0.5 mg/kg administered i.v.once 
every week for four weeks and then once every 2 weeks for 4 weeks. Succeeding dose 
levels will be 1, 3, and 10 mg/kg as feasible. 
 
Standard 3+3 cohorts for safety and DLT detection will be utilized. Each cohort will consist 
of at least three subjects. Patients in each cohort must complete the first 4 weeks of study 
therapy prior to enrollment of subsequent cohorts. If DLT is observed in 0/3 subjects, 
escalation to the next dose level will occur. If DLT detected in 1 of 3 subjects, then three 
more subjects will be added at that dose level. If DLT is demonstrated in an additional 
subject, dose escalation will cease. Cohorts of 3 to 6 subjects will be treated until either 
DLT, or maximal dose level is achieved. If a subject discontinues from the study for 
reasons other than DLT prior to receiving four complete infusions (Week 4), the subject 
will be replaced. 
 
Sequential Cohorts 
Dose (mg/kg) 
1 
0.5 
2 
1.0 
3 
3.0 
4 
10 

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Definition of Treatment Course 
 
In the first treatment course, KW-0761 will be administered i.v. once a week for four weeks 
(Cycle 1) and subsequently every 2 weeks for 4 weeks (Cycle 2). Subsequent treatment 
courses are permissible for subjects demonstrating a response or maintaining stable 
disease and will consist of an infusion of KW-0761 every other week. Each subsequent 
course (treatment course 2, treatment course 3, etc.) will be defined as completion of two 
additional infusions of KW-0761 over 4 weeks. In the absence of progression or toxicity 
subjects may continue treatment up to one year. If a subject experiences an overall CR, 
the subject may continue on study for up to an additional four infusions beyond CR, then 
discontinue treatment in order to determine duration of response. If a subject experiences 
a PR or SD, the subject may continue therapy after consultation between the investigator 
and the Principal Investigator until disease progression occurs or other withdrawal criteria 
are met (refer to Section 4.8, Criteria for Study Termination). 
 
Definition of Maximum Tolerated Dose (MTD) 
 
The MTD is defined as the dose below that dose at which at least 2 of up to 6 subjects in a 
dosing cohort experience DLT. The MTD will be determined during the first part of this trial. 
 
Definition of Phase II Dose 
 
The Phase II dose will be the MTD as determined in the Phase I part of the trial. If three 
evaluable subjects do not experience a DLT in the 10 mg/kg dosing cohort then the Phase 
II dose will be 10 mg/kg. 
Dose-Limiting Toxicity 
 
A dose limiting toxicity (DLT) is any toxicity that does not have a clear-cut alternative 
explanation. Any of the following, specified below, will be considered a DLT: 
 
A DLT will be defined as any > Grade 3 non-hematologic or hematologic toxicity that is 
related to treatment . The following are exceptions to the definition and will be considered 
a DLT if: 
 
• Grade 4 neutropenia > 7 days 
 
• Grade 4 thrombocytopenia 
 
• Grade 3 thrombocytopenia associated with clinically significant bleeding 
 
Dose Escalation 
 
The dose for the first cohort will be 0.5 mg/kg. In the absence of a DLT, dose will be 
escalated in the following increments, 1, 3, and 10 mg/kg as feasible. Dose escalation will 
cease when at least one of the following endpoints is reached: 

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• 
The MTD is exceeded; OR 
 
• 
A cohort of at least 3 subjects has been dosed with 10 mg/kg KW-0761 
 
Dose escalation will be based on three subjects receiving four complete infusions of KW- 
0761. 
Replacement of Subjects 
 
During Phase 1, subjects who do not complete the first four infusions for reasons other 
than a DLT will be replaced. 
 
Phase II 
 
After determination of the recommended dosing level, additional subjects with gastric 
adenocarcinoma, non-small cell lung carcinoma, and triple-negative breast carcinoma will 
then be enrolled and treated at that dose. A maximum of 48 subjects, 16 of each 
carcinoma type are to be treated with the dose determined from the initial portion of the 
study. A total of 15 subjects, including those receiving the dose determined from Phase 1, 
will be treated initially. 
 
Criteria for Evaluation: 
 
• 
Safety: The safety of KW-0761 will be determined by reported AEs, changes in 
physical examinations, vital sign measurements, ECGs and laboratory analyses.  
Safety evaluations will be performed throughout the study. All AEs and serious AEs  
will be graded according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) Scale, Version 4.03. A dose limiting toxicity (DLT) is 
defined as any Grade 3 or higher infusion reaction or any Grade 3 or 4 toxicity, unless 
the AE is clearly and incontrovertibly due to extraneous causes. 
• 
Pharmacodynamics: A detailed assessment of the biologic activity of KW-0761 will 
be completed on all subjects enrolled into this study. This will include acquisition of 
serial serum, peripheral blood mononuclear cells, stool samples, and tumor tissue to 
evaluate the immunoregulatory activity of this agent. 
 
• 
Efficacy: Efficacy evaluations will be based on response to treatment (PR or better), 
time to PD and duration of overall response. Changes in tumor measurements and 
tumor responses will be assessed by the investigator using RECIST 1.1 and irRC . 
 
Statistical Methods 
 
Categorical variables will be summarized using counts and percentages, while continuous 
variables will be summarized using the mean, median, standard deviation, minimum, 
maximum, and number of observations. Any statistical testing will be two tailed at the 5% 
significance level. The frequency of AEs will be tabulated. Baseline, end-of-study, and 
change from baseline for clinical laboratories, vital signs, and ECG data will be 
summarized. Descriptive statistics will be computed for safety parameters as appropriate. 

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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objectives: 
• 
Phase I: Determine safety and tolerability profiles, maximum tolerated dose (MTD) if 
achieved, recommended Phase II dose (RP2D), and dose-limiting toxicity (DLT) of KW- 
0761. 
• 
Phase II: Determine the safety and preliminary efficacy of KW-0761 as determined by 
immune-related response criteria (irRC) in subjects with triple-negative breast cancer, 
non-small cell lung cancer, and gastric adenocarcinoma. 
 
Secondary Objectives: 
• 
Explore the antitumor activity of KW-0761 using measures of activity; including Best 
Overall Response Rate (BORR), Disease Control Rate, Duration of Response, Time to 
Response, and Progression Free Survival (PFS) using both RECIST v1.1 and immune- 
related response criteria (irRC) in cohorts of three specific tumor types treated at the MTD. 
• 
Evaluate the effect of KW-0761 on peripheral and intratumoral lymphocyte subset 
composition and function. 
• 
Evaluate the long-term and/or post-treatment safety of KW-0761 
 
Exploratory Objectives: 
• 
Evaluate the effect of KW-0761 on the fecal microbiota. 
• 
Evaluate KW-0761 dose-response relationships. 
 
3.0 
BACKGROUND AND RATIONALE 
 
A large body of research suggests that the 
immune system aids in controlling the 
development of cancer in normal animals by 
ongoing immune surveillance1. Once 
developed, the tumor microenvironment 
becomes a site of immune privilege as 
tumor-specific tolerance has been identified 
in the absence of generalized 
immunosuppression2,3. As such, immune 
evasion, resulting from both passive and 
active tolerizing forces that inhibit antitumor 
immunity, is a hallmark of cancer 4. Passive 
mechanisms include immunoediting, which results in selection for low antigenicity. Active 
means of tolerization include direct suppression of effector T cells5. Regulatory T cells 
(Treg) are a subset of CD4+ T cells that are requisite for control of autoimmunity, 
dampening excessive inflammation caused by the immune response to pathogens, and 
maintaining maternal-fetal tolerance6-8. While Treg cells are critical for maintaining 
peripheral tolerance, their potent immunoregulatory properties can promote the 
development and progression of numerous types 
of malignancies by inhibiting effector 
responses9,10. Treg cell recognition of self- 
antigens is in part responsible for their ability to 
Figure 1. Ablation of Treg cells affects the growth 
of fully established primary tumors. 
maintain immune homeostasis. As most tumor associated antigens are modified or 
aberrantly expressed self antigens, Treg are considered to be active participants in tumor 

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specific immune privilege11. This is particularly exemplified in the observed regression of 
established tumors in experimental models of Treg cell depletion.12-14 
Treg cells exert their suppressive function through a number of different mechanisms10. 
CD25, a subunit of the IL-2 receptor and the original Treg cell surface marker, is 
constitutively and highly expressed on Treg cells but also upregulated on effector T cells15. 
The high level of expression on Treg cells could deprive effector T cells of IL-2 and inhibit 
their proliferation16. CTLA-4 is well known in limiting responses of activated T cells and is 
also implicated in Treg cell−mediated suppression17. Treg cells can also inhibit the function 
of dendritic cells. LAG-3, a CD4 homologue that exhibits high binding affinity with MHC 
class II is thought to be required for maximal suppressive action of Treg cells18. Binding of 
major histocompatibility complex (MHC) molecules by LAG-3 on immature dendritic cells 
(DCs) may lead to inhibition of maturation and decreased costimulatory capacity19. Treg 
cells can produce several suppressive proteins including IL-10, IL-35, granzyme B, IL-9, 
and TGF-β20. Treg cells are capable of killing effector T cells and antigen presenting cells 
(APC)21,22. In a model of infection, Treg cells have also been shown through their influence 
on DCs to play a critical role in the homeostasis of CD8+ T cell priming by regulating the 
expansion and avidity of effectors23. 
Treg cells were originally characterized as CD4+CD25+ lymphocytes and subsequently 
found to specifically express the forkhead/winged helix family transcription factor 
Foxp3.24,25 Treg cell differentiation and function are dependent on the expression of the 
lineage-specifying transcription factor Foxp326. Furthermore, the entire range of Treg cell 
functions depends on a Foxp3-dependent hierarchical transcriptional program27-29. Mice 
with a loss-of-function mutation in Foxp3 lack functional Treg cells and develop lethal 
autoimmunity and lymphoproliferative disease at an early age28. Similarly humans 
harboring mutations in FOXP3 suffer from immune dysregulation, polyendocrinopathy, 
enteropathy, X-linked syndrome (IPEX)30. Expression of Foxp3 drives Treg cell 
differentiation in the thymus, but they can also be induced in the periphery through 
mechanisms that involve TGF and IL2 31. Accumulating evidence demonstrates that Treg 
cells utilize components of the specific immune response in which they are acting, to 
suppress it. For example, expression of the transcription factor Irf4 is required for Treg 
cells to be able to suppress TH2 responses, and Irf4 controls a module of the Foxp3 
program that contains 20% of its targets32. Similarly, CXCR3, a target of Tbet, is required 
for control of TH1 responses33, and Stat3 for TH17 responses10. These observations 
suggest that Treg cells integrate external local cues to modulate specific segments of their 
transcriptomic programme, and they do so by a set of common regulators they share with 
the ongoing immune response. 

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Figure 2. Ablation 
of Treg cells 
reduces lung 
metastasis. Fraction 
and representative 
image of mice with 
detectable lung 
metastasis upon 
bioluminescence 
imaging of the 
dissected lungs from 
mice with mammary 
tumors treated with DT 
(red) or control (black). 
 
Therapeutic modulation of the immune system for clinical benefit in cancer patients has 
been demonstrated by numerous modalities including antibody blockade of inhibitory 
molecules, adoptive T cell transfer, and autologous cell-based vaccines34-37. Treg cells are 
generally considered to be the most potent inhibitor of antitumor immunity and are 
suspected to be responsible for the limited response rates to current immunotherapeutic 
regimens11. Analysis of tumor infiltrating lymphocyte (TIL) subset composition has shown a 
clear association between the composition of the infiltrate and patient survival. TIL 
composed of primarily cytotoxic T cells are generally associated with a favorable 
prognosis, where as TIL with a predominance of Treg cells correlate with poor outcomes38- 
40. 
 
Recruitment of Treg cells into the tumor microenvironment is likely secondary to a number 
of factors. Chemokines are a superfamily of chemotactic cytokines that control leukocyte 
migration through G protein-coupled receptors on target cells41. The chemokine receptor 
CCR4 has been shown to be important for trafficking of Treg cells and this function is 
critical for Treg cell-mediated suppression of inflammation42. CCR4 is the receptor for CC- 
chemokine ligand 17 (CCL17) and CCL2243. Chemokines are considered to play a role 
both in the recruitment of immune and inflammatory cells for anti-tumor response and in 
the selective homing of neoplastic B and T cells44. In normal tissue, CCR4 is known to be 
selectively expressed on a subset of activated Th2 type CD4+ T cells that produce 
inflammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13, and has garnered 
attention as a molecular target for the treatment of allergic disorders such as asthma, 
atopic dermatitis or allergic rhinitis45-49. CCR4 is also expressed on primed human Treg 
cells, activated natural killer (NK) cells, basophils, monocytes, and platelets50-53. The 
CCR4 ligands, CCL17 and CCL22, share 37% homology, are both encoded on 
chromosome 16, and are highly expressed in the thymus, lymph nodes, and skin, but 
barely expressed in other tissues44,54. MDC and TARC are synthesized mostly by 
macrophages and dendritic cells43,47. 
CCR4 has been shown to play a central role in Treg homing to the skin where they 
regulate local immune homeostasis 55. Reduced levels of skin associated Treg has been 
found to coexist with numerous immune related skin diseases. Circulating and skin 
CCR4+ Treg have been shown to be reduced in patients with dermatomyositis 56. Treg 
function has been found to be significantly impaired in patients with toxic epidermal 

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11% 
43% 
36% 
0.6% 
4% 
88% 
CD44 
necrolysis 57. Similarly, administration of Treg has been shown to prevent experimental 
TEN in mice 58. Treg may also function to limit skin related autoimmunity as suggested by 
a reduced homing of functional Treg in patients with vitiligo 59. Treatment of human 
subjects with an anti-CCR4 antibody has been shown deplete skin associated Treg, lead 
to an altered skin immune microenvironment, and potentially be associated with skin 
immunopathology 60. The accumulated data regarding Treg mediated immune 
homeostasis suggests CCR4 to be a major factor in Treg homing to the skin and clinical 
studies involving interrupting this mechanism should account for this both in monitoring for 
adverse events as well as a potential biomarker of response. 
 
A 
B 
Figure 3. Treg ablation leads to an 
increased proportion of T cells 
infiltrating mammary tumors and 
CD4+ T cell activation. Analysis of 
TILs from PyMT mammary tumors 
orthotopically injected in Foxp3DTR 
mice treated with control (A) or DT 
(B). Tumor-infiltrating CD4+ T cell 
expression of activation markers 
from PyMT mammary tumors 
C 
D 
orthotopically injected in Foxp3DTR 
mice treated with control (C) or DT 
(D). 
 
 
 
 
 
 
 
 
Accumulation of CCR4+ Treg has been shown to occur in colon adenocarcinomas and 
correlates with a reduced frequency of effector T cells61. Ovarian tumors, Hodgkin 
lymphoma, and breast cancers are found to contain large amounts of CCL22 that 
correlates with the presence of tumor infiltrating Treg40,62-64. Treg cell migration can be 
inhibited through CCR4 blockade65. Activated Treg cells preferentially express CCR4 over 
conventional T cells, which is important when considering immunotherapeutic targeting of 
Treg cells via CCR466,67. A small molecule inhibitor of CCR4 designed in silico has been 
shown to prevent the interaction of CCL22 and CCL17 with CCR4 and consequently 
inhibit the recruitment of Treg cells in experimental models68. Further work with this 
molecule showed that CCR4 antagonism could enhance dendritic cell−mediated CD4+ T 
cell proliferation in vitro as well as offer potent adjuvant activity in an in vivo viral infection 
model69. Similarly, in tumor models, CCR4 antagonism induced expansion of antigen 
specific CD8+ T cells, and in combination with vaccination, promoted tumor immunity70. 
Excluding skin malignancies, breast cancer is the most common cancer among women 
and the second leading cause of cancer death in women71. Clinically, pathologic 
evaluation of breast cancer specimens has revealed the prognostic value of certain 
histopathologic features of breast tumors that reflect alterations in the microenvironment 
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1.7% 
2.5% 
15% 
19% 
CD8 
CD62L 
CD4 

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including lymphocytic infiltration, fibrosis, and angiogenesis. While breast cancer has not 
traditionally been considered an immunogenic tumor, evidence of tumor infiltrating 
lymphocytes (TILs) and their subset composition paralleling disease progression suggest 
that the immune response may be important72,73. The clinical relevance of tumor infiltrating 
T cells has been intensively studied74. An increased ratio of CD4+ to CD8+ T cells 
correlates with lymph node metastases and reduced overall survival75. The tumor 
microenvironment can also influence the recruitment and regulation of immune cells in 
breast tumors76,77. High levels of Treg cells in breast tumors is associated with an invasive 
phenotype and diminished relapse-free as well as overall survival57,58,60. In addition, a 
substantial decrease in the number of breast tumor infiltrating Treg cells is positively 
associated with a pathological response to neoadjuvant chemotherapy56. 
Breast cancer is a heterogeneous disease and is generally classified into three basic 
therapeutic groups, based on the expression of the estrogen receptor (ER), progesterone 
receptor (PR), and HER278. Triple negative breast cancers (TNBC), also known as basal- 
like breast cancers lack the expression of ER, PR, and HER279. These tumors account for 
up to 15% of all invasive breast cancers and are frequently observed in patients with 
BRCA1 germline mutations and of African ancestry. TNBC characteristically are densely 
infiltrated by lymphocytes suggestive of an anti-tumor response, yet are associated with a 
more aggressive clinical course characterized by shorter survival and higher risk of 
metastases80. This paradox is hypothesized to be secondary to effective immune 
suppression by the tumor microenvironment with preclinical data implicating Treg cells. 
Foxp3 expression among tumor infiltrating lymphocytes is significantly associated with the 
TNBC subtype of invasive breast cancers81. High levels of Treg cell infiltration of TNBCs is 
associated shorter survival82. TNBC represents a relevant target for immunotherapy as 
there is a robust pre-existing infiltrate which can potentially  mount an anti-tumor response 
once the Treg cell−mediated immunosuppression is diminished through KW-0761- 
mediated Treg cell depletion. 
 
The association of Treg cell accumulation in the peripheral blood and tumor infiltrating 
lymphocytes with clinical outcome is not limited to patients with breast cancer. As Treg 
cells represent a central mechanism of tumor immune evasion, robust tumor infiltration by 
Treg cells correlates with poor survival in patients affected by many tumor types. Gastric 
cancer represents one of the most common causes of cancer-related deaths worldwide83. 
In metastatic gastric cancer, chemotherapy remains the mainstay of therapy and results in 
objective response rates of only 20-40%, with a median overall survival of 8-10 months84. 
This particularly grim prognosis has led to the investigation of immunotherapy as a means 
to improve survival85. Promising results from initial trials suggest that gastric cancer may 
be amenable to treatment by modulating the immune system. A clinical trial investigating 
the use of autologous cytokine-induced killer cells for locally advanced gastric cancer 
patients showed significant improvements in disease-free and overall survival86. A 
significant amount of preclinical data also suggests that targeting Treg cells in gastric 
cancer holds therapeutic promise. A study of 133 patients with gastric cancer revealed that 
high numbers of intratumoral Treg cells significantly correlated presence of lymph node 
metastases and was an independent factor for adverse overall survival87. Regulatory T 
cells from patients with gastric cancer have also been shown to produce the 
 
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immunosuppressive cytokines IL-4 and IL-10, and inhibit cytokine production from CD4+ T 
cells in vitro88. Treg cell infiltration of gastric cancers may be in part related to hypoxia, a 
feature common to many solid tumors. Treg cell infiltration into gastric cancers is positively 
correlated with HIF-1α expression and supernatants from gastric cancer cells cultured in 
hypoxic conditions can induce the expression of Foxp3 in naïve CD4+ T cells via TGF- 
β189. The well-documented adverse clinical correlation of Treg cell infiltration into gastric 
cancers, and the preliminary evidence that they may be sensitive to immunotherapy 
provide the rationale for targeting this disease with KW-0761. 
 
Lung cancer is the leading cause of cancer deaths worldwide. The overall 5-year survival 
rate for advanced non-small cell lung cancer (NSCLC) is 2%-4%, depending on 
geographic location90. Whereas renal cell carcinoma and melanoma are traditionally 
considered immunogenic, as evidenced by spontaneous regressions and occasional 
dramatic responses to high-dose IL-2, NSCLC has been notoriously resistant to 
immunotherapy91,92.  Pre-clinical data suggest that the immune system may have a role in 
this disease. High levels of CD4+/CD8+ T cells infiltrating resected NSCLC tumors are 
associated with a favorable prognosis and high levels of infiltrating Treg cells are 
associated with increased risk of relapse93,94. In early-stage NSCLC the ratio of Treg cells 
to CD3+ TILs correlates with disease specific survival and can reliably distinguish patients 
with tumors who are at high risk for recurrence95,96. Genetic evidence pointing to the role of 
Treg cells in the risk of developing NSCLC was documented by determining the presence 
of a single nucleotide polymorphism (SNP) associated with Graves disease in a cohort of 
patients with NSCLC and healthy controls. The study demonstrated a significant 
association of this SNP with a risk of developing NSCLC97. Recently there have been 
significant breakthroughs in harnessing the immune system though the use of checkpoint 
blockade inhibitory antibodies to treat NSCLC. In a Phase I dose escalation study of 207 
patients treated with an anti-PD-L1 monoclonal antibody, a response rate of 10% was 
observed in patients with NSCLC98. Another Phase I dose-escalation study of 296 patients 
treated with an anti-PD-1 antibody reported a response rate of 18% in patients with 
NSCLC99. Based on the association of Treg cells with the clinical course of NSCLC 
patients as well as the significant pool of proof-of-principle clinical data that immune 
modulation can yield therapeutic responses in this disease, KW-0761 is a promising 
therapeutic modality for NSCLC patients. 
 
 
3.1 Preliminary Data 
 
Preliminary data from the laboratory of Dr. Rudensky at the Sloan-Kettering Institute 
supports the notion that specific ablation of Treg cells is also effective in experimental 
models of breast cancer. Using a poorly immunogenic, oncogene driven breast cancer cell 
line in an orthotopic model of mammary carcinoma, we show that Treg cells significantly 
contribute to breast cancer progression and metastasis. For these studies, we made use 
of a knock-in mouse generated in our laboratory where the Foxp3 locus controls 
expression of the human diphtheria toxin (DT) receptor (Foxp3DTR)100. In these mice, 
administration of DT leads to the rapid and specific ablation of Treg cells. Mice expressing 
a transgene encoding the Polyoma middle T antigen (PyMT) under a mammary gland 
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specific promoter leads to the rapid development of mammary tumors and lung metastasis 
faithfully recapitulating human breast cancer carcinogenesis101. To determine the role of 
Treg cells in this process, we orthotopically implanted 1x105 PyMT tumor cells in the 
inguinal mammary glands of Foxp3DTR mice which, when left untreated, developed 
uniformly growing mammary tumors that metastasized to the lungs with complete 
penetrance in approximately 3 to 4 weeks. If Treg cells were ablated by injection of 25 
μg/kg of DT on 2 consecutive days after tumor reached approximately 100 mm3, the 
primary tumor growth of large established tumors was significantly hindered (Fig. 1). In 
addition, this treatment also resulted in the almost complete disappearance of metastatic 
tumor nodules in the lungs (Fig. 2). Analysis of TILs by flow cytometry revealed that Treg 
cell ablation leads to a dramatic increase in the proportion of TILs represented by CD4+ 
and CD8+ T cells (Fig. 3A,B), as well as an increase in activated CD4+ T cells (Fig. 3B,C). 
This finding again supports the hypothesis that Treg cells actively suppress potentially 
beneficial endogenous anti-tumor immune responses. 
 
Unfortunately, there are no readily available means of selectively targeting Treg cells in 
humans. Preclinical models support the notion that Treg cells are central to the regulation 
of immune responses to many different types of cancer. Our own preliminary data reveal 
that the specific ablation of Treg cells in advanced murine breast tumors leads to a 
significant delay in tumor growth and reduction in metastatic burden. These data suggest 
targeting Treg cells with KW-0761 may be useful in the treatment of a wide variety of 
cancers and support its evaluation in this study. 
3.2 KW-0761 
 
KW-0761 (also known as AMG 0761 and POTELIGEO®) is a recombinant, humanized 
monoclonal antibody (mAb) of the immunoglobulin (Ig) G subclass 1 kappa (IgG1κ)  
isotype that targets CC chemokine receptor 4 (CCR4)- expressing cells that is being 
developed by Kyowa Hakko Kirin Pharma, Inc (KHK) 
for 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amen 
the treatment of T-cell malignancies including 
peripheral T-cell lymphoma (PTCL), cutaneous T-cell 
Figure 4. T-cell subset analysis 
from Phase II clinical trial of KW- 
0761 for relapsed ATL. (A) Numbers 
of CD4+CCR4+ cells from KW- 
0761–treated patients with ATL in 
blood samples taken (i) just before 
the first KW-0761 infusion, (ii) just 
before the second infusion, (iii) just 
before the fifth infusion, (iv) 1 week 
after the eighth infusion, and (v) 4 
months after the eighth infusion and 
those from 10 controls are shown as 
box and whisker plots indicating 
minimum, lower quartile, median, 
upper quartile, and maximum 
values. The number of samples 
used for analysis at each point is 
indicated below the graph. The 
differences between before and 
each point after KW-0761 treatment 
[(i) v (ii), (iii), (iv), or (v)] are 
indicated as a P value (Wilcoxon 
signed-rank test) below the graph. 
Numbers of (B) CD4+CD25+Foxp3+; 
(C) CD4+CCR4−; and (D) CD4−CD8+ 
cells are presented in the same 
manner. 

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lymphoma (CTCL), and adult T-cell leukemia/lymphoma (ATL). KW-0761 was produced 
using technology developed by Kyowa Hakko Kirin Co., Ltd., that eliminates fucose from 
the carbohydrate structure of the antibody. It contains 2 heavy and 2 light chains linked 
together by 16 disulfide bonds. Glycosylation of KW-0761 occurs at amino acid Asn299 
and the mAb has typical biantennary structure lacking a core fucose. KW-0761 has a 
molecular weight of ~149,000 Daltons and an isoelectric point (pI) range of ~8.1 to 8.7. 
Due to the absence of fucose from the complex-type oligosaccharide at the constant (Fc) 
region, KW-0761 has enhanced antibody-dependent cellular cytotoxicity (ADCC) activity, 
but does not exhibit any complement dependent cytotoxic (CDC) activity or neutralizing 
activity of the ligand of CCR4. In vitro, the EC50 for ADCC against human T-cell 
lymphoma cell lines is between 0.01 and 0.1 μg/ml. 
 
 
KW-0761 has potent cytolytic activity against CCR4-expressing target cells, and has been 
shown in in vivo non-clinical studies to eliminate the T-helper 2 (Th2) subset of T cells that 
express this chemokine receptor. When compared to conventional T cells CCR4 is 
preferentially expressed in Treg, both in mice and humans66,67. KW-0761 therefore is a 
promising immunotherapeutic agent targeting Treg induced immunosuppression in the 
tumor microenvironment. There is substantial preliminary data in the published work on 
KW-0761 that suggests it can target Treg. A recently published phase II study of KW-0761 
for relapsed ATL showed that compared to healthy controls, KW-0761 led to a significant 
and lasting decrease in the number of CD4+CCR4+ but not CD4+CCR4- or CD8+CD4- cells 
in patients with ATL (Fig. 4)102. Further subset analysis of CD4 T cells showed that there 
was a significant depletion of CD4+CD25+Foxp3+ cells, which included both ATL cells and 
endogenous non-ATL Treg. The ability of KW-0761 to deplete Treg was also examined in 
a phase I/II clinical trial in patients with cutaneous T cell-lymphoma (CTCL)103. KW-0761 
in these patients led to a significant reduction in circulating Treg as well as Foxp3 mRNA 
as compared to pretreatment levels (Fig 5). 
 
 
 
 
 
 
 
 
Figure 5. Effect of KW-0761 on Treg in CTCL 
patients. Fifteen of 20 patients (75.0%) had 
detectable CD3+CD4+CD25+CD127- Treg 
(1.26±1.09 % or 33.79±46.88 /μl) at baseline with 
60 –100 % of Treg positive for CCR4. After 4–6 
weeks of treatment with KW-0761, all 15 patients 
had a decrease in Treg numbers (0.39±0.49 % or 
5.65±8.95 /μl, *p<0.05). CCR4+ Treg was 
significantly reduced from an average of 67.2% to 
24.6% (p<0.01). In parallel, foxp3 mRNA levels 
were also significantly decreased from baseline 
levels (0.57±0.91 to 0.07±0.08, **p<0.01). 
 
 
1.60 
 
 
1.20 
 
 
0.80 
 
 
0.40 
 
 
0.00 
*
** 
Before 
After 
Before 
After 
Tregs(%) 
Foxp3 (fold change) 

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In vitro and in vivo pharmacology studies have demonstrated the immunologic and anti- 
tumor effects of KW-0761. KW-0761 has been examined for safety and toxicology in non- 
human primates with little toxicity. The No Observed Adverse Effect Level (NOAEL) in a 
13 week repeat dose toxicology study conducted in Cynomolgus monkeys was 40 mg/kg, 
the highest dose evaluated. Additionally, an embryo-fetal development study performed in 
Cynomolgus monkeys demonstrated that the NOAEL for general toxicity and reproductive 
function in dams was 40 mg/kg. 
 
In preliminary human clinical trials, doses of up to 1.0 mg/kg have been well tolerated. As 
of 03 December 2012, approximately 243 subjects have received at least one dose of KW- 
0761 in clinical studies. Efficacy has been demonstrated in subjects with T-cell lymphoma 
including ATL, CTCL, and PTCL, with overall response rates (ORRs) ranging from 31% to 
50%. Adverse events (AEs) have generally been mild to moderate in severity. In three 
studies in subjects with T-cell lymphoma in the US and Japan, the most frequent 
treatment-emergent adverse events (TEAEs) that were considered at least possibly 
related to study drug include infusion related reaction (53%), decreased lymphocyte count 
(48%), pyrexia (47%), chills (40%), decreased white blood cell count (33%), rash/drug 
eruption (32%), decreased neutrophil count (28%), decreased platelet count (27%), and 
nausea (21%). For the 1.0 mg/kg dose level (regimen=once per week for the first 4 weeks 
then every other week), the mean (SD) half-life values were 184 (64) and 332 (86) hours 
on Days 1 and 22, respectively. 
 
POTELIGEO® (mogamulizumab) was approved by the Ministry of Health, Labor and 
Welfare in Japan on 30 March 2012, for the treatment of relapsed or refractory CCR4- 
positive ATL. 
 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a Phase I/II single institution study. Phase I of the study will be an open label, non- 
randomized, dose escalation, and safety study in adults with histologically confirmed 
metastatic solid tumor malignancies. Subjects who sign an Informed Consent form and 
who meet the eligibility criteria will be enrolled to receive a weekly intravenous (IV) dose of 
KW-0761 ranging from 0.5 mg/kg to 10.0 mg/kg as feasible starting on Day 1 for 4 weeks. 
In the absence of toxicity or progression of disease, patients may continue receiving KW- 
0761 for up to 12 months. Subsequent treatment courses will consist of an infusion every 
other week (Figure 6). Following the end of treatment or treatment completion date, a 24- 
week short term follow-up (STFU) period of observation will begin. If a subject 
discontinues from the study for reasons other than DLT prior to receiving four complete 
infusions (Week 4), the subject will be replaced. Subsequent treatment courses are 
permissible for subjects demonstrating a response or maintaining stable disease and will 
consist of an infusion of KW-0761 every other week. 
 
Subjects will undergo assessments with each dosing visit during Course one and Course 
2 and at weeks 2, 3, 6, 12, 18, 24 following the last dose (Figure 6). Telephonic 

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assessments or medical record reviews will occur at Months 6, 12, 18, and 24 after last 
dose is administered. The Investigator can elect to conduct additional tests and/or follow- 
up visits in clinic during this period as needed to evaluate and/or treat any adverse event 
(AEs). 
 
Phase II of the study will enroll a total of 48 subjects, 16 patients in 3 tumor-specific 
expansion cohorts each treated at the RP2D (MTD, or highest dose tested in Phase I part 
of trial). The 3 tumor-specific expansion cohorts will include NSCLC, gastric 
adenocarcinoma, and triple-negative breast adenocarcinoma (TNBC). 
 
The following definition will be used to identify TNBC subjects: 
 
• <1% immunohistochemical staining for the estrogen receptor AND 
 
• <1% immunohistochemical staining for the progesterone receptor AND 
 
• 0-1+on IHC staining for HER2 or FISH not amplified as per the ASCO/CAP 
guidelines (single-probe average HER2 copy number <4.0 signals/cell; dual-probe 
HER2/CEP17 ratio <2.0 with an average HER2 copy number <4.0 signals/cell). 
 
These cohorts were chosen because they are abundantly infiltrated by Treg cells, the 
proposed target of KW-0761 (Section 3.0, Background and Rationale) 104-106. As the Phase 
II part of the study requires specific tumor types there will be no overlap of patients from 
the Phase I to the Phase II component of the study. 
 
Screening 
Core Study Period 
Additional 
Courses 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
KW-0761 
Injection 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Study Day 
-30 to -1 
1 
8 
15 
22 
29 
44 
Study 
Week 
1 
2 
3 
4 
5 
7 
 
 
Follow-Up 
Short-term (STFU) 
Long- Term 
Weeks after End of Treatment/Treatment 
Completion 
Months after STFU/End of 
Treatment or Treatment 
Completion 
2 
3 
6 
12 
18 
24 
6 
12 
18 
24 
Figure 6. Study Timeline 
 
4.2 Definition of Treatment Course 

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In the first treatment course, KW-0761 will be administered i.v. once a week for four weeks 
(Cycle 1) and subsequently every 2 weeks for 4 weeks (Cycle 2). Subsequent treatment 
courses are permissible for subjects demonstrating a response or maintaining stable 
disease and will consist of an infusion of KW-0761 every other week. Each subsequent 
course (treatment course 2, treatment course 3, etc.) will be defined as completion of two 
additional infusions of KW-0761 over 4 weeks. If a subject experiences an overall CR, the 
subject may continue on study for up to an additional four infusions beyond CR, then 
discontinue treatment in order to determine duration of response. If a subject experiences 
a PR or SD, the subject may continue therapy for up to one year or until disease 
progression occurs or other withdrawal criteria are met (refer to Section 4.8, Criteria for 
Study Termination). If a subject are not available for administration of KW-0761 a 3 day 
window before or after the scheduled dose date will be allowed. 
 
4.3 Dose Escalation 
 
Standard 3+3 cohorts for safety and DLT detection will be utilized (Table 1). Each cohort 
will consist of at least three subjects. If DLT is observed in 0/3 subjects, escalation to the 
next dose level will occur. If DLT detected in 1 of 3 subjects, then three more subjects will 
be added at that dose level. If DLT is demonstrated in an additional subject, dose 
escalation will cease (see Table 6 for a summary). The dose will depend on the cohort in 
which they have been enrolled. Subjects will be assigned sequentially to a cohort in the 
order screening is completed. No effort will be made to stratify types of subjects into a 
particular cohort (e.g., reserve more severe subjects or tumor distribution patterns for the 
higher doses). 
 
In the absence of progression or toxicity subjects may continue treatment up to one year. 
If a subject experiences an overall CR, the subject may continue on study for up to an 
additional four infusions beyond CR, then discontinue treatment in order to determine 
duration of response. If a subject experiences a PR or SD, the subject may continue 
therapy after consultation between the investigator and the Principal Investigator until 
disease progression occurs or other withdrawal criteria are met (refer to Section 4.8, 
Criteria for Study Termination). 
 
 
Table 1. Phase I Dose Escalation Schema 
 
Cohort 
Dose 
(mg/kg) 
1 
0.5 
2 
1 
3 
3 
4 
10 

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4.4 Study Conduct 
 
Table 2 is a tabular view of the Study Assessments. 
 
Visit 1 is designated as Day 1 and the day of KW-0761 administration. Screening for 
criteria will begin no more than 30 days prior to KW-0761 dosing on Day 1 with the signing 
of the ICF. Unless otherwise specified, all screening assessments should be performed 
during this period. Assessments required for screening eligibility that are already available 
in a subject's medical records at the time the subject is consented may be used to satisfy 
screening requirements as long as they have been obtained within 30 days of the planned 
KW-0761 dosing on Day 1. If screening assessment results for eligibility are not available 
in a subject's medical record then they must be obtained to establish eligibility. Pathologic 
review of most recent biopsy for confirmation of diagnosis will be obtained during the 
screening period. The imaging studies for TNM staging that will be used to establish 
eligibility and baseline must have been performed within 30 days of KW-0761 dosing. For 
women of child bearing potential a negative urine pregnancy test must be documented on 
Day 1 prior to KW-0761 dose administration. Information to be collected during the Long- 
term Follow-up will include: vital status; treatments received post KW-0761 dosing. This 
information will be sought first from hospital and/or outpatient medical records. If the 
subject has not been seen for follow-up care in the 30 days prior to scheduled visit, then a 
study staff member will contact the subject by telephone to collect information regarding 
vital status and treatments. 

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Table 2. Assessments 
Procedures 
Screening 
Treatment Course 1 
Subsequent 
Courses 
 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
 
Days (+/- 3 days) 
 
(-30) to  (-1) 
1 
8 
15 
22 
1 
15 
1 
15 
Informed Consent 
X 
Entry Criteria 
X 
Medical History 
X 
Karnofsky 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
Urine Bhcg 
X 
X 
Serum Chemistry 
X 
X 
X 
X 
Urinalysis 
X 
X 
CBC with 
Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
profile 
X 
Stool Analysis1 
X 
X 
X 
X 
X 
X 
Cytokines/Flow 
Cytometry/ 
Lymphocyte 
counts 
X 
X 
X 
X 
X 
X 
CMV Ag and Ab 
X 
HIV 
, Hepatitis panel 
X 
Quantitative 
Immunoglobulins 
X 
X 
Humoral and 
cellular responses 
to tumor antigens 
X 
X 
Tumor Imaging 
(CT or MRI scan 
or equivalent)3 
X 
X 
X 
AJCC Tumor 
Staging 
X 
Tumor Biopsy2 
X 
X (+ 4 days) 
Mogamulizumab 
infusion 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1Since the bowel habits of individual subjects may vary widely it is likely that not all of the collections may be possible. Subjects are to bring in samples when feasible. If a 
subject misses collections they will be allowed to continue on the study. 
2If a site of tumor is readily available as a cutaneous lesion a simple punch or excisional biopsy under local anesthesia can be performed by the principal investigator or 
qualified personnel. If however tumor is not as readily accessible then an image-guided core needle biopsy will be obtained following consultation with the radiology staff to 
determine the overall risk of the procedure. Invasive procedures that require general anesthesia should not be performed to obtain a biopsy specimen. If a surgical procedure 
is performed for a clinical indication a sample may be used for research purposes. During the course of treatment a decision may be made to perform the post-treatment 
biopsy earlier than 15 days if there is evidence to suggest a possibility that by day 15 there will be no available tumor for biopsy due to a rapid clinical response. Similarly 
tumor biopsy may be delayed if there is evidence of a delayed response. 
3Tumor imaging will occur on even courses starting with cycle 4. 

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Procedures 
Follow-Up 
Short-term (STFU) 
Long- Term 
Weeks after End of 
Treatment or Treatment 
Completion 
Months after STFU/End of 
Treatment or Treatment 
Completion 
2 
3 
6 
12 
18 
24 
6 
12 
18 
24 
Telephone assessments or medical 
record reviews will occur at 6, 12, 
18, and 24 months after the end of 
the Short-term follow up period, the 
end of treatment or treatment 
completion date. Vital status, 
directed AE assessment for new 
onset or exacerbation of pre- 
existing autoimmune disease. 
Karnofsky Performance 
Status 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
Height 
Vital Signs 
X 
X 
X 
X 
X 
X 
CBC with Differential 
X 
X 
Stool Analysis 
X 
X 
X 
Cytokines/Flow Cytometry/ 
Lymphocyte counts 
X 
X 
X 
X 
Tumor Imaging 
X 
AJCC Tumor Staging 
X 
Assessment of response 
X 
AE assessment 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
4.5 Assessments 
As shown in Table 2, screening assessments will be performed to determine eligibility. At a minimum, 
demography, medical and disease history, concurrent and recently taken medications, and laboratory 
and physical examination results will be reviewed to confirm that a subject is eligible to screen for 
enrollment. An original medical history including complete past medical and surgical history, review of 
systems, complete history of present illness for all active medical and surgical problems, and current 
prescription and non-prescription medications will be recorded. 
4.5.1 Vital Signs 
Vital signs including temperature, respiratory rate, heart rate, and blood pressure will be recorded at 
each visit. During Phase 1, vital signs will be checked and recorded prior to administration of KW-0761, 
every 15 minutes (+ 5 minutes) during infusion for the first treatment course and midway through and at 
the end of the infusion on subsequent treatment courses. Vital signs will also be measured every 30 
minutes (+ 5 minutes) for the first hour following administration of KW-0761. During Phase 2 of the 
study, vital signs will be checked and recorded prior to start of infusion and at the end of the infusion. 

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4.5.2 Physical Examination 
Complete physical examinations will be performed at Screening/Baseline to document that candidates 
meet all eligibility criteria and will be repeated weekly during the core study period and with every short- 
term follow-up visit. Height will be recorded at Baseline. Weight will be recorded at Baseline, at the end 
of Cycle 1 and at the end of Cycle 2. Complete examinations include all major organ systems. The 
Investigator will preferably complete these examinations. 
Directed physical examinations can be performed by study staff at other points if deemed necessary by 
clinical presentation of the subject. 
4.5.3 Electrocardiogram (ECG) 
A 12-lead ECG will be obtained and recorded at Screening Baseline (Days -35 to -1) and prior to the 
initial KW-0761dose. Additional ECGs will be obtained only as clinically indicated. 
4.5.4 Tumor Imaging for AJCC TNM Staging 
Chest, abdominal, pelvic, and CNS imaging scans will be documented at Screening / Baseline to stage 
subject's tumor according to the American Joint Committee on Cancer Tumor-Node Metastases (AJCC 
TNM) scoring system. As noted in Section 4.4, the imaging studies used to stage the subject's tumor 
may have been obtained as part of the subject's routine cancer care prior to study enrollment but must 
have been obtained within 30 days of KW-0761 dosing on Day 1. 
4.5.5 Laboratory Assessments 
The following laboratory evaluations at Screening / Baseline and Day1 prior to KW-0761 dosing to 
document eligibility and establish baseline values. 
• 
Serum creatinine (Cr) ≤1.5 X upper limit of normal (ULN) 
• 
Serum total bilirubin (T-Bil) ≤1.5 X ULN (prior diagnosis or past history consistent with Gilbert's 
syndrome is an exception) 
• 
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 X ULN 
• 
Platelets (Plts) ≥ 100,000 cells/µl 
• 
Hemoglobin (Hgb) ≥ 9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥1000/mm3 
Serum chemistry [including sodium (Na), potassium (K), chloride (Cl), carbon dioxide (C02), albumin 
(Alb), alkaline phosphatase (ALP), Bil total, aspartate transaminase (AST), alanine transaminase (ALT), 
blood urea nitrogen (BUN), total protein (TP), calcium (Ca), creatinine (Cr), phosphorus (Phos), glucose 
(Glu), and lactate dehydrogenase (LDH)], CBC with differential, and urinalysis (U/A) will be performed 
prior to KW-0761 dosing. All of these will be repeated as shown in Table 2. Additional laboratory tests 
will be repeated as needed. 
4.5.6 Pregnancy Screen 
For women of childbearing potential, urine pregnancy testing will be performed at Screening / Baseline 
and on Day 1 prior to dosing. 

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4.5.7 Adverse Events (AE) Assessment 
Evaluation of AEs will occur continuously throughout the study.  Scheduled safety assessments 
including AE reporting is shown in Table 2. The definition and reporting of AE are described in Section 
9. During Phase 1, subjects who do not complete the first four infusions for reasons other than a DLT 
will be replaced. Based on the tolerability of KW-0761 in previous trials we expect a very low drop-out 
rate. If a subject begins a new treatment investigational or otherwise following participation in this study 
information regarding adverse events will continue to be collected but will not be considered secondary 
to KW-0761. 
4.6 Number of Subjects 
Enrollment of up to 72 subjects is planned. Of the 72 subjects a maximum of 24 will be enrolled in the 
dose escalation part of this study and the remaining 48 will be enrolled to 3 tumor-specific expansion 
cohorts. Depending on the dose escalation cohort, 2 to 5 additional subjects may be added to a cohort 
in whom a dose limiting toxicity has been observed to confirm results. During Phase 1, subjects who do 
not complete the first four infusions for reasons other than a DLT will be replaced. 
4.7 Treatment Assignment 
After informed consent has been obtained, subjects will be assigned a sequential screening number 
when screen procedures commence. Subjects are assigned a screening number after signing the 
informed consent form and prior to conducting any other study-related procedures. Those who 
withdraw or screen fail after being assigned a screening number will retain that number and the 
screening number will not be reassigned to another subject. Upon meeting all eligibility requirements 
and receiving KW-0761, subjects will be assigned a sequential study number. The first subject will be 
given the number 0001, the second will be 0002, and so on. This subject number will be maintained 
throughout the study. 
Subjects will be enrolled and dosed in sequential cohorts as outlined in the dosing schedule (Table 1). 
The Principal Investigator will conduct safety monitoring and cohort dosing will proceed conservatively. 
Prior to initiating dosing, the Investigator will send selected screening data on the Eligibility Checklist to 
the Principal Investigator for review and approval. Following enrollment of the first (sentinel) subject into 
a cohort and review of that subject's data through Day 8 (see Section 4.4), the Principal Investigator will 
determine if additional subjects may be enrolled in that cohort. 
Details regarding safety criteria for advancing or stopping subjects are summarized in Section 9.5 and 
Table 6. 
4.8 Criteria for Study Termination 
Safety-related Stopping Rules are outlined in Section 9.5. If a Stopping Rule is met, then further 
enrollment will cease and all available data on all subjects enrolled thus far will be reviewed by the and 
Principal Investigator to determine if the study should proceed and if so, what changes must be 
implemented. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 KW-0761 

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5.1.1 Description 
The KW-0761 drug product will be provided as an injectable solution, contained in single-use, 
ready-to-use 10 mL vials. Each vial contains 5 mL of a 4 mg/mL solution of KW-0761 drug 
substance in a colorless glass vial with fluoropolymer coated butyl rubber stoppers and 
polypropylene flipoff cap with aluminum overseal. 
5.1.2 Preparation of Dose 
The dose and volume of the study drug to be administered will be dependent upon the  
subject’s weight. If the subject’s body weight changes 10% or more at any time during the study 
relative to Day 1, subsequent doses of the study drug should be adjusted relative to the new 
weight. 
The appropriate volume of KW-0761 based on weight will be withdrawn and diluted into 
normal saline (NS, 0.9% sodium chloride). KW-0761 can be diluted with normal saline to various 
concentrations ranged (0.07 to 1.44 mg/mL in a 250-mL bag; 0.19 to 2.40 mg/mL in a 
500-mL bag; or 0.10 to 1.20 mg/mL in a 1000-mL bag) and stored at 25°C for up to 24 hours to 
effectively deliver the planned clinical doses. However, since there are no preservatives, it is 
recommended the product be used within 8 hours. KW-0761 will then be filtered through a 0.22 μm 
protein-sparing/low-protein binding in-line filter. Refer to the KW-0761 Pharmacy Manual for additional 
details. 
5.2 Study Drug Administration 
Subjects will receive KW-0761 as an i.v. infusion over 1 hour for the 0.5 and 1.0 mg/kg dose, 1.5 hours 
for the 3.0 mg/kg dose and 2 hours for the 10 mg/kg dose. Subjects will be observed closely for 1 hour 
following each administration of KW-0761 for any potential AEs in an area with resuscitation 
equipment. During Phase 1, vital signs (including temperature, pulse, respiratory rate, and blood 
pressure) will be checked and recorded prior to administration of KW-0761, every 15 minutes (± 5 
minutes) during infusion for the first treatment course and midway through and at the end of the 
infusion on subsequent treatment courses. Vital signs will also be measured every 30 minutes (± 5 
minutes) for the first hour following administration of KW-0761. During Phase 2 of the study, vital signs 
will be checked and recorded prior to start of infusion and at the end of the infusion. 
KW-0761 should only be administered under the supervision of a qualified physician. Premedication 
with acetaminophen 650 mg orally and diphenhydramine 50 mg i.v. or other antihistamine will be 
administered to all subjects. In the event that a subject experiences a grade 1 or 2 hypersensitivity 
reaction, the KW-0761 administration time may be increased. If this is not effective, removal of the 
subject from the study should be considered. Should a hypersensitivity reaction to KW-0761 occur, the 
subject must be treated according to the best available medical practices. Subjects should be 
instructed to report any delayed reactions to the investigator immediately. 
5.3 KW-0761 Formulation and Storage 

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For this study, KW-0761 is formulated at 20 mg/vial in 2.1 mM sodium citrate buffer, pH 5.5 containing 
300 mM glycine, and 0.02% polysorbate 80 (Tween 80). KW-0761 should be stored at a temperature 
of 2°C to 8°C. Drug supplies must be kept in a secure, limited access storage area under the 
recommended storage conditions. 
5.4 Packaging and Labeling of KW-0761 
KKP will distribute the study drug to the pharmacies at the study site. Vial labels will bear the 
appropriate text as required by regulatory agencies. At a minimum, the label will include: 
• 
appropriate cautionary statement limiting, by Federal Law, the new drug to investigational use; 
• 
product name (KW-0761) 
• 
drug storage requirements 
• 
lot number 
5.5 Drug Accountability 
The Principal Investigator and pharmacy at the study site are responsible for maintaining 
accurate records of the receipt, dispensing, and return of all investigational materials. The 
Investigator may dispense study drug only to subjects enrolled in the study. All dispensing 
must be from the site listed in the FDA form 1572. Under no circumstance will the 
Investigator allow study drug to be used other than as directed by the protocol. 
5.6 Return and Destruction 
Upon completion or termination of the study, all unopened vials of KW-0761 must be 
destroyed at the site. Disposal of these containers should occur at the investigational center according 
to the investigational site’s standard chemotherapy or biohazardous waste procedures. It will be the 
Investigator’s responsibility to arrange for disposal of all drug products with containers, provided that 
procedures for proper disposal have been established according to applicable regulations and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. A 
copy of the certificate of destruction must be placed in the trial master file. If the institutional site is 
unable to dispose of the study drug, then KKP should be contacted to arrange for destruction. All KW- 
0761 returned to should be accompanied by the appropriate documentation and be clearly identified by 
protocol number on the outermost shipping container. Returned supplies should be in the original 
containers (i.e., subject study drug containers that have clinical labels attached). Refer to the KW-0761 
Pharmacy Manual for additional details. 
5.7 KW-0761 Clinical Safety 
As of December 03, 2012, approximately 243 study subjects have received at least one dose of KW- 
0761 (doses of KW-0761 ranging from 0.0001 to 1.0 mg/kg in clinical studies of KW-0761) and safety 
information is summarized in Investigator’s Brochure Edition Number:9 (IB, see Appendix), Section 
5.2.1. Pooled treatment emergent adverse events (TEAEs) and serious adverse event (SAE) data 
considered at least possibly related to study drug for KKP Study KW-0761-001 and KHK Studies 0761- 
0501 and 0761-002 are summarized in IB Sections 5.2.1 and 5.2.1.1, respectively. Individual study 
synopses are provided in IB Section 5.2.3. 

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5.7.1 Safety Summary 
The most frequently observed TEAEs (≥ 10% of total subjects) that were considered to be at least 
possibly related to KW-0761 in completed studies of subjects with T-cell lymphoma in the US and 
Japan are presented in Table 3. The TEAEs observed have been generally mild to moderate (≤ Grade 
2) in severity. 
Infusion reaction was the most common TEAE. Most infusion reactions were generally mild to moderate 
in severity and symptoms (chills, fever, headache, etc.) were similar to what has been observed with 
other monoclonal antibodies. More subjects in the Japanese studies experienced infusion reactions 
than in the US, which may be attributable to more frequent and intensive monitoring in the in-patient 
hospital setting and the way infusion reactions are assessed in Japan. 
Skin rashes, including drug eruptions, considered to be at least possibly related to KW-0761 
administration have been reported in all studies. In the US Study KW-0761-001 in CTCL/PTCL with a 
dosing regimen of four weekly doses followed by one dose every other week, 17% of subjects (7 
subjects) experienced a study drug related rash, most of which were considered mild or moderate in 
severity. One subject had a Grade 3 rash. In the Japanese studies, study drug related rashes were 
observed in 25% of subjects (4 subjects) in the Phase 1 Study 0761-0501 (4 doses given weekly) and 
59% of subjects (16 subjects) in the Phase 2 Study 0761-002 (8 doses given weekly). The incidence 
and severity of the rashes observed in subjects in Japan is notably greater than what has been 
observed in the study conducted in the US. This may be related to differences in the dosing regimen, 
differences in underlying biology of the malignancies and/or differences in 
Table 3: TEAEs Considered at Least Possibly Related to KW-0761: Oncology Studies KW-0761- 
001, 0761-001, 0761-0501 and 0761-002 

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the underlying genetic predispositions (most subjects in Japan had ATL, while all but one in the US had 
CTCL). In the 0761-002 study, dosing with KW-0761 was not required to be discontinued after the 
appearance of rash, which was medically treated. In this study the number of doses received was 
related to both the incidence and grade of the skin rashes. After 4 weekly doses, the incidence of skin 
rash increased markedly with continued weekly dosing and the most severe skin adverse event 
experienced by a patient in this study tended to be with the highest number of doses. Cutaneous SAEs, 
including rash and Stevens- Johnson syndrome that were reported as possibly or probably related to 
KW-0761 are described in Section 5.7.2. 
In the non-oncology studies, one subject in a Phase 1 study in asthma (Study 20080407) developed a 
Grade 2 psoriasiform rash after receiving a single dose of KW-0761 (0.6 mg) administered 
subcutaneously. 
Most rashes observed in the studies in T-cell lymphomas have been characterized as spongiotic 
dermatitis, although there has been some variability in presentation. The rash observed in the subject 
with asthma was characterized as psoriasiform. There is also great variability in the time to onset of 
rash among subjects. The majority of subjects with ATL and CTCL/PTCL have underlying skin 
involvement and dysregulated skin immunity as a result of the underlying lymphoma/leukemia. 
Although the mechanism is unclear in terms of how skin rashes develop in these oncology subjects, 
rash appears to be manageable by temporarily withdrawing KW-0761 or adding topical and/or oral 
steroids. 

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The most common related ≥ Grade 3 laboratory TEAEs included lymphocyte count decreased (35.3%), 
white blood cell count decreased (11.8%), neutrophil count decreased (9.4%) and platelet count 
decreased (5.9%). Alterations in lymphocyte counts were anticipated based on the pharmacological 
activity of KW-0761. 
5.7.2 Serious Adverse Events 
Forty-six SAEs considered at least possibly related to KW-0761 were reported for 32 subjects. Data are 
presented for all studies in Table 4. 
Several SAEs have been the result of CMV reactivation (chorioretinitis, pneumonia). In Study 0761- 
003, KW-0761 is given in combination with the chemotherapeutic regimen, mLSG15, in subjects with 
ATL. Both the chemotherapeutic regimen and the disease itself are immunosuppressive. A recent study 
demonstrated that subclinical reactivation of CMV was common (50.6%) in ATL patients receiving 
chemotherapy.44 Since there is a temporal association between the KW-0761 and chemotherapy 
infusions, relationship to KW-0761 cannot be ruled out. 
One subject in Study 0761-0501 with ATL experienced hepatitis B (HB) reactivation following treatment 
KW-0761. Blood samples obtained from the subject after the onset of symptoms were positive for 
hepatitis core antibody. Repeat testing confirmed that HBs antigen and HBs antibody were both 
negative prior to antibody treatment. The protocol did not require testing for hepatitis B core antibody or 
HBV-DNA at the time the subject was enrolled in the study. The protocol was subsequently amended to 
require such testing to prevent HBV activation in other subjects. 
One subject in Study 0761-0501 who received 4 weekly infusions of 0.01 mg/kg of KW-0761 
experienced herpes zoster on study Day 99. Another subject in Study 0761-004 experienced herpes 
esophagitis on study Day 68. These subjects did not have a prior history of herpes infection. 
Seven subjects in clinical trials experienced SAEs of rash and one subject experienced an SAE of 
Stevens-Johnson syndrome (SJS) that were reported as possibly or probably related to KW-0761; 7 of 
these subjects were treated in Japanese studies of KW-0761. SJS was reported for a subject in the 
Phase 2 ATL study in Japan (0761-002). A 71-year-old woman received 1 mg/kg KW-0761 weekly for 8 
weeks and developed a Grade 1 skin eruption suspected of being a drug eruption related to a 
concomitant medication on Day 21. The skin eruption worsened over a period of several weeks and the 
subject was hospitalized with SJS on Day 75. It should be noted that the subject was on numerous 
medications, several of which have been associated with SJS. The subject was treated with ophthalmic, 
iv and oral steroids, antihistamines, anti-virals and immunoglobulin. As of Day 401, the event            
was reported as resolving. 
Several SAEs have been the result of new onset malignancies. Two subjects with Sézary syndrome in 
study KW-0761-001, both from the same study site, were reported to have secondary T-cell 
malignancies that were immunophenotypically distinct T-cell lymphomas, i.e., gene rearrangements 
different from their initial diagnoses. It is well known, however, that in patients with CTCL, the presence 
of multiple T-cell clones, although not common, does occur with regularity. 

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Table 4. Serious Adverse Events at Least Possibly Related to KW-0761 (all studies) 
 

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A male subject who was enrolled as a healthy volunteer and received 0.001 mg/kg of KW-0761 in 
Protocol 0761-EU-001 developed B-cell lymphoma on study Day 66. Following study participation, 
subject presented to primary physician with swelling on the right side of his groin. It was not routine 
policy in this Phase 1 unit to include assessment of inguinal lymph nodes on routine physical 
examinations and so this was not assessed at protocol screening visit. An independent  review of the 
case by expert hematologists/oncologists concluded that given the indolent nature of this disease and 
its extensive spread in this subject, it was not likely that it developed, in this timescale, as a 
consequence of injection of the study drug. The Investigator later concurred, noting this was subclinical 
disease not detected at screening. 
5.7.3 Deaths 
There have been 11 deaths reported while on study in subjects receiving KW-0761 all of which were 
considered not related to the study drug. The causes of death included bronchopneumonia, disease 
progression, pneumonia, and septic shock. 
5.8 Concomitant Medications 
During the study period, subjects should not receive treatment with systemic corticosteroids or other 
immunosuppressive agents including chemotherapy unless approved by the principal investigator. 
Topical and inhaled steroids are permitted. Treatment with antihistamines and non-steroidal anti- 
inflammatory drugs, including COX-2 inhibitors, are not recommended but may be continued or 
instituted at the discretion of the treating physician if necessary. Investigator may prescribe all other 
concomitant medications or treatments deemed necessary to provide adequate subject care. All 
prescription and nonprescription concomitant medications must be recorded in CRDB, listing generic 
name, indication, dose and schedule and dates of administration. 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.2 
Subject Inclusion Criteria 
A subject will be eligible if all of the following apply: 
1. Informed Consent form signed by the subject. 
2. Males and females 18 years or older at the time of dose initiation. 
3. Histologically confirmed unresectable solid tumor malignancies with at least 1 measurable 
lesion in dose escalation. In the expansion phase, eligibility limited to metastatic triple negative 
breast cancer that has received prior taxane and anthracycline therapy; Metastatic NSCLC that 
is not ALK+ and does not have a EGFR sensitizing mutation; and metastatic gastric cancer. 
4. Previously treated for advanced cancer and there are no curative therapy options available. 
5. Karnofsky Performance Status ≥70 in the 30 day baseline period immediately prior to dosing. 
6. All female subjects of child bearing age must be either surgically sterile, postmenopausal for at 
least 1 year, or using an acceptable method of contraception. Examples of adequate methods of 

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contraception include abstinence, intrauterine device, hormonal contraception, use of spermicide 
and a condom by sexual partner, or partner with a vasectomy. Adequate contraception         
must be used from the beginning of the screening period until at least 16 weeks                     
after the last dose of KW-0761. Male subjects with partners of childbearing potential must use a 
barrier method of contraception from the day of the first dose of KW-0761 until at least 16 weeks 
after the last dose. 
7. Evidence of adequate organ function by standard laboratory tests: 
a. Cr ≤ 1.5 X upper limit of normal (ULN). 
b. Total Bilirubin (T-Bil) ≤ 1.5 X ULN (prior diagnosis or past history consistent with Gilbert's 
syndrome is an exception). 
c. AST and ALT ≤ 2.5 X ULN. 
d.  Plts ≥ 100,000 /L 
e. Hgb ≥ 9.0 g/dL. 
f. 
Absolute neutrophil count (ANC) ≥ 1000/mm3 
8. Life expectancy > 12 weeks 
9. Previously treated for advanced cancer with no additional therapy options available known to 
prolong survival. 
6.3 
Subject Exclusion Criteria 
A subject will be ineligible if any of the following apply: 
1. Evidence of clinically significant central nervous system (CNS) metastases or symptomatic CNS 
metastases within 30 days prior to dosing. 
2. History of autoimmune disease, except for vitiligo, diabetes, and autoimmune thyroiditis. 
3. A history of any major surgery within 6 weeks prior to dosing. 
4. Any history of systemic anti-cancer therapy (standard or experimental) completed within 30 
days prior to dosing, with the exception of palliative ablation of lesion(s) as long as measurable 
disease lesion(s) remain for evaluation of exploratory endpoints. 
5. Any concomitant serious physical illness other than cancer (i.e., immune deficiency disease, 
bleeding disorder, etc.) within 1 year prior to dosing. 
6. Any history of Stevens-Johnson syndrome. 
7. Clinically significant heart disease, defined as NYHA Class III or IV. 
8. Any allergic reaction to a previously administered monoclonal antibody or other therapeutic 
protein. 
9. Any significant systemic infection within 4 weeks prior to dosing. 

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10. Pregnancy or breast-feeding. 
11. An existing diagnosis of HIV, hepatitis B, hepatitis C, or any current laboratory findings or 
clinical signs and symptoms that suggest these conditions. 
12. Subjects with active herpes simplex or herpes zoster. Subjects with a history of herpes zoster 
who have had an outbreak within the last year will also be excluded. Subjects on prophylaxis for 
herpes who started taking medication at least 30 days prior to study entry, should continue to 
take the prescribed medication for the duration of the study. 
13. Unresolved immune-related adverse events following prior biological therapy 
14. Use of any investigational drugs within 30 days prior to dosing. 
15. Any condition that requires or is likely to require treatment with systemic corticosteroids within 
the Core Study Period and short term follow-up. 
16. Subjects that have had a myocardial infarction within the last 6 months. 
17. Subjects on any immunomodulatory drug. 
7.0 
RECRUITMENT PLAN 
Potential research subjects will be identified by a member of the patient’s treatment team, the protocol 
investigator, or research team at Memorial Sloan Kettering Cancer Center (MSKCC). If the investigator 
is a member of the treatment team, s/he will screen their patient’s medical records for suitable research 
study participants and discuss the study and their potential for enrolling in the research study. Potential 
subjects contacted by their treating physician will be referred to the investigator/research staff of the 
study. 
The principal investigator may also screen the medical records of patients with whom they do not have 
a treatment relationship for the limited purpose of identifying patients who would be eligible to enroll in 
the study and to record appropriate contact information in order to approach these patients regarding 
the possibility of enrolling in the study. 
During the initial conversation between the investigator/research staff and the patient, the patient may 
be asked to provide certain health information that is necessary to the recruitment and enrollment 
process. The investigator/research staff may also review portions of their medical records at MSKCC in 
order to further assess eligibility. They will use the information provided by the patient and/or medical 
record to confirm that the patient is eligible and to contact the patient regarding study enrollment. If the 
patient turns out to be ineligible for the research study, the research staff will destroy all information 
collected on the patient during the initial conversation and medical records review, except for any 
information that must be maintained for screening log purposes. 

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In most cases, the initial contact with the prospective subject will be conducted either by the treatment 
team, investigator or the research staff working in consultation with the treatment team. The recruitment 
process outlined presents no more than minimal risk to the privacy of the patients who are screened 
and minimal PHI will be maintained as part of a screening log. For these reasons, we seek a (partial) 
limited waiver of authorization for the purposes of (1) reviewing medical records to identify potential 
research subjects and obtain information relevant to the enrollment process; (2) conversing with 
patients regarding possible enrollment; (3) handling of PHI contained within those records and provided 
by the potential subjects; and (4) maintaining information in a screening log of patients approached (if 
applicable). 
Before being enrolled, subjects must consent to participate after the nature, scope, and possible 
consequences of the study have been explained in a form understandable to them. An informed 
consent form will be prepared and given to the subject. This document will contain all the elements 
required by FDA CFR Part 50 the ICH E6 Guideline for GCP and any additional elements required by 
local regulations. The document must be in a language understandable to the subject. Where required 
by local law, the person who informs the subject must be a physician. 
After reading the informed consent form and any other IRB approved subject-specific study information, 
and having had ample opportunity for his questions to be answered by an adequately trained medical 
professional, the subject must give consent in writing before any study-specific procedures can 
commence. The subject's consent must be confirmed at the time of consent by the personally dated 
and timed signature of the subject. 
A copy of the consent document and any other subject-specific information reviewed as part of the 
consent process must be given to the subject The original signed consent document will be retained by 
the Investigator. 
If the subject is unable to read, oral presentation and explanation of the patient information sheet and 
the informed consent form and any information to be supplied to subjects must take place in the 
presence of an impartial witness. Consent must be confirmed at the time of consent orally and by the 
personally dated and timed signature of the subject or by a local legally recognized alternative (e.g., the 
subject's thumbprint or mark). The witness to the informed consent discussions must also sign and 
personally date the consent document. 
The Investigator will not undertake any measures required for the clinical study until valid consent has 
been obtained. 
This protocol will take due notice of NIH/ADAMHA policies concerning inclusion of women and 
minorities in clinical research populations. We expect that the study population will be fully 
representative of the range of patients referred for treatment without exclusion as to age, gender, or 
ethnic background. Pregnant women are excluded from participation in this study. 
This cost of this study will be covered by a combination of funds from Kyowa Hakko Kirin Pharma, 
grants awarded to the Co-Principal Investigator, and additional funding from the Ludwig Institute for 
Cancer Research at MSKCC. 
The anticipated study accrual time is 2.5 years. 

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8.1 
PRETREATMENT EVALUATION 
Pre-treatment evaluations used to determine the subject’s study eligibility must be completed within 30 
days prior to the first dose of KW-0761, except as otherwise specifically noted below. Written informed 
consent must be obtained prior to any study-specific screening evaluations and before subject 
enrollment. 
All subjects must undergo the following screening evaluations: 
• 
medical history including cancer history and prior therapies, as well as concomitant medical 
conditions and medication use 
• 
physical examination (including height [at baseline only] and weight measurements) 
• 
Karnofsky performance status 
• 
vital signs 
• 
ECG 
• 
urine pregnancy test in women of childbearing potential 
• 
urinalysis 
• 
chemistry profile 
• 
hematology profile 
• 
coagulation profile 
• 
flow cytometry of lymphocyte subsets 
• 
serum cytokines 
• 
CMV Ag and Ab 
• 
quantitative immunoglobulins 
• 
HIV 
• 
hepatitis panel 
• 
concomitant medication assessment and those medications taken 30 days prior to the first dose 
of study medication 
• 
chest, abdominal, pelvic CT or MRI scans or PET/CT (within 30 days prior to the first dose of 
KW-0761) 
Results of all screening evaluations must be reviewed by the Principal Investigator or his/her designee 
to ensure that all eligibility criteria have been satisfied prior to subject treatment. 
9.1 
TREATMENT/INTERVENTION PLAN 
9.2 Dose Schedule 
As shown in Section 4.1, in the first treatment course, KW-0761 will be administered i.v. once a week 
for four weeks (Cycle 1) and subsequently every 2 weeks for 4 weeks (Cycle 2). Subsequent treatment 
courses are permissible for subjects demonstrating a response or maintaining stable disease and will 
consist of an infusion of KW-0761 every other week. Each subsequent course (treatment course 2, 
treatment course 3, etc.) will be defined as completion of two additional infusions of KW-0761 over 4 
weeks. In the absence of progression or toxicity subjects may continue treatment up to 1 year. If a 
subject experiences an overall CR, the subject may continue on study for up to an additional four 
infusions beyond CR, then discontinue treatment in order to determine duration of response. If a 
subject experiences a PR or SD, the subject may continue therapy after consultation between the 

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Investigator and the Principal Investigator until disease progression occurs or other withdrawal criteria 
are met (refer to Section 4.8, Criteria for Study Termination). 
Standard 3+3 cohorts for safety and DLT detection will be utilized (Table 1). Each cohort will consist of 
at least three subjects. If DLT is observed in 0/3 subjects, escalation to the next dose level will occur. If 
DLT detected in 1 of 3 subjects, then three more subjects will be added at that dose level. If DLT is 
demonstrated in an additional subject, dose escalation will cease (see Section 14 - Biostats for a 
summary). 
Phase II of the study will enroll a total of 48 subjects, 16 patients in 3 tumor-specific expansion cohorts 
each treated with the MTD (or highest dose tested) as determined in Part 1 of the study. The 3 tumor- 
specific expansion cohorts will include non-small cell lung cancer, gastric adenocarcinoma, and triple- 
negative (negative for immunohistochemical expression of the estrogen receptor, progesterone 
receptor, and the Her2 protein) breast adenocarcinoma. 
9.3 Toxicity Definitions 
All AEs will be evaluated and reported according to the NCI CTCAE v.4.03. For toxicity grading based 
on laboratory tests, an abnormality must be confirmed (when appropriate) by repeat testing. 
9.3.1 Dose Limiting Toxicity 
The occurrence of the following toxicities will be considered a DLT, if judged by the Investigator to be 
possibly, probably or definitely related to study drug administration: 
The definition of DLT is any > Grade 3 hematologic or non-hematologic toxicity that is related to 
treatment. 
Exceptions: 
The following are exceptions to the definition and will be considered a DLT if: 
• 
Grade 4 neutropenia > 7 days 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 thrombocytopenia associated with clinically significant bleeding 
In the case of Grade 2 immune related adverse events (irAE, defined below) study drug administration 
will be delayed until event diminishes to Grade 1 or less. 
Immune related Adverse Events 
An irAE is defined as a clinically significant adverse event of any organ that is associated with study 
drug exposure, of unknown etiology, and is consistent with an immune-mediated mechanism. 
Serologic, immunologic, and histologic (biopsy) data should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic 
causes of the irAE. 

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Given the intended mechanism of action of KW-0761, particular attention will be given to adverse 
events that may follow enhanced T-cell activation such as dermatitis and colitis, endocrinopathies, or 
other irAEs. 
9.3.2 Infusion Reactions: Grading and Management 
Intravenous administration of biologic agents carries a potential risk of hypersensitivity reactions. 
Infusion reactions will be graded according to the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03. 
Table 5 outlines the infusion reaction grading system, associated symptoms, and the recommended 
actions to be taken regarding treatment. Reactions occurring within 24 hours after the start of KW-0761 
infusion will be considered to be infusion related AEs. Premedication with acetaminophen 650 mg orally 
and diphenhydramine 50 mg i.v.  or other antihistamine will be administered to all subjects. 
As with all AEs, infusion-related signs or symptoms which, in the Investigator's judgment, are not 
related to hypersensitivity reactions (e.g., dyspepsia, urinary frequency, etc.) should be recorded and 
graded as AEs according to NCI CTCAE v.4.03 criteria in CRDB. Based on nonclinical in vitro and in 
vivo data, KW-0761 administration is not expected to cause cytokine release syndrome (CRS). 
Although there is significant overlap in the clinical presentations of anaphylaxis and CRS and either can 
occur during or within 2 hours of completion of infusion of biologic agents, some symptoms, such as 
arthralgia and chills, are more likely to be due to CRS than anaphylaxis. The NCI CTCAE v.4.03 will be 
used to grade and report infusion reactions consistent with CRS. 
Stopping Rules will not apply to a specific toxicity if it is clearly unrelated to KW-0761 infusion (e.g., 
laceration, burn, or similar accidental trauma unrelated to some other infusion-related AE). 
Table 5: Infusion Reaction Grading 
Grade Symptoms 
Course of Action 
1 
Transient flushing or rash, drug 
fever (≥38˚C) 
No intervention required 
2 
Rash, flushing, urticarial, 
dyspnea, drug fever (≥38˚C) 
Decrease the infusion rate by 50% and 
proceed with dosing. 
3 
Symptomatic bronchospasm and 
urticarial with need for parenteral 
medication(s), allergy-related 
edema/angioedema, hypotension 
Stop infusion. Give supplemental oxygen and 
bronchodilators as necessary. Subject will not 
receive any further KW-071. 
4 
Anaphylaxis 
Stop infusion. Administer no further KW-0761 
to subject. Contact principal investigator 
immediately. Investigator(s) review within 72 
hours. Further actions related to study 
conduct will be submitted to IRB for approval 
before initiation. 
5 
Death 
Contact principal investigator immediately. 
Further cohort dosing suspended. 
Investigator(s) review within 72 hours. Further 
actions will be submitted to IRB for approval 
before study resumed. 

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9.3.3 Treatment of Emergent Skin Rash 
In the event a patient develops a treatment emergent skin rash, the following measures must be taken 
to appropriately document the event: 
Initial Work-up of all skin rashes (new and re-challenge) 
1) 
Photograph the rash. 
2) 
If the rash is ≥ Grade 2 or if the affected area cannot be differentiated from a new area of 
cutaneous metastasis, a biopsy must be performed. Biopsy the rash as well as an area 
of unaffected skin in order to compare possible drug eruption to background involved 
skin. 
3) 
Confer with Principal Investigator after completion of one week of treatment with topical 
corticosteroids to assess response to treatment. 
4) 
Forward all results to the Principal Investigator and discuss a treatment plan with 
medical follow up. 
5) 
Biopsy should be read by the dermatopathologist at the study center. 
Rash Treatment Guidelines (after initial work-up): 
Grade 1 rash (drug related or non-drug related) 
1) 
Treatment with study drug may continue. 
2) 
Treat rash with topical corticosteroids as needed. 
Grade 2 or above rash (drug related) 
1) 
Treatment with study drug must be stopped. 
2) 
Treat rash with 2-week course of topical corticosteroids. 
3) 
After 2-week course, re-assess rash per the steps outlined in initial assessment; if 
resolved completely or to Grade 1, study drug treatment may be resumed. If not 
resolved, contact the Principal Investigator for further discussion. 
4) 
Subjects with Grade 3 or 4 rash will not receive any further KW-0761. 
Grade 2 or above rash on re-challenge 
1) 
If rash recurs and becomes a Grade 3, the patient must be discontinued from the trial 
and the rash work up above must be completed. 
2) 
If the rash recurs at a Grade 2, follow the steps above for Grade 2 Rash. 
3) 
If the rash recurs at Grade 2 or higher for a third time, the rash work up must be 
performed and the patient must be discontinued from the trial. 
4) 
Subjects with Grade 3 or 4 rash will not receive any further KW-0761. 
9.3 Assessment of Safety 
Safety is a primary endpoint for this study. Safety will be evaluated for all treated subjects using 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.03 (CTCAE). 

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Safety assessments will be based on medical review of adverse event reports and the results of vital 
sign measurements, physical examinations, and clinical laboratory tests. The incidence of observed 
adverse events will be tabulated and reviewed for potential significance and clinical importance. The 
reporting period for safety data will be from the time following the subject’s written consent to participate 
in the study until 90 days after the last dose. The timing of all Safety assessments, including AE 
reporting and laboratory assessments, is shown in the Schedule of Assessments, Table 2. 
9.4 Serious and Serious Adverse Events 
9.4.1 Definition of Adverse Events 
An AE is any untoward medical event that occurs in a subject who has received an investigational 
product, and does not necessarily need to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an investigational product, whether or not related to 
the product. 
All AEs will be evaluated and reported according to the NCI CTCAE v.4.03. 
9.4.2 Treatment Emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is an AE that begins or that worsens in severity after the 
start of the first exposure to KW-0761. Only TEAEs will be recorded in CRDB. For the purposes of this 
study, the terms "AE" and "TEAE" may be used interchangeably. Adverse events that occur during the 
Screening and Baseline periods are not treatment emergent and will be recorded in the subject's 
medical records, but not in CRDB. 
An illness present at study entry is considered a pre-existing condition, not an AE. Pre-existing 
conditions will be recorded in CRDB. If a subject experiences clinically relevant worsening of a pre- 
existing condition after any KW-0761 has been administered, this will be considered an AE. 
Signs and symptoms present at baseline will be documented as pre-existing symptoms in CRDB. 
9.4.3 Serious Adverse Event 
An SAE is any untoward medical occurrence that: 
1. Results in death, 
2. Is life-threatening,A 
3. Requires in-patient hospitalization or prolongation of existing hospitalization, 
4. Results in persistent or significant disability or incapacity, 
5. Is a congenital anomaly or birth defect, and/or 
6. Is another medically important conditionB 
A. The term "life-threatening" in the definition of "serious" refers to an event in which the subject is at 
risk of death at the time of the event; it does not refer to an event, which hypothetically might have 

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caused death if it were more severe. The term "severe" is often used to describe the intensity (severity) 
of an event (such as: mild, moderate, or severe, e.g., pain). The event itself may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious", which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to the 
subject's life or vital functions. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
B. Medically important conditions that may not result in death, but may be immediately life-threatening 
or require hospitalization may be considered as SAE when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require intervention to prevent one of the outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
Reporting requirements for SAEs are described in Section 9.4. 
9.4.4 Relationship to KW-0761 
The relationship of all AEs to KW-0761 will be determined by the Investigator on the basis of clinical 
judgment, using one of the following terms (in accordance with NCI Guideline "Expedited Adverse 
Event Reporting Requirements for NCI Investigational Agents", NCI Cancer Therapy Evaluation 
Program, January 2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 
Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment of causality, it should be taken into consideration that 
immunomodulatory agents have the potential to cause late and/or permanent effects on the immune 
system, i.e., a causal relationship could exist despite a lack of apparent temporal relationship. 
Information provided in the IB and/or in this protocol may support these evaluations. 
9.5 Safety Criteria for Advancement, Adjustment, or Stopping Dosing Within a Cohort 
This is safety and tolerability study. Safety monitoring will be conducted by the Principal Investigator. 
Subjects will be monitored at the investigative site according to the schedule of assessments outlined in 
Table 2. Additional assessments to evaluate and/or treat any AEs may be performed at the discretion of 
the Principal Investigator. In the event that a subject will need to undergo palliative surgery or radiation, 
the schedule of dosing and assessments will be modified to allow for the treatment to be administered. 
The adjustments will be made in coordination with the Principal Investigator and the subject’s 
physicians. 

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9.5.1 Dose Limiting Toxicity 
Patients in each cohort must complete the first 4 weeks of study therapy prior to enrollment of 
subsequent cohorts. For the purpose of determining the MTD, the timeframe for evaluating patients for 
DLT will be within 4 weeks of study therapy. All adverse reactions should be considered relevant to 
determining dose limiting toxicity and to reporting, unless the event can clearly be determined to be 
unrelated to the drug. Sites must notify the Principal Investigator within 24 hours of having knowledge 
of DLT. All investigators in the study will be notified of any DLTs at each dose level before dose 
escalation. 
Subjects experiencing a DLT during any course of treatment should receive no further administration of 
KW-0761. However, subjects exhibiting clinical benefit and who experience DLT may be eligible for 
further administration of KW-0761 on a case by case basis following discussion with the Principal 
Investigator. 
A dose limiting toxicity (DLT) will be defined as any toxicity that does not have a clear-cut alternative 
explanation. Any of the following, specified below, will be considered a DLT: 
• 
>Grade 3 non-hematologic toxicity 
• 
>Grade 3 hematologic toxicity 
• 
>Grade 3 allergic reaction/hypersensitivity reaction (including drug fever) 
• 
>Grade 3 cytokine release syndrome/acute infusion reaction 
9.5.2 Exceptions to Dose Limiting Toxicity 
The following are exceptions to the definition and will be considered a DLT if: 
• 
Grade 4 neutropenia > 7 days 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 thrombocytopenia associated with clinically significant bleeding 
Patients who enter the trial with Grade 2 elevation of liver enzymes due to hepatic 
involvement by malignancy must have an increase in hepatic enzymes to Grade 3 that persists for at 
least 7 days for this toxicity to represent a DLT. 
9.5.3 Definition of Maximum Tolerated Dose (MTD) and definition of Maximal Dose Level 
The MTD is defined as the dose below that dose at which at least 2 of up to 6 subjects in a dosing 
cohort experience DLT. The MTD will be determined during Phase 1. In the absence of MTD, the 
maximal dose level is the highest dose evaluated in this study without evidence of DLT. 
9.6 Dose Escalation 
Toxicity data for each cohort will be reviewed prior to dose escalation. The dose for the first cohort will 
be 0.5 mg/kg. In the absence of a DLT, dose will be escalated as indicated in the cohorts listed in Table 
1. Dose escalation will cease when at least one of the following endpoints is reached: 

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• 
The MTD is exceeded; Or 
• 
A cohort of at least 3 subjects has been dosed with 10 mg/kg KW-0761 
Dose escalation will be based on at least three evaluable subjects receiving four complete infusions of 
KW-0761. 
9.7 Cohort Size and Stopping Rules 
See Table 6 for a summary. 
Table 6. Determination of DLT and MTD 
 
9.8 Replacement of Subjects 
During the dose escalation phase of this study subjects who do not complete the first four infusions for 
reasons other than a DLT will be replaced. 
9.9 Phase II – Preliminary Assessment of Efficacy and Further Assessment of Safety 
After determination of the MTD or maximal dose level if MTD is not exceeded, additional subjects will 
then be enrolled and treated at that dose if feasible, or a lower dose if not feasible in three disease 
specific cohorts. Fourty-eight subjects, are to be treated with the dose determined from the initial 
portion of the study. 
If during Phase I/II portion of the study compelling evidence collects of response in a particular tumor 
type the protocol may be amended to include an expansion cohort. 
There will be no dose reductions allowed during the Phase II portion of the study. 
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9.11 Pharmacodynamic Assessments 
Pharmacodynamic assessments will be performed on all patients in this study. Available research blood 
and tumor samples will be delivered to the Immune Monitoring Facility (IMF) for processing and 
cryopreservation.  Available stool samples will be similarly brought to the Molecular Microbiology Core 
Facility. Subjects will bring in samples when feasible.  It is understood that the bowel habits of subjects 
will vary widely and as such it is likely that not all collections are possible, if this is the case subjects will 
be allowed to continue on study. 
If a site of tumor is readily available as a cutaneous lesion a simple punch or excisional biopsy under 
local anesthesia can be performed by the co-principal investigator or qualified personnel. If tumor is as 
readily accessible then an image-guided core needle biopsy will be obtained following consultation with 
the radiology staff to determine the overall risk of the procedure. Invasive procedures that require 
general anesthesia should not be performed to obtain a biopsy specimen. If a surgical procedure is 
performed for a clinical indication a sample may be used for research purposes. During the course of 
treatment a decision may be made to perform the post-treatment biopsy earlier than 15 days if there is 
evidence to suggest a possibility that by day 15 there will be no available tumor for biopsy due to a 
rapid clinical response. Similarly the biopsy may be performed later than 15 days if there is evidence to 
suggest a delayed response. 
Tumor tissue obtained from biopsies will be divided equally for fresh frozen paraffin embedding and 
cryopreservation by the IMF. 
9.11.1 CCR4+ T cell depletion 
The degree of depletion of CCR4+ T cells by KW-0761 will be determined by flow cytometry. The 
proportion of CCR4+ T cells to other T cell subsets as well as the concentration in a fixed volume of 
blood will expressed in relation to base line levels as well as time. 
9.11.2 Serum Biomarkers 
Pre-treatment and on-treatment serum levels of chemokines, cytokines, and tumor-associated soluble 
proteins will be assessed by techniques that may include but are not limited to, ELISA or multiplex 
assays. Analytes may include markers of inflammation, immune activation, host tumor growth factors, 
and tumor-derived proteins. These assays will take place in the Immune Monitoring Facility (IMF) and a 
messenger will bring the samples to the IMF from the ITC. The sample will need to arrive to the ITC 
within 6 hours of blood draw. 
Serologic assays using multiplexed ELISA to determine antibody titers to tumor-associated antigens will 
also be performed by the IMF. Theses assays are used to estimate the titer of antibodies specific to one 
or more tumor-associated antigens, including but not limited to cancer-testis (CT) antigens such as NY-
ESO-1, in human serum or plasma samples. Monitoring of potential changes in particular tumor 
antigen-specific antibody responses during the course of cancer immunotherapy may predict response 
or provide further understanding of the mechanism of action of KW-0761. 
9.11.3 Immunophenotyping 
Immunophenotyping will be determined using flow cytometry to determine the effect on individual 
lymphocyte subsets in peripheral blood mononuclear cells (PBMC) and in tumor if sufficient tumor 
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tissue is present. Flow cytometric assessment of the lymphocyte subsets CD4+, CD8+, CD16+, CD19+ 
and CD56+ will be examined as percent and absolute number. FOXP3+ and FOXP3- lymphocytes with 
the following markers will also include but not limited to: CD4+, CD25, CD45RA, CD45RO, LAG3, 
GARP, PD1, and CTLA4. Activation markers such as CD44 and CD69, will also be examined. These 
assays will take place in the Immune Monitoring Facility (IMF). 
In order to determine if the depletion of Treg cells has an effect on pre-existing immunity to multiple 
non-tumor antigens, PBMC will be analyzed with a panel of HLA tetramers to common antigens 
including those used in routine vaccinations. This will be done in collaboration with Dr. Ton 
Schumacher of the Netherlands Cancer Institute who has developed and validated the panel of HLA- 
Tetramers. In order to choose tetramers that are specific to the individual patients HLA, a sample of 
PBMCs will undergo HLA typing by the New York Blood Center. The samples that will be sent to The 
New York Blood Center as well as to Dr. Schumacher’s group will be de-identified to ensure that 
privacy will be maintained. 
Phenotypic analysis of TILs by immunohistochemistry will be performed to identify and characterize 
tumor infiltrating immune cells. We will also assess tumor cell apoptosis, hypoxia, vascularization, and 
proliferative activity as described. These assays will be performed by MSKCC tumor pathology core, 
where tumor hypoxia, apoptosis, and proliferation indices are analyzed in a standardized manner by 
MSKCC Molecular Cytology facility. The tumor tissue will be accessioned and stored by the IMF until 
analysis. 
Archival tumor biopsy material if present may be examined for biomarkers of interest and/or infiltrating 
immune cells and their presence or absence correlated with observed clinical outcomes. If such an 
analysis is planned a separate tissue procurement protocol will be submitted for review. 
9.11.4 Cellular Assays 
To explore if KW-0761 has an effect on the function of T cells assays that determine the production of 
effector molecules including but not limited to IFN-g and Granzyme B will be assessed by flow 
cytometry in response to non-specific or antigen specific restimulation. Examples of antigen specific 
stimulation include the use of either tumor specific antigens or commonly exposed antigens such as 
influenza proteins. These assays will be performed on cryopreserved PBMC in the IMF. 
The IMF may also perform ELISPOT, flow tetramer staining, and/or intracellular polyfunctional cytokine 
staining, TCR Vβ Repertoire analysis and Spectratyping to further characterize tumor-antigen specific 
CD4+ and CD8+ T cell response before and after treatment. PBMCs and TILs from relevant tissue will 
be archived for all patients to support complete analysis of the profile. 
9.11.5 Gene Expression Profiling 
Analysis of the transcriptome of PBMC or tumor tissue may provide further understanding of the 
mechanism of action of KW-0761. Cryopreserved PBMC and tumor tissue will submitted to the 
Integrated Genomics Core Facility for RNA extraction, SMARTer amplification, and mRNA sequencing 
on the HiSeq sequencing platform. Analysis of the data will be performed with the assistance of the 
bioinformatics core facility. Further analysis of gene expression may be performed with quantitative 
real-time polymerase chain reaction (qPCR) or additional multiplexed gene expression assays to detect 
expression of selected immune-related genes. 
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9.11.6 Stool Microbial Composition and Metabolite Analysis 
The composition of the stool microbiota modulates the activity of the immune system through the 
production of various bioactive metabolites. Modulation of the immune system by KW-0761 may alter 
the composition of the stool microbiota that can lead to adverse events such as colitis. Thus, we will 
collect fecal samples from patients prior to, and after treatment and assess changes in composition of 
microbial community using 16S RNA sequencing and metagenomic analysis as a correlate for intestinal 
inflammation as a result of Treg cell depletion. Analysis of various bacterial metabolites including but 
not limited to short-chained fatty acids will also be performed by nuclear magnetic resonance or 
chromatography. Subjects at home will collect the stool samples with the use of a stool collection kit. 
The kit will include detailed instructions on collection, handling, and transport of the sample. When the 
sample is brought to the ITC, it will be refrigerated and sent to the Molecular Microbiology Core Facility 
by a messenger. The sample should arrive at the core facility within 12 hours of arrival at the ITC. The 
sample should be collected by the patient within 24 hours of arrival to the ITC. 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1 Treatment course Evaluations 
A series of clinical tests and procedures will be performed at different intervals throughout the study 
(Table 2). 
Evaluations to be performed periodically during the study include: 
• 
Physical examination 
• 
Karnofsky PS 
• 
Vital signs 
• 
ECG 
• 
Urinalysis 
• 
Chemistry profile 
• 
Hematology profile 
• 
Coagulation profile 
• 
Flow cytometry of peripheral blood lymphocytes 
• 
AE assessment 
• 
Concomitant medication assessment 
• 
Cross-sectional imaging (Chest, abdominal, pelvic CT or MRI scans, or PET/CT) 
• 
Assessment of tumor response (AJCC, TNM and irRC) 
10.2 Disease Monitoring Criteria 
Disease stage will be assessed by the AJCC TNM Clinical Staging 107. Clinical stage from medical 
history will be documented from medical records during Screening (Inclusion/Exclusion Review). 
Clinical staging will be assessed by review of medical records, review of pathologic staging of the most 
recent lymph node biopsies, and imaging for evaluation of metastases within 30 days of KW-0761 

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dosing and at Day 15 of Cycle 2. Clinical staging will be documented at Baseline/Screening and 
repeated and documented at Day 15 of Cycle 2. When possible, tumor progression will be assessed 
according to irRC at Baseline, Day 15 of Cycle 2 and every 2 cycles thereafter, and as data are 
available and/or clinically indicated- during Long-term Follow-up 108,109. 
The irRC criteria allow for continued treatment beyond progression of disease (in order to confirm 
response). Treatment beyond what would be considered progression of disease using RECIST 1.1 
criteria will be permitted if the following criteria are met: 
• Investigator-assessed clinical benefit, and do not have rapid disease progression 
• Continue to meet all other study protocol eligibility criteria 
• Tolerance of study drug 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g. CNS metastases) 
10.3 
Discontinuation of Study Therapy 
In accordance with the Declaration of Helsinki, ICH Good clinical Practice Guidelines, and the US FDA 
Regulations, a research subject has the right to withdraw at any time for any reason without prejudice 
to future medical care. Further criteria for removal from the study are described in Section 13. In the 
absence of a medical contraindication or significant protocol violation, every effort will be made by the 
Principal Investigator to keep the subject in the study; however, should the subject decide to 
discontinue treatment, all efforts will be made to complete and report the observations as thoroughly as 
possible, including a complete final evaluation at the time of the subject's withdrawal with an 
explanation of why the subject is withdrawing from the study. If the subject is agreeable they will be 
eligible for short term and long term follow up at listed in Table 2 regardless of duration of treatment. If 
the subject declines consent for final assessments these will not be done and a note will be recorded in 
CRDB. 
10.4 4 Post-therapy Monitoring 
The Investigator can elect to conduct additional tests and/or follow-up visits in clinic during the post- 
therapy monitoring period as needed to evaluate and/or treat any adverse event (AEs). 
Subjects will return for assessments at weeks 2, 3, 6, 12, 18, 24 following the last dose (Figure 6). 
Telephonic assessments or medical record reviews will occur at Months 6, 12, 18, and 24 after last 
dose is administered. The Investigator can elect to conduct additional tests and/or follow-up visits in 
clinic during this period as needed to evaluate and/or treat any adverse event (AEs). 
10.4.1 Short-Term Follow-Up (STFU) 

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Following the end of treatment or treatment completion date, a 24-week short term follow-up (STFU) 
period of observation will begin. Patients will be seen at weeks 2,3,6,12,18, and 24 following the last 
dose during which the following evaluations will take place (see Table 2): 
• 
Karnofsky Performance Status (every visit) 
• 
Physical Examination (every visit) 
• 
Vital Signs (every visit) 
• 
CBC (weeks 12, 24) 
• 
Stool analysis (Weeks 3, 12, 24) 
• 
Flow Cytometry and Serum Cytokines (Weeks 3, 12, 18, 24) 
• 
Tumor Imaging (Week 18) 
10.4.2 Long-Term Follow-Up (LTFU) 
Telephone assessments or medical record reviews will occur at 6, 12, 18, and 24 months after the end 
of the Short-term follow up period (Table 2), the end of treatment date or treatment completion date. 
Vital status and any new therapies started will be determined. 
11.0 TOXICITIES/SIDE EFFECTS 
As with all therapeutic proteins, there is a potential for immunogenicity. Subjects will be monitored for 
autoimmune syndrome development, including but not limited to colitis, dermatitis, thyroiditis and 
uveitis. Subjects administered KW-0761 may be at risk of developing an infection, as KW-0761 may 
affect host defenses. The impact of treatment with KW-0761 on the development and course of active 
and/or chronic infections is not fully understood, therefore, subjects developing an infection during 
treatment with KW-0761 should be monitored closely. Subjects should be monitored for tumor lysis 
syndrome, a metabolic oncologic emergency associated with hematologic malignancies that presents 
as severe electrolyte abnormalities. Signs and symptoms include azotemia, acidosis, 
hyperphosphatemia, hyperkalemia, hypocalcemia, and acute renal failure. Treatment of tumor lysis 
syndrome includes in-subject monitoring, vigorous fluid resuscitation, and allopurinol or urate oxidase 
therapy to lower uric acid levels, urinary alkalinization, and hemodialysis. 
Subjects experiencing Grade 4 neutropenia should have a white blood cell count done every other day 
until absolute neutrophil count (ANC) is above 1,000 cells/μl. If the Grade 4 neutropenia persists for > 7 
days, this is a DLT and subject must be removed from study. Administration of G-CSF and/or other 
appropriate supportive care measures should be considered. 
Additional information about potential toxicities can be found in section 9.2. 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 Disease Progression Monitoring Criteria 
Disease stage will be assessed by the AJCC TNM Clinical Staging 107. Clinical stage from medical 
history will be documented from medical records during Screening (Inclusion/Exclusion Review). 

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Clinical staging will be assessed by review of medical records, review of pathologic staging of the most 
recent lymph node biopsies, and imaging for evaluation of metastases within 30 days of KW-0761 
dosing at Week 8, and every eight weeks thereafter. Clinical staging will be documented at 
Baseline/Screening and repeated and documented at Day 15 of Cycle 2, and every 2 cycles thereafter. 
When possible, tumor progression will be assessed according to irRC at Baseline, at Day 15 of Cycle 2, 
and every 2 cycles thereafter, and as data are available and/or clinically indicated- during Long-term 
Follow-up 108,109. See Appendix I for detailed monitoring criteria. 
If possible a tumor biopsy will be obtained at Baseline and at Day 15 (+/- 4 days) from all subjects. 
Qualified personnel trained in the procedure will take the tumor biopsy. If a site of tumor is readily 
available as a cutaneous lesion a simple punch or excisional biopsy under local anesthesia can be 
performed by the principal investigatory or qualified personnel. If tumor is not readily accessible then an 
image-guided core needle biopsy will be obtained following consultation with the radiology staff to 
determine the overall risk of the procedure. Invasive procedures that require general anesthesia should 
not be performed to obtain a biopsy specimen. If a surgical procedure is performed for a clinical 
indication a sample may be used for research purposes. During the course of treatment a decision may 
be made to perform the post-treatment biopsy earlier than 15 days if there is evidence to suggest a 
possibility that by day 15 there will be no available tumor for biopsy due to a rapid clinical response. 
Similarly tumor biopsy may be delayed if there is evidence of a delayed response. 
From the biopsy specimens, immune cell subsets including dendritic cells, T and B lymphocytes will be 
evaluated by IHC and flow cytometry for morphology, activation, and maturation status. Isolation of 
individual populations of lymphocytes or tumor cells may be performed for gene expression analysis 
and DNA/RNA sequencing. Additional correlative exploratory immunologic studies including, but not 
limited to, enumerating and characterizing circulating cytokines, immune cells, and tumor cells will be 
performed. 
13.1 
CRITERIA FOR REMOVAL FROM STUDY 
In accordance with the Declaration of Helsinki, ICH Good Clinical Practice Guidelines, and the US FDA 
Regulations, a research subject has the right to withdraw at any time for any reason without prejudice to 
future medical care. The investigators also have the right to withdraw subjects. Should a subject (or 
legally authorized representative) decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible. 
A complete final evaluation should be made at the time of withdrawal with an explanation of why the 
subject is withdrawing. An attempt should be made to perform a follow-up study visit at the time of 
withdrawal. This discussion will be documented in the EMR. 
Subjects may be removed from study if one or more of the following occur: 
• 
Significant protocol violation by the Investigator. 
• 
Significant subject noncompliance. 
• 
Refusal of the subject to continue treatment or observations. 
• 
Disease recurrence or progression that prevents further participation. 
• 
Investigator decides that termination is in the subject's best medical interest. 
• 
Lost to follow-up. 

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With the consent of the subject or the legally authorized representative the Investigator may determine 
that limited data collection may be continued (e.g., through medical record review) for the duration of 
the study after a subject has withdrawn. 
Subjects who do not complete the study for reasons other than dose limiting toxicity (DLT) will be 
replaced at the discretion of the Principal Investigator. In an effort to have a sufficient number of 
patients to evaluate saphety in the Phase I portion of the trial and to obtain 16 evaluable patients per 
tumor specific cohort in the Phase II portions replacement of such patients will also occur. Inevaluable 
patients will be reported. All subjects will be included in the analysis of results. 
14.1 
BIOSTATISTICS 
Categorical variables will be summarized using counts and percentages, while continuous variables will 
be summarized using the mean, median, standard deviation, minimum, maximum, and number of 
observations. All summaries will be presented by cohort. Any statistical testing performed will be two- 
tailed at the 5% significance level. A detailed description of statistical analyses will be presented in a 
Statistical Analysis Plan, which will be completed and approved by the PI before the database is  
locked. 
This phase I/II trial to determine the maximum tolerated dose (MTD) of mogamulizumab (KW-0761) in 
patients with advanced and/or metastatic solid tumors. A standard 3+3  design will be utilized to 
determine the MTD. Four dose levels of KW-0761 will be investigated (0.5mg/kg, 1mg/kg, 3mg/kg, 
10mg/kg). Patients will be treated in cohorts of size three to six and the dosage will be escalated if the 
clinical toxicity is acceptable. Toxicity severity will be graded according to the CTCAE (ver. 4.03). 
A dose-limiting toxicity (DLT) will be defined as any toxicity that does not have a clear-cut alternative 
explanation. Any of the following, specified below, will be considered a DLT: 
> Grade 3 non-hematologic toxicity 
> Grade 3 hematologic toxicity 
> Grade 3 allergic reaction/hypersensitivity reaction (including drug fever) 
> Grade 3 cytokine release syndrome/acute infusion reaction 
The following are exceptions to Dose-Limiting Toxicity 
For neutropenia and thrombocytopenia, the following criteria must be met to be considered a DLT: 
Grade 4 neutropenia lasting >7 days 
Grade 4 thrombocytopenia 
Grade 3 thrombocytopenia with bleeding 
Patients who enter the trial with Grade 2 elevation of liver enzymes due to hepatic involvement by 
malignancy must have an increase in hepatic enzymes to Grade 3 that persists for at least 7 days for 
this toxicity to represent a DLT. 
The design is constructed to reduce the chance of escalating the dose when the probability of DLT is 
high, and increase the chance of escalating the dose when the probability of DLT is low. The maximum 
tolerated dose (MTD) is defined as the highest dose level where a DLT occurs within at most one out of 
six patients treated. The escalation scheme is as follows: 
(1) If none of the initial three patients in a cohort experiences a DLT, then a new cohort of three 
patients will be treated at the next higher dose level. 

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(2) If one of the three patients in a cohort experiences a DLT, then up to three additional 
patients will be treated at the same dose. Escalation will continue if only one of the six patients 
experiences DLT. 
(3) If two or more patients in a cohort experience DLT, then the MTD will have been exceeded, 
and no further dose escalation will occur. The previous dose level will be considered the MTD. 
(4) If only three patients were treated at a dose level under consideration as the MTD, then up 
to three additional patients will be accrued. If no more than one of the six patients at that dose 
level experience a DLT, then that dose level will be confirmed as the MTD. If two or more 
patients in that cohort experience DLT, then the previous dose level will be studied in the same 
fashion. 
The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 
33%.  Frequencies of toxicities will be tabulated according to the NCI Common Toxicity Criteria. 
Table 7 below gives the probabilities of dose escalation based on true DLT risk in the 3+3 design. 
True DLT rate 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 
Probability of 
escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.03 
0.01 
0.001 
Phase II portion: Additional patients will be accrued to the disease specific expansion cohorts at the 
MTD for evaluation of safety, tolerability, pharmacodynamics, and activity potential in the Phase II 
portion. The diseases included in these cohorts include triple-negative breast carcinoma, non-small cell 
lung carcinoma, and gastric adenocarcinoma for which there will be cohort sizes of 16 subjects for a 
total of 48 subjects in the Phase II portion. The primary activity parameter is disease response, as 
measured by irRC at 6 months from the initiation of therapy in the phase II portion of the expansion 
cohorts. It is assumed that none of the subjects would have a response if they had not received any 
therapy and the response rate (RR) for subjects treated with KW-0761 would be 10%. A one-sample 
exact binomial test will be used in testing the alternative hypothesis Ha: RRwith treatment = 10% against the 
null hypothesis H0: RRwithout treatment = 0.1%. A sample size of 16 evaluable subjects is required to provide 
more than 80% power in a one-sample exact Binomial test at the significance level of 0.05. If one 
response is observed out of 16 patients in a particular cohort then the treatment will be considered 
worthy of further study in that cohort. 
The 10% response rate was chosen based on the response rates observed with ipilimumab, arguably 
the most successful and best-studied immunotherapy in current clinical use, whose mechanism of 
action is mediated at least in part through Treg cell depletion 110. The Phase II study of ipilimumab 
showed a best overall response rate of 11.1% in heavily pretreated melanoma patients 111. The best 
overall response rate of 10.9% in the Phase III clinical trial of ipilimumab in patients with metastatic 
melanoma which translated to an improved overall survival 34. 
Overall and progression-free survival will be estimated using Kaplan-Meier methodology. Toxicity will 
be reported by type, frequency and severity according to the most recent NCI Common Toxicity Criteria 

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Response rate (CR+PR) and disease control rate (CR+PR+SD) (estimated by RECIST and immune 
related response criteria) will be calculated along with the corresponding confidence interval will be 
reported.  Duration of response will be summarized among responders. 
A minimum of of 2 patients and a maximum of 24 patients will be accrued to the phase I portion of this 
trial. Forty-eight patients will be accrued to the phase II portion of the trial. It is anticipated that 8 
patients per month will be accrued and the entire study will be completed within 4 years. 
For the correlative studies, the analysis is primarily exploratory for the subjects from whom we obtain 
biologic samples. Appropriate descriptive statistical measures will be used to summarize the data.  For 
each tumor specific cohort separately, pre and post comparisons will be assessed on the biopsy 
specimens.  For binary markers, McNemars test  and for continuous markers, the Wilcoxon signed rank 
test will be utilized to assess changes pre versus post treatment. 
14.2 1 Pharmacodynamic Analysis 
Correlative studies will be performed on biologic specimens obtained from subjects in the Phase I and 
Phase II portions of this trial. 
Flow cytometric results for lymphocyte subsets and CCR4+ T cell counts will be tabulated and 
presented graphically by cohort and time. The results of other PD assessments (will be summarized 
using descriptive statistics. 
Treg cells constitute a significant proportion of TILs and based on their potent immunoregulatory 
properties we hypothesize that Treg cell depletion will lead to significant alteration in the tumor immune 
microenvironment. A tumor biopsy will be obtained at Baseline and at Day 15 and investigated for the 
extent and consequences of Treg depletion. The tumor biopsy will be taken by qualified personnel 
trained in the procedure. In these specimens, immune cells and cell subsets including dendritic cells, 
and T and B lymphocytes as well as their subsets will be qualitatively and quantitatively evaluated by 
IHC for morphology, activation, and maturation status. Phenotypic analysis of TILs by flow cytometry  
will be performed using validated antibody panels to identify and characterize tumor infiltrating T cells 
and myeloid cells. Activation state of CD4 and CD8 T cells will be determined by staining for lineage 
specific transcription factors (T-BET, GATA3, FOXP3, RORC) as well as intracellular cytokine analysis 
following in vitro re-stimulation. Correlative exploratory immunologic studies including, but not limited to, 
circulating cytokines, circulating immune cells, and tumor cells will be performed. 
Treg cells are critical mediators of peripheral tolerance and their complete absence leads to 
autoimmunity in animal models and in human patients with Foxp3 deficiency. CCR4+ Treg cells 
represent a subset of activated Treg cells and Treg cells capable of migrating to the skin. Specific 
depletion of Treg cells induced by KW-0761 will provide a unique opportunity to characterize the 
consequences of Treg cell depletion not only for the tumor growth, but also for systemic immune 
activation and the homeostasis of a normal tissue. If during the course of treatment with KW-0761 there 
is a clinical evident focus of skin pathology it will be targeted for biopsy as well as nearby normal skin. 
Hematoxylin and eosin, CD3, CD4, CD8, FoxP3, CCR4, CD68, and neutrophil elastase stainings will be 
performed on 4 mm sections. 

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A relatively recently appreciated modulator of intestinal homeostasis and systemic immunity is the 
intestinal commensal microbiota. The host immune system and particularly Treg cells are central to 
maintaining tolerance to commensal microbiota112,113112,113111,112. The crosstalk between commensals 
and local immune cells by Treg can for the first time be investigated in humans with the proposed 
clinical trial. Fecal specimens will be collected and the intestinal microbiota will be characterized 
characterized by 454 pyrosequencing of the V1-V3 region of bacterial 16S ribosomal RNA genes. 
Microbial diversity will be estimated by grouping sequences into operational taxonomic units and 
calculating the Shannon diversity index. Phylogenetic classification will be obtained using the 
Ribosomal Database Project classifier. Associations of the microbiota with KW-0761 treatment will be 
evaluated. 
14.3 2 Safety Analyses 
Safety data from subjects who have received any portion of KW-0761 will be included in the safety 
analyses. The frequency and severity of AEs will be tabulated. Baseline, end-of-study, and change from 
baseline laboratory, vital signs, and ECG parameters will be summarized. Shift tables will be prepared 
for laboratory parameters. Dot plots or box and whisker plots of selected lab tests over time will be 
prepared where appropriate. A listing of Baseline and end-of-study concomitant medications will be 
provided. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.2 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 8:30am – 
5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic Registration System 
(http://ppr/). The completed signature page of the written consent/RA or verbal script/RA, a completed 
Eligibility Checklist and other relevant documents must be uploaded via the PPR Electronic Registration 
System. 
16.1 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
include project compliance, data collection, abstraction, and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization and coordination of activities of the protocol study 
team. 

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The data collected for this study will be entered into a secure database at MSKCC. Data from this trial 
will be entered in the Clinical research Database (CRDB). Source documentation will be available to 
support the computerized patient record. 
16.2 Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study period. 
Random-sample data quality and protocol compliance audits will be conducted by the study team, at a 
minimum of two times per year, more frequently if indicated. 
16.3 2 Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at MSKCC were approved by the National Cancer 
Institute in September 2001. The plans address the new policies set forth by the NCI in the document 
entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials” which 
can be found at: http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at : http://mskweb2.mskcc.org/irb/index/htm. 
There are several different mechanisms by which clinical trials are monitored for data, safety, and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical research 
QA) and departmental procedures for quality control, plus there are two institutional committees that 
are responsible for monitoring the activities of our clinical trials programs. The committees: Data and 
Safety Monitoring Board (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and Institutional 
Review Board. 
During the protocol development and review process, each protocol will be assessed for its level of risk 
and degree of monitoring required. Every type of protocol (e.g. NIH sponsored, in-house sponsored, 
industrial sponsored, NCI cooperative group, etc.) will be addressed and the monitoring procedures will 
be established at the time of protocol activation. 
17.1 
PROTECTION OF HUMAN SUBJECTS 
17.2 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A Research 
Authorization form must be completed by the Principal Investigator and approved by the IRB and 
Privacy Board (IRB/PB). 

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The consent indicates that samples and genetic information collected may be shared with other 
qualified researchers and placed in online databases. An example of an online database is the NIH 
dbGAP database, which is monitored by the National Institutes of Health, and may be made accessible 
to investigators approved by the U.S. government. Such information will not include identifying 
information such as name. 
The requirements for submission of genotype/phenotype data into the NIH dbGAP or any other public 
database will be followed as per the IRB SOP for Genomic Data Sharing. 
17.3 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon 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 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is required for 30- 
days after the participant’s last investigational treatment. Any events that occur after the 30-day period 
and that are at least possibly related to protocol treatment must be reported. 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious Adverse 
Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. The IRB requires a 
Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE Office as 
follows: 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to saemskind@mskcc.org. 
For all other trials: Reports that include a Grade 5 SAE should be sent to saegrade5@mskcc.org. All 
other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 

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Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number written at 
the top of the report. If appropriate, the report will be forwarded to the FDA by the SAE staff through the 
IND Office. 
17.2.1 
SAE will be reported to the FDA through the IND Office and the report must include the FDA assigned 
BB-IDE, BB-IND or IND number and name. 
17.2.2  SAE Reporting to Kyowa Hakko Kirin Pharma (KKP) 
MSKCC must report all SAEs to Kyowa on a MedWatch 3500A form, or institutional SAE form within 
five (5) calendar days of the Awareness date. The completed MedWatch/case report should be faxed 
immediately upon completion to Kyowa Drug Safety at: 
KKP Drug Safety Surveillance 
Phone: 1-609-919-1100 
Available 9:00am-5:00PM (EST) 
2:00PM-10:00PM (GMT) 
US Fax: 1-800-209-2251 
Email address: saesource@kyowa-kirin-pharma.com 
Available 24 hours daily 
Additional Reporting Requirements to Kyowa include the following: 
Any reports of pregnancy following the start of administration with KW-0761 will be transmitted 
to Kyowa within thirty (30) calendar days of the Awareness Date. 
All Non-serious Adverse Events originating from the Study will be forwarded in a Kyowa 
quarterly report. 
17.3 3 Ethical Conduct of the Study 

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The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation of this 
study, are designed to ensure that the PI,  authorized representatives and Investigators abide by GCP 
as described in International Conference on Harmonization (ICH) guideline E6, and in 21 Code of 
Federal Regulations (CFR) parts 50, 54, 56, and 312. Compliance with these regulations also 
constitutes compliance with the ethical principles described in the most recent revision of the 
Declaration of Helsinki that is recognized by the US FDA and the EMA. 
The Investigator should ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their trial- 
related duties and functions. The Investigator should maintain a list of sub-Investigators and other 
appropriately qualified persons to whom significant trial-related duties have been delegated. 
17.4 Institutional Review Board 
The Principal Investigator will be responsible for obtaining annual IRB approval and renewal throughout 
the duration of the study and retain all of this documentation in the study file. It is also the responsibility 
of the Principal Investigator to obtain other committee approvals based on the policies of his institution. 
Initial IRB approval, and all materials approved by the IRB including the subject consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. The 
Investigator must submit and, where necessary, obtain approval from the IRB for all subsequent 
protocol amendments and changes to the informed consent form. 
The Investigator will notify the IRB of deviations from the protocol or any SAE occurring at the site, in 
accordance with local procedures. 
17.5 Audits and Inspections 
The Governing Regulatory Authorities, the IRB, and an auditor authorized by the PI may request 
access to all source documents, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the Investigator who must provide support at all 
times for these activities. Medical records and other study documents may be copied during audit or 
inspection provided that subject names are obliterated on the copies to ensure confidentiality. 
18.1 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain full details of 
the protocol and study procedures as well as the risks involved to participants prior to their inclusion in 
the study. Participants will also be informed that they are free to withdraw from the study at any time. All 
participants must sign an IRB/PB-approved consent form indicating their consent to participate. This 
consent form meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
4. The name of the investigator(s) responsible for the protocol. 

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5. The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully explain 
the aspects of patient privacy concerning research specific information. In addition to signing the IRB 
Informed Consent, all patients must agree to the Research Authorization component of the informed 
consent form. 
Each participant and consenting professional will sign the consent form. The participant must receive a 
copy of the signed informed consent form. 

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19.0 
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Appendix 1. 
Overall Response using RECIST based immune related response criteria (irRC) 
Antitumor response based on total measurable tumor burden. 
For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional 
criteria, which do not require the measurement of new lesions, nor do they include new lesion measurements 
in the characterization of evolving tumor burden). At the baseline tumor assessment, the sum of the products  
of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral 
lesions and five cutaneous index lesions) is calculated. At each subsequent tumor assessment, the SPD of the 
index lesions and of new, measurable lesions (≥5 x 5 mm; up to 5 new lesions per organ: 5 new cutaneous 
lesions and 10 visceral lesions) are added together to provide the total tumor burden: 
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions 
Overall response using the irRC. 
The overall response according to the irRC is derived from time-point response assessments (based on tumor 
burden) as follows: 
Immune related complete response (irCR): complete disappearance of all lesions (whether measurable or 
not, and no new lesions) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date 
first documented 
Immune related partial response (irPR): decrease in tumor burden ≥30%relative to baseline confirmed by a 
consecutive assessment at least 4 weeks after first documentation 
Immune related stable disease (irSD): not meeting criteria for irCR or irPR, in absence of irPD 
Immune related progressive disease (irPD): increase in tumor burden ≥20% relative to nadir (minimum 
recorded tumor burden) confirmation by a repeat, consecutive assessment no less than 4 weeks from the date 
first documented 
An irRC overall response of irCR or irPR requires confirmation by a second (confirmatory) evaluation meeting 
the criteria for irRC response and performed no less than 4 weeks after the criteria for response are first met.