A Phase I and Randomized Phase II Study of KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab) in Relapsed, Refractory Diffuse Large-B Cell Lymphoma
Phase: PHASE1
Conditions: Recurrent Diffuse Large B-Cell Lymphoma, Recurrent High Grade B-Cell Lymphoma, Recurrent Transformed B-Cell Non-Hodgkin Lymphoma, Refractory Diffuse Large B-Cell Lymphoma, Refractory High Grade B-Cell Lymphoma, Refractory Transformed B-Cell Non-Hodgkin Lymphoma
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
i 
 
To:  
CTEP Protocol and Information Office 
 
From:  
Erel Joffe, MD 
 
Date:  
May 21, 2020 
 
Re: 
Amendment 18 
 
 
SUMMARY OF CHANGES – Protocol 
 
I. 
PIO Recommendations: 
 
# 
Section 
Comments 
1. 
8.1.1 
The MK-3475 (pembrolizumab) vial equilibration to room temperature is no longer 
required by the pharmaceutical collaborator and can be removed from the preparation 
instructions. 
“Preparation: MK-3475 solution for infusion must be diluted prior to 
administration.  Allow the required number of vials to equilibrate to room 
temperature.  Do not shake the vials.” 
PI Response: 
This sentence was removed. 
2. 
8.1.1 
The MK-3475 (pembrolizumab) infusion solution stability is updated per the 
current Investigator Brochure with refrigerated temperature allowance from 20 
hours to 24 hours and room temperature allowance from 4 hours to 6 hours.  
Please update accordingly. 
“Stability: Stability testing of the intact vials is on-going. 
Administer prepared solutions immediately after preparation.  If not administered 
immediately, prepared solutions may be stored refrigerated for up to 24 hours.  MK-
3475 solutions may be stored at room temperature for a cumulative time of up to 6 
hours.” 
PI Response: 
These times were updated. 
 
 
 

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II. 
PI Requested Changes 
 
# 
Section 
Comments 
1. 
All 
General formatting throughout the document. 
2. 
Cover 
Page 
Changed the Protocol Contact’s information. 
3. 
Schema 
5.1 
Added the following statement:  
“As of 08/10/2019, we are using dose level (-1) due to limited feasibility of 
administering dose level 1.” 
 
In the corresponding table, Dose Level 1 was retained but crossed out. 
4. 
2.1 
Clarified the study is for relapsed or refractory patients with DLBCL. 
5. 
3.1.5 
Changed the eligibility Performance Status criteria to ECOG ≥ 1 (Karnofsky ≥ 80 
%). 
6. 
3.1.10 
Corrected section numbering 3.1.11 to 3.1.10. 
7. 
3.2.1 
Revised prior systemic anti-cancer therapy washout from 3 weeks to 2 weeks or 5 
half lives (the shorter of the two). 
8. 
5.2 
Removed the first DLT (Grade 4 nonhematologic toxicity (not laboratory)). 
Renumbered subsequent items. 
9. 
5.3 
Under Prohibited Concomitant Medications, removed the statement in 
parentheses and added information pertaining to radiation therapy. 
10. 
5.6 
Removed the section Criteria to Resume Treatment in its entirety and renumbered 
the subsequent sections. 
11. 
5.9 
Revised the maximum number of cycles of mogamulizumab from 35 to 34. 
12. 
10 
Calendar: Added +/- 2 days windows to the study calendar. 
Footnote c: Clarified EKGs are every 3 weeks from C4 onward. 
Footnote j: Added timeframe for the Off Treatment visit. 
 
 
 

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SUMMARY OF CHANGES – Consents 
 
I. 
Phase 1 
 
# 
Section 
Comments 
1. 
Header 
Protocol version date revised. 
 
II. 
Phase 2 
 
# 
Section 
Comments 
1. 
Header 
Protocol version date revised. 
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
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Local Protocol #:  19-018  
 
ClinicalTrials.gov Identifier:  NCT03309878  
 
TITLE:  A phase I and randomized phase II study of KW-0761 (Mogamulizumab) and MK-3475 
(Pembrolizumab) in relapsed, refractory diffuse large-B cell lymphoma  
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Erel Joffe 
                                                      Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
646-449-1820 (telephone) 
646-227-7257 (fax) 
joffee@mskcc.org 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistician 
LAO Protocol Contact: 
 
Andy Ni, PhD 
Judy Murray, CCRC 
 
485 Lexington Ave 
Johns Hopkins University 
 
New York, NY 10017 
201 N. Broadway, Suite 9130 
 
Telephone: (646) 888-8122 
Baltimore, MD 21287 
 
nia@mskcc.org  
Telephone: (410) 955-4044 
 
 
jmurra33@jhmi.edu   
 
 

NCI Protocol #: 10106 
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NCI-Supplied Agents:  MK-3475 (pembrolizumab) (NSC 776864) 
                                        KW-0761 (mogamulizumab) (NSC 791064 
 
 
IND Sponsor: NCI  
 
Protocol Type / Version # / Version Date: 
Original / Version 1 / 8/14/2017 
 
 
 
 
      Revised / Version 1 / 10/26/2017 
 
 
 
 
      Revised / Version 1 / 11/13/2017 
 
 
 
 
      Revised / Version 2/ 12/12/2017 
 
 
 
 
      Revised / Version 3 / 02/28/2018 
 
 
 
 
      Revised / Version 4 / 03/06/2018 
 
 
 
 
      Revised / Version 5 / 03/12/2018 
 
 
                                          Revised / Version 6 / 03/27/2018 
 
 
 
 
      Revised / Version 7 / 04/10/2018 
 
 
 
 
      Revised / Version 8 / 04/23/2018 
 
 
 
 
      Revised / Version 9 / 05/15/2018 
 
 
 
 
      Revised / Version 10 / 10/03/2018 
 
 
 
 
      Revised / Version 11 / 11/09/2018 
 
 
 
 
      Revised / Version 12 / 11/14/2018 
 
 
 
 
      Revised / Version 13 / 12/13/2018 
Revised / Version 14 / 02/07/2019 
Revised / Version 15 / 08/28/2019 
Revised / Version 16 / 10/25/2019 
Revised / Version 17 / 03/10/2020 
Revised / Version 18 / 05/21/2020 

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SCHEMA 
 
There are two parts to this study. The first part is a phase I, multicenter, open-label study designed 
to evaluate the safety and tolerability of KW-0761 (mogamulizumab) and MK-3475 
(pembrolizumab) in patients with relapsed, refractory diffuse large B-cell lymphoma. A 
traditional 3+3 phase I design on sequential dosing cohorts will be applied. MK-3475 
(pembrolizumab) will be given at a dose of 200mg IV on day 1 of every 21-day cycle. KW-0761 
(mogamulizumab) will be administered at the doses specified in Table 1. The starting dose level 
for the Phase I is Level 1 (see Table 1).  
 
Table 1.  
As of 08/10/2019, we are using dose level (-1) due to limited feasibility of administering dose 
level 1. 
 
Dose Escalation Schedule 
Dose Level 
Dose 
MK-3475 [Pembrolizumab] 
(mg) 
KW-0761 [Mogamulizumab] 
(mg/kg) 
Level -1 
200mg IV day 1 every 21 
days 
Induction: 0.5 mg/kg IV weekly for 
3 weeks  
Maintenance: 1mg/kg IV day 1 
every 21 days 
Level 1 
200mg IV day 1 every 21 
days 
Induction: 1 mg/kg IV once weekly 
for 3 weeks  
Maintenance: 1.5mg/kg IV day 1 
every 21 days 
 
The primary objective of this part of the study is to determine the maximum tolerated dose (MTD) 
or recommended phase II dose (RP2D) of KW-0761 (mogamulizumab) in combination with MK-
3475 (pembrolizumab) and characterize the safety and toxicity profile of the combination. The 
maximum treatment duration for the phase I part of the study is 2 years.  
 
The second part of this study is a phase II, randomized, multi-center, open-label study designed to 
evaluate the efficacy of the combination of MK-3475 (pembrolizumab) and KW-0761 
(mogamulizumab) versus single-agent MK-3475 (pembrolizumab) (see Figure 1). In the phase II 
portion of the study, patients with relapsed, refractory diffuse large B-cell lymphoma will be 
treated. Patients will be randomly assigned, in a 1:1 ratio, to receive either MK-3475 
(pembrolizumab) and KW-0761 (mogamulizumab) in combination versus MK-3475 
(pembrolizumab) alone. In other words, there will be two treatment groups: Group 1 (MK-3475 
[pembrolizumab] and KW-0761 [mogamulizumab]) and Group 2 (MK-3475 [pembrolizumab] 
alone). Patients will receive either MK-3475 (pembrolizumab) 200mg IV on day 1 of every 21-
day cycle and KW-0761 (mogamulizumab) at the induction RP2D once weekly for 3 weeks 
(C1D1, C1D8, C1D15) and thereafter at the maintenance RP2D on day 1 of every 21-day cycle 
(C2D1, C3D1, etc) (Group 1) or MK-3475 (pembrolizumab) alone (Group 2). MK-3475 
(pembrolizumab) will be administered in both arms at a dose of 200mg IV on day 1 of every 21-

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day cycle. The primary endpoint for the phase II portion is progression free survival.  
 
Figure 1 
 
 
 
 
 

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TABLE OF CONTENTS 
SCHEMA ........................................................................................................................................ 3 
1. 
OBJECTIVES ..................................................................................................................... 7 
1.1 
Primary Objectives .................................................................................................. 7 
1.2 
Secondary Objectives .............................................................................................. 7 
1.3 
Exploratory Objectives ........................................................................................... 7 
2. 
BACKGROUND ................................................................................................................ 9 
2.1 
Study Disease .......................................................................................................... 9 
2.2 
CTEP IND Agents .................................................................................................. 9 
2.3 
Rationale ............................................................................................................... 17 
2.4 
Correlative Studies Background ........................................................................... 19 
3. 
PATIENT SELECTION ................................................................................................... 23 
3.1 
Eligibility Criteria ................................................................................................. 23 
3.2 
Exclusion Criteria ................................................................................................. 24 
3.3 
Inclusion of Women and Minorities ..................................................................... 26 
4. 
REGISTRATION PROCEDURES .................................................................................. 28 
4.1 
Investigator and Research Associate Registration with CTEP ............................. 28 
4.2 
Site Registration .................................................................................................... 29 
4.3 
Patient Registration ............................................................................................... 31 
4.4 
General Guidelines ................................................................................................ 32 
5. 
TREATMENT PLAN ....................................................................................................... 33 
5.1 
Agent Administration ............................................................................................ 33 
5.2 
Definition of Dose-Limiting Toxicity ................................................................... 35 
5.3 
General Concomitant Medication and Supportive Care Guidelines ..................... 37 
5.4 
Duration of Therapy .............................................................................................. 38 
5.5 
Criteria to Resume Treatment ............................................................................... 39 
5.6 
Contraception and Pregnancy ............................................................................... 39 
5.7 
Treatment Beyond Progression ............................................................................. 41 
5.8 
Discontinuation of Treatment Following Complete Response ............................. 42 
5.9 
Treatment Up to 2 Years ....................................................................................... 42 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 43 
6.1 
Dose modifications and supportive care guidelines for drug-related adverse 
events with the combination of MK-3475 (Pembrolizumab) and KW-0761 
(Mogamulizumab). ................................................................................................ 43 
6.2 
Specific Immune-mediated Reactions ................................................................... 46 
6.3 
Infusion-related Reactions ..................................................................................... 50 
6.4 
Non-immune-mediated Reactions ......................................................................... 51 
6.5 
Tumor lysis syndrome ........................................................................................... 51 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................... 52 

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7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ................ 52 
7.2 
Adverse Event Characteristics .............................................................................. 60 
7.3 
Expedited Adverse Event Reporting ..................................................................... 60 
7.4 
Routine Adverse Event Reporting ........................................................................ 62 
7.5 
Pregnancy .............................................................................................................. 62 
7.6 
Secondary Malignancy .......................................................................................... 63 
7.7 
Second Malignancy ............................................................................................... 63 
8. 
PHARMACEUTICAL INFORMATION ......................................................................... 64 
8.1 
CTEP IND Agent(s) .............................................................................................. 64 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 69 
9.1 
Integrated and Exploratory Correlative Studies .................................................... 69 
9.2 
Collection, Handling and Shipping of biomarker specimens to sites 
performing correlative studies .............................................................................. 71 
9.3 
Shipping ................................................................................................................ 72 
10. 
STUDY CALENDAR ...................................................................................................... 73 
11. 
MEASUREMENT OF EFFECT ....................................................................................... 75 
11.1 
Antitumor Effect – Solid Tumors ......................................................................... 75 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ............................................................................................................ 78 
12.1 
Study Oversight .................................................................................................... 78 
12.2 
Data Reporting ...................................................................................................... 78 
12.3 
CTEP Multicenter Guidelines ............................................................................... 80 
12.4 
Collaborative Agreements Language .................................................................... 81 
12.5 
Genomic Data Sharing Plan .................................................................................. 82 
13. 
STATISTICAL CONSIDERATIONS .............................................................................. 83 
13.1 
Study Design/Endpoints ........................................................................................ 83 
13.2 
Sample Size/Accrual Rate ..................................................................................... 84 
13.3 
Stratification Factors ............................................................................................. 85 
13.4 
Analysis of Secondary Endpoints ......................................................................... 85 
13.5 
Reporting and Exclusions ..................................................................................... 86 
REFERENCES ............................................................................................................................. 87 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................. 92 
APPENDIX B       PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD .............................................................................................................. 93 
APPENDIX C       PBMC ISOLATION PROCEDURE .............................................................. 94 

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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
The primary objectives of the Phase I portion of the study are the following:  
 
1.1.1 To determine the MTD or RP2D of KW-0761 (mogamulizumab) when administered in 
combination with MK-3475 (pembrolizumab) in patients with relapsed, refractory diffuse 
large B-cell lymphoma.  
 
1.1.2 To assess the safety and tolerability of KW-0761 (mogamulizumab) when administered in 
combination with MK-3475 (pembrolizumab) in patients with relapsed, refractory diffuse 
large B-cell lymphoma.  
 
The primary objective of the Phase II portion of the study is the following:  
 
1.1.3    To assess the progression-free survival of KW-0761 (mogamulizumab) when administered 
in combination with MK-3475 (pembrolizumab) compared to MK-3475 (pembrolizumab) 
alone in patients with relapsed and refractory diffuse large B-cell lymphomas. 
 
1.2 
Secondary Objectives 
 
The secondary objective of the Phase I portion of the study is the following:  
 
1.2.1 To observe and record anti-tumor activity. Although the clinical benefit of this drug has 
not yet been established, the intent of offering this treatment is to provide a possible 
therapeutic benefit, and thus the patient will be carefully monitored for tumor response 
and symptom relief in addition to safety and tolerability. 
 
The secondary objective of the Phase II portion of the study is the following:  
 
1.2.2    To assess the overall response rate, complete response rate, partial response rate, duration 
of response of KW-0761 (mogamulizumab) and MK-3475 (pembrolizumab) compared to 
MK-3475 (pembrolizumab) alone in patients with relapsed and refractory diffuse large B-
cell lymphomas. 
 
1.3 
Exploratory Objectives  
 
1.3.1    To determine whether the progression-free survival of KW-0761 (mogamulizumab) and 
MK-3475 (pembrolizumab) when administered to patients with relapsed and refractory 
diffuse large B-cell lymphomas differs based on the presence or absence of mutations in 
B2M or CD58 or amplifications in PD-L1. 
1.3.2 To determine whether the progression-free survival of KW-0761 (mogamulizumab) and 
MK-3475 (pembrolizumab) when administered to patients with relapsed and refractory 
diffuse large B-cell lymphomas differs based on changes in CD8 T-cell, NK cell, and 
FoxP3+ Treg prevalence in response to therapy as measured by immunohistochemistry 

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1.3.3 To determine whether KW-0761 (mogamulizumab) and MK-3475 (pembrolizumab) alters 
the prevalence of peripheral blood CCR4+/FoxP3+ regulatory T-cells as well as effector 
CD4 and CD8 T-cells by multi-parametric flow cytometry 
 
 
 

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2. BACKGROUND 
 
2.1 
Study Disease 
 
The phase I portion of the study will be open to patients with relapsed or refractory DLBCL. 
Patients with these diseases who experience a relapse after more than one line of treatment or 
after autologous stem cell transplant generally have poor outcomes. Evasion of the immune 
system through various mechanisms has been shown to be an important part of lymphoma 
pathogenesis and immune blockade of the PD-1/PD-L1 interaction with monoclonal antibodies to 
augment antitumor activity has shown therapeutic promise in many subtypes of lymphoma 
(Ansell et al., 2015; Lesokhin et al., 2016). 
 
 Diffuse large B-cell lymphoma (DLBCL) represents a unique and ongoing therapeutic challenge 
in clinical oncology.  Only about half of patients are cured with standard chemotherapy-based 
approaches.  For relapsed patients, curative therapy requires autologous or allogeneic transplant, 
which carries a high risk of treatment-related morbidity and maybe inappropriate for elderly or 
comorbid patients.  Additionally, a significant proportion of patients experience disease relapse 
following transplant, at which point therapeutic options are limited and conventional 
chemotherapeutic agents show limited activity and duration of response.  This underscores the 
need for well-tolerated targeted therapies that can promote long-lasting remissions.   
 
2.2 
CTEP IND Agents 
 
2.2.1 MK-3475 (Pembrolizumab) 
 
MK-3475 (pembrolizumab) has high affinity and potent receptor-blocking activity for the 
programmed cell death 1 (PD-1) receptor, based on preclinical in vitro data (Investigator’s 
Brochure, 2016).  MK-3475 (pembrolizumab) has an acceptable preclinical safety profile and is 
being advanced for clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. The importance of intact immune surveillance function in controlling outgrowth of 
neoplastic transformations has been known for decades (Disis et al., 2010).  Accumulating 
evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and 
favorable prognosis in various malignancies.  In particular, the presence of CD8+ T-cells and the 
ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic 
cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-
infiltrating lymphocytes can be expanded ex vivo and re-infused, inducing durable objective 
tumor responses in cancers such as melanoma (Dudley et al., 2005; Hunder et al., 2008).   
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to 
cluster of differentiation 28 (CD28) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) 
that has been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands (programmed cell death ligand 1 [PD-L1] and/or programmed cell death ligand 2 [PD-
L2]) (Greenwald et al., 2005; Okazaki et al., 2001).   

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The structure of murine PD-1 has been resolved (Zhang et al., 2004).  PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable–type (IgV type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP 1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 2009).  The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from, that 
of CTLA-4, because both molecules regulate an overlapping set of signaling proteins (Parry et al., 
2005; Francisco, 2010).   
 
2.2.2 MK-3475 (pembrolizumab) Background and Clinical Trials 
 
MK-3475 (pembrolizumab, Keytruda®), a humanized monoclonal antibody against the PD-1 
protein, has been developed by Merck & Co. for the treatment of cancer.  MK-3475 
(pembrolizumab) is approved for treatment of melanoma in several countries; in the United States 
(US) and European Union it is approved for the treatment of advanced (unresectable or 
metastatic) melanoma in adults.  MK-3475 (pembrolizumab) has also been approved for treatment 
of NSCLC in several countries; in the US it is indicated for the treatment of patients with 
metastatic NSCLC whose tumors express PD-L1 as determined by a Food and Drug 
Administration (FDA)-approved test and who have disease progression on or after platinum-
containing chemotherapy.  Patients with NSCLC and epidermal growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) genomic tumor aberrations should also have disease 
progression on FDA-approved therapy for these aberrations prior to receiving MK-3475 
(pembrolizumab).  MK-3475 (pembrolizumab) is approved in the US for the treatment of patients 
with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease 
progression on or after platinum-containing chemotherapy. 
 
MK-3475 (pembrolizumab) has demonstrated initial clinical efficacy in single-arm monotherapy 
trials in patients with NSCLC, HNSCC, urothelial cancer, gastric cancer, triple negative breast 
cancer, and Hodgkin’s Lymphoma as determined by response rate.  Ongoing clinical trials are 
being conducted in these tumor types as well as a number of other advanced solid tumor 
indications and hematologic malignancies.  For study details please refer to the Investigator’s 
Brochure (2016). 
 
2.2.3 Rationale for MK-3475 (pembrolizumab) Dose Selection 
The dose of MK-3475 (pembrolizumab) planned to be studied in this trial is 200 mg administered 
IV every 3 weeks (Q3W).  The dose recently approved in the US and several other countries for 
treatment of melanoma patients is 2 mg/kg Q3W.  Information on the rationale for selecting 200 
mg Q3W is summarized below. 
 
The initial phase 1 study of MK-3475 (pembrolizumab) evaluated 5 dose levels (1 mg/kg every 2 

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weeks [Q2W], 3 mg/kg Q2W, 10 mg/kg Q2W, 2 mg/kg Q3W, and 10 mg/kg Q3W) in patients 
with advanced solid tumors.  All 5 dose levels were well tolerated and no dose-limiting toxicities 
(DLTs) were observed.  MK-3475 (pembrolizumab) showed evidence of target engagement and 
objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg, and 10 mg/kg 
Q2W).  No maximum tolerated dose (MTD) has been identified to date.  In addition, 2 
randomized cohort evaluations of melanoma patients receiving MK-3475 (pembrolizumab) 2 
mg/kg or 10 mg/kg Q3W have been completed, and 1 randomized cohort evaluating 10 mg/kg 
Q3W or 10 mg/kg Q2W has also been completed.  The clinical efficacy and safety data 
demonstrate a lack of any important differences in efficacy or safety profile across doses. 
 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.  Previously, a flat MK-3475 
(pembrolizumab) exposure-response relationship for efficacy and safety has been found in 
patients with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures for 200 
mg Q3W are expected to lie within this range and will be close to those obtained with 2 mg/kg 
Q3W dose. 
 
The PK profile of MK-3475 (pembrolizumab) is consistent with that of other humanized 
monoclonal antibodies, which typically have a low clearance and a limited volume of distribution.  
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed.  The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose and importantly 
will maintain individual patient exposures within the exposure range established in melanoma as 
associated with maximal clinical response.  The PK properties of MK-3475 (pembrolizumab), 
specifically the weight-dependency in clearance and volume of distribution, are consistent with no 
meaningful advantage to weight-based dosing relative to fixed dosing. 
 
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in patients with melanoma can be expected.  As the antitumor 
effect of MK-3475 (pembrolizumab) is driven through immune system activation rather than 
through a direct interaction with tumor cells, it is rendered independent of the specific tumor type.  
In addition, available PK results in patients with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in PK exposures obtained at tested doses across tumor 
types.  Thus, the 200 mg Q3W fixed-dose regimen is considered an appropriate fixed dose for 
other tumor indications as well. 
A fixed-dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed-dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. The existing data suggest 200 mg Q3W 
as the appropriate dose for MK-3475 (pembrolizumab). 
 
2.2.4 Summary of safety  
 
MK-3475 (pembrolizumab) has a positive benefit-risk profile and is well tolerated in the approved 
indications, as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs (13.8%), 
discontinuations due to AEs (11.9%), and deaths due to drug-related AEs (0.4%). Furthermore, 
the frequency of immune-mediated AEOSIs is low, and these events are readily managed in the 

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clinical setting with widely available set of guidelines. The safety and efficacy data generated to 
date provide a favorable benefit-risk assessment for the use of MK-3475 (pembrolizumab) as a 
treatment for subjects with advanced/metastatic melanoma, NSCLC, and HNSCC (Investigator’s 
Brochure, 2017). 
 
2.2.5 KW-0761 (Mogamulizumab) 
 
KW-0761 (also known as AMG 761, mogamulizumab, 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 Kirin Pharmaceutical Development, Inc. (KKD) for the treatment of T-cell malignancies 
including peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), and adult T-
cell leukemia-lymphoma (ATL), and solid tumors (Investigator’s Brochure, 2016). 
 
KW-0761 (mogamulizumab) was produced using technology developed by Kyowa Hakko Kirin 
Co., Ltd. (KHK, the parent company of KKD), that eliminates fucose from the carbohydrate 
structure of the antibody. Due to the absence of fucose from the complex-type oligosaccharide at 
the constant (fragment crystallizable) region, KW-0761 (mogamulizumab) 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. 
 
KW-0761 (mogamulizumab), which eliminates CCR4+ cells, has induced anti-tumor responses in 
patients with CCR4+ T-cell malignancies, which is thought to be due to ADCC-mediated killing 
of CCR4+ malignant cells (Ishida et al., 2012). KW-0761 (mogamulizumab) has also been shown 
to deplete a subset of T regulatory cells (Tregs) which expresses CCR4. Sugiyama et al. showed 
that CCR4 was specifically expressed by a subset of terminally differentiated highly suppressive 
CD45RA-FOXP3hiCD4+ Tregs but not by CD45RA+FOXP3lowCD4+ naive Treg cells in the 
peripheral blood of healthy individuals and cancer patients (Sugiyama et al., 2013). They showed 
that KW-0761 (mogamulizumab) produced a substantial reduction in the number of circulating 
Tregs in a patient with ATL. In addition, peripheral blood mononuclear cells (PBMCs) were 
collected from patients with melanoma whose tumors expressed the NY-ESO-1 antigen, but in 
whom there was no evidence of an immune response against this antigen. When these PBMCs 
were cultured in the presence of the NY-ESO-1 antigen and with an antibody to CCR4 to deplete 
the CCR4+ cells, the remaining CD4+ cells activated to secrete interferon gamma (IFN-γ) and 
tumor necrosis factor-alpha (TNF-α). This indicated that the immunosuppressive influence of 
Treg cells had been removed by removing cells expressing CCR4 (Sugiyama et al., 2013; Kurose 
et al., 2015). 
 
Additional evidence for the role of KW-0761 (mogamulizumab) in depleting Tregs is provided by 
the results of a Phase 2 study in subjects with relapsed ATL, which demonstrated that a single 
treatment course with KW-0761 (mogamulizumab) (8 doses of 1 mg/kg given once weekly) 
resulted in a marked decrease in CD4+CD25+FoxP3+ cells after the first dose, which persisted 
for at least 4 months after the last dose of KW-0761 (mogamulizumab) (Ishida et al., 2012). 
 
KW-0761 (mogamulizumab) has been examined for safety and toxicology in non-human primates 
with little toxicity. The No Observed Adverse Effect Level (NOAEL) in a 26-week repeat-dose 

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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 human clinical trials, doses of up to 1.0 mg/kg have been well tolerated. As of 30 Sep 2016, 
more than 800 subjects have received at least one dose of KW-0761 (mogamulizumab) in 
company-sponsored clinical studies. 
 
POTELIGEO® (mogamulizumab) was approved by the Ministry of Health, Labor and Welfare in 
Japan for the treatment of primary (14 Dec 2014) and relapsed or refractory CCR4+ ATL (30 Mar 
2012), relapsed or refractory CCR4+ PTCL (17 Mar 2014), and relapsed or refractory CCR4+ 
CTCL (17 Mar 2014).  
 
2.2.6 Summary of nonclinical pharmacology 
 
Nonclinical pharmacological studies designed to examine the anti-tumor activity of KW-0761 
(mogamulizumab) identified: (1) the binding of KW-0761 (mogamulizumab) to CCR4 peptide, 
FcγRIIIa (F) and FcγRIIIa (V); (2) the binding of KW-0761 (mogamulizumab) to T-cell 
lymphoma cell lines (3) the in vitro ADCC activity to T-cell lymphoma/leukemia cell lines and 
tumor cells from ATL and PTCL-NOS patient; and (4) the in vivo effects of KW-0761 
(mogamulizumab) to ATL and CTCL cell lines in a SCID mouse model. These results 
demonstrated that KW-0761 (mogamulizumab) exhibited potent ADCC activity against CCR4-
expressing lymphoma cell lines in vitro and exerted anti-tumor activity in vivo against T-cell 
lymphoma making KW-0761 (mogamulizumab) a promising candidate for a single agent 
treatment for T-cell lymphomas.  
 
Other characteristics are summarized as below: 
• KW-0761 (mogamulizumab) induced reduction of CCR4+ cells, including Treg cells, in 
peripheral blood of cynomolgus monkeys. 
• KW-0761 (mogamulizumab) neither affected the binding of CCR4 ligands (TARC or 
MDC) to CCR4 nor the viability of CCR4-expressing human cutaneous T cell lymphoma 
HuT78 cells. 
• KW-0761 (mogamulizumab) binding had little effect on the level of CCR4 expression on 
the CTCL surface. 
•KW-0761 (mogamulizumab) exhibited no CDC activity against human T-cell leukemia 
and lymphoma cell lines. 
 
KW-0761 (mogamulizumab) did not bind to platelets and had no effect on platelet aggregation or 
on reduction of platelet counts in the whole blood. KW-0761 (mogamulizumab) induced TNF-α, 
IFN-γ, and IL-6 release from human whole blood and PBMCs. 
 
2.2.7 Summary of nonclinical pharmacokinetics  
 
Absorption  
Pharmacokinetic analysis of plasma KW-0761 (mogamulizumab) concentration profiles following 

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a single intravenous dose to male and female cynomolgus monkeys was conducted at doses 
between 0.01 and 100 mg/kg. Plasma KW-0761 (mogamulizumab) concentration decreased 
biphasically after an iv administration in the 0.01 to 100 mg/kg dose groups. Pharmacokinetic 
parameters were calculated with a two-compartment open model. Pharmacokinetic parameters 
were similar among groups dosed from 0.5 to 100 mg/kg, with average elimination half-lives 
(t1/2β) of 13.9 to 20.8 days. The volume of distribution at steady-state of KW-0761 
(mogamulizumab) for all groups almost corresponded to the plasma volume of monkeys 
(approximately 45 mL/kg). The plasma KW-0761 (mogamulizumab) concentration decreased 
rapidly in the monkeys that generated anti-KW-0761 (mogamulizumab) antibodies. 
 
The area under the concentration-time curves (AUCs) was approximately dose-proportional 
between the 1.2 mg/kg and 40 mg/kg doses. Compared with t1/2β at 40 mg/kg, the t1/2β at 0.05 
mg/kg was significantly shorter. No sex-related differences in the pharmacokinetic parameters of 
KW-0761 (mogamulizumab) were observed at either dose level were apparent.  
 
The accumulation ratios (Cmin, Day 28/Cmin, Day 8) were 2.04 to 3.12 following repeated 
administration in the 1.2 and 40 mg/kg dose groups and were approximately consistent with those 
predicted from the t1/2β value.  
 
At 0.05 mg/kg, the plasma KW-0761 (mogamulizumab) concentration after repeated doses 
rapidly decreased when compared with those after the first dose due to the production of anti-
KW-0761 (mogamulizumab) antibodies.  
 
Following multiple IV administrations once a week for 13 weeks at doses of 2.5, 10 or 
40 mg/kg, AUC from time 0 to 168 hours (AUC0-168) values of KW-0761 (mogamulizumab) 
(early and late in the study) reflected the differences in dose levels. There were no sex differences 
in the toxicokinetic (TK) data. Anti-KW-0761 (mogamulizumab) antibodies were not detected in 
any monkeys at any dose level. 
 
In a 26-week multiple-dose study with once weekly doses of 2.5, 10, or 40 mg/kg, the maximum 
observed concentration (Cmax), AUC from time 0 to 7 days (AUC0-7days), and AUC from time 
0 to infinity (AUCinf) of KW-0761 (mogamulizumab) increased as the dose level increased. The 
Cmax and AUC0-7days after repeated dosing increased when compared with those after the first 
dosing, yielding AUC0-7days accumulation ratios of 2.6 to 8.2 across all dose groups. In one 
animal at 2.5 mg/kg, KW-0761 (mogamulizumab) was not detected in plasma on and after Day 29 
due to the production of anti-KW0761 (mogamulizumab) antibodies. 
 
Distribution 
After a single IV administration of [125I] KW-0761 (mogamulizumab) at a dose of 1.0 mg/kg to 
male cynomolgus monkeys, the extent of tissue distribution of the radioactivity was relatively low 
with the maximum tissue to plasma radioactivity ratio of 0.26. The elimination of radioactivity 
from all the tissues nearly paralleled that from plasma (implying no accumulation in tissues).  
 
Metabolism and Excretion 
Metabolism and excretion studies were not conducted. The expected metabolism of KW-0761 
(mogamulizumab) is degradation to small peptides and amino acids.  

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Pharmacokinetics Interaction 
No in-vitro or in-vivo pharmacokinetic interaction studies have been conducted to date. Based on 
the expected mechanism of metabolism (proteolysis), no drug-drug interactions are expected. 
 
Nonclinical toxicology 
Based on comparable binding affinity for cynomolgus monkey and human lymphocytes and 
pharmacological activity (reduction in CCR4 positive cells in peripheral blood) in cynomolgus 
monkeys, the cynomolgus monkey was selected for nonclinical safety assessments of KW-0761 
(mogamulizumab). 
 
Results from both single- and repeat-dose iv (up to 26 weeks) or subcutaneous (sc) (single-dose) 
nonclinical toxicology studies of KW-0761 (mogamulizumab) in cynomolgus monkeys have 
demonstrated an acceptable safety profile, supporting its continued clinical use up to the highest 
planned iv clinical dose of 1 mg/kg (dosing regimen). 
 
2.2.8 Summary of clinical pharmacodynamics 
 
Weekly doses of KW-0761 (mogamulizumab) at 1.0 mg/kg iv given for eight weeks resulted in 
marked reductions in CD4+ CD25+ CCR4+ cells, as the indicator of peripheral blood ATL cells, 
decreased immediately after the first dosing of KW-0761 (mogamulizumab), and remained almost 
completely suppressed over a long period of time also after the second dose. In addition, the 
number of CD4-positive CD25-+ Foxp3+ cells, as the indicator of peripheral blood regulatory T 
cells, decreased immediately after the first dose of KW-0761 (mogamulizumab), and also 
remained almost completely suppressed over a long period of time after the second dose. 
 
Immunogenicity: T-cell Lymphomas 
Plasma samples from two clinical studies, KW-0761-001 and KW-0761-002, were analyzed for 
the presence of anti-drug antibodies to KW-0761 (mogamulizumab) in a screening assay, if 
positive, continued with a confirmatory assay, and if positive, continued with a neutralizing assay 
(Study Report 10/065-021). A total of 263 samples were analyzed (252 for Study KW-0761-001 
and 11 for Study KW-0761-002). A total of 7 subjects from Study KW-0761-001 showed positive 
screening assay results. No subject showed positive screening assay results from Study KW-0761-
002. Four out of 7 subjects who tested positive in the screening assay showed positive results for 
the confirmatory assay in the post-treatment samples collected from Cycle 1 to 11 and at the final 
visits. One subject showed positive result for confirmatory assay in the pre-treatment sample only.  
 
Previously, interference of KW-0761 (mogamulizumab) with the neutralizing assay at 
concentrations of 1 μg/mL and higher had been noted (Study Report 08/065-011). In Study KW-
0761-001, plasma KW-0761 (mogamulizumab) concentration data were not considered to be 
reliable because the analytical method utilized to measure the plasma KW-0761 
(mogamulizumab) concentrations did not yield acceptable results for incurred sample reanalysis. 
Therefore, despite negative final results, no conclusion can be drawn from the neutralizing assay 
data regarding the potential presence of neutralizing antibodies in the samples tested positive in 
the confirmatory assay. 
 
 

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2.2.9 Summary of clinical pharmacokinetics 
 
The mean plasma concentration-time profiles and summary of pharmacokinetic parameters of 
mogamulizumab after eight repeated doses of 1.0 mg/kg of iv  KW-0761 (mogamulizumab) at 1-
week intervals in subjects with CCR4+ ATL based on a Phase 2 Repeated Dose Study in Subjects 
with CCR4+ ATL.  
 
The mean Cmax and Ctrough increased as the number of doses increased over time; steady state 
was not reached after eight weekly doses. The mean cumulative ratio after the 8th administration 
was 2.25 for Cmax, 3.56 for Ctrough, and 2.87 for AUC0-7 days. The mean t1/2 after the 8th dose 
was 422 ± 147 hours (17.6 ± 6.1 days). The estimated Cmax and Ctrough, based on a two-
compartment open model analysis of the mean plasma concentration data, were 40993.2 ng/mL 
and 29 546.4 ng/mL after the 8th administration, respectively. These model-predicted values were 
similar to the observed mean Cmax and Ctrough values, indicating that the pharmacokinetics of 
mogamulizumab was stable after repeated doses. 
 
2.2.10 Rationale for KW-0761 (mogamulizumab) dose selection and schema 
 
The dose of KW-0761 (mogamulizumab) planned to be studied in this trial is induction dosing of 
1.0 mg/kg administered IV weekly for three weekly doses followed by maintenance dosing of 
1.5mg/kg every 21 days until disease progression. Dosage of up to 1.0 mg/kg was approved in 
Japan for T-cell lymphomas. There is a high likelihood that induction dose of 1mg/kg will be safe 
and well tolerated as demonstrated in clinical trial with monotherapy KW-0761 
(mogamulizumab). We are, however, including a de-escalation dose level of 0.5 mg/kg, 50% of 
starting dose. The maintenance dosing of every 21 days will allow for ease of administration with 
MK-3475 (pembrolizumab). To maintain dose intensity with every 21 days schedule (versus 
every 14 days schedule), the maintenance dosing will be increased to 1.5mg/kg. KW-0761 
(mogamulizumab) has been given at doses of 3mg/kg in combination with durvalumab with no 
unexpected adverse events. Since the terminal half-life after 8-week therapy was found to be 
around 18 days, dosing every 21 days should still allow for substantial drug serum concentration 
at 21 days. Additional information on the rationale for dosage selecting is summarized below. 
 
Pharmacokinetics of KW-0761 (mogamulizumab) following bi-weekly dosing of KW-0761 
(mogamulizumab) in combination with mLSG15 was characterized in subjects with CCR4+ ATL 
(Study 0761-003). All of the 29 subjects who received KW-0761 (mogamulizumab) were 
included in the pharmacokinetic analysis set. The mean Cmax and Ctrough concentrations after 
repeated iv administrations every two weeks in subjects with CCR4+ ATL. After the 8th dose, the 
mean Cmax and Ctrough of KW-0761 (mogamulizumab) were 22814.3 ± 4634.1 ng/mL and 9420.9 
± 3845.6ng/mL, respectively. The Robs of the 8th dose to the first dose for Cmax and Ctrough 
were 1.49 and 2.92, respectively.  
 
Multiple phase I and II studies (KW-0761-001; KW-0761-002; 0761-007) with monotherapy 
KW-0761 (mogamulizumab), in the US and Europe, included patients with relapsed PTCL and 
CTCL. Phase 1 doses were 0.1, 0.3 and 1.0 mg/kg iv. Phase 2 dose was 1.0 mg/kg iv. The 
regimen was weekly for four weeks, then every other week until progression or DLT.  
 

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2.2.11 Summary of Safety 
 
The most frequent treatment-emergent adverse events reported in phase I/II study in T-cell 
lymphomas were: nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related 
reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic 
effects (Duvic et al., 2015).  
 
As of 30 Sep 2016, an estimated 3244 patients have received at least one dose of KW-0761 
(mogamulizumab). The most frequently reported SAEs (occurring in three or more patients) 
considered to be at least possibly related to KW-0761 (mogamulizumab). Rash (1.26%), infusion 
reactions (1.05%), CMV infections (0.71%), pneumonia (0.71%), erythema (0.59%), febrile 
neutropenia (0.52%), leukopenia (0.46%), sepsis (0.40%), and SJS (0.46% overall and 
approximately 1% in Japanese patients) have been reported most frequently (Investigator’s 
brochure 2016).  
 
The potential complications observed in patients underwent hematopoietic stem cell 
transplantation after exposure to KW-0761 (mogamulizumab) supports the relevance of CCR4-
expressing Tregs after allo-HSCT in humans. In patients treated with KW-0761 
(mogamulizumab) who subsequently received HSCT, the incidence of GVHD is estimated to be 
30% to 50% based on the total number of transplant recipients reported in the DURS and recent 
reports in the literature (Sugio et al., 2016; Inoue et al., 2016; Fuji et al., 2016). These reports 
indicate that KW-0761 (mogamulizumab) therapy prior to HSCT may be associated with more 
severe GVHD and poor outcomes post-transplant.  
The importance of these findings is related to the possibility that HSCT may offer a curative 
treatment option for patients with aggressive ATL (Chihara et al., 2013; Fuji et al., 2016).  
 
Care should be taken with the use of KW-0761 (mogamulizumab) in patients who have received 
HSCT or may go on to HSCT as CCR4 is expressed not only on tumor cells but also on normal 
regulatory T cells and Th2 cells, cells that may influence immune reconstitution and occurrence of 
GVHD post-transplant. Patients should be monitored for complications of allo-HSCT after KW-
0761 (mogamulizumab). Exposure to KW-0761 (mogamulizumab) should be considered when 
evaluating a patient for transplant and appropriate methods to prevent or mitigate GVHD should 
be strongly considered (Investigator’s Brochure 2016). 
 
2.3 
Rationale 
 
An emerging therapeutic strategy for relapsed, refractory diffuse large B-cell lymphoma has been 
to augment the host immune response.  The extent of the host immune response, as demonstrated 
by the presence tumor-infiltrating effector CD8+ T cells and the ratio of effector to regulatory T 
cells, correlates with therapeutic outcomes in various lymphomas.  The use of allogeneic 
transplant and donor lymphocyte infusions to promote durable remissions further emphasizes the 
potential for tumor immunotherapy in lymphoma.  DLBCL has been shown to suppress the host 
immune response via a variety of mechanisms.  These include genetic deletion of genes required 
for anti-tumor T-cell responses such as beta-2 microglobulin and CD58 (Challa-Malladi et al., 
2011;  de Miranda et al., 2014), which prevent recognition by effector CD8 and NK cells, 
respectively, as well as pathologic upregulation of ligands for the inhibitory receptor Programmed 

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Cell Death-1 (PD-1) (Chen et al., 2013; Georgiou et al., 2016; Kataoka et al., 2016; Laurent et al., 
2015).  PD-1 is normally engaged on T-cells following activation in order to appropriately limit 
the extent of T-cell responses to foreign antigens, but in lymphomas, abnormal expression of PD-
1 ligands results in inappropriate suppression of anti-tumor responses.  Targeting this negative 
regulatory interaction has resulted in dramatic clinical responses in solid tumors and has more 
recently shown promising activity in multiple lymphomas, including Hodgkin lymphoma (HL) 
and follicular lymphoma (FL), with responses rates of 50-80% and 40%, respectively in patients 
with multiply relapsed disease (Armand et al., 2016; Lesokhin et al., 2016; Younes et al., 2016).   
MK-3475 (pembrolizumab) is thought “unlicense” tumor-infiltrating T-cells, permitting anti-
tumor responses to low-affinity neoantigens that would otherwise be ineffective at inducing 
productive T-cell activation. Treatment of DLBCL with nivolumab, a humanized IgG4 
monoclonal antibody that binds PD-1, resulted in responses in 36% of patients with DLBCL in a 
phase I study, but responses were transient with a median duration of response of only 7 weeks 
(Lesokhin et al., 2016).  This suggests that alternative immunosuppressive mechanisms exist 
within the DLBCL tumor microenvironment that continues to restrain effective anti-tumor 
responses, even in the presence of PD-1 blockade. 
 
One potential contributor to persistent immunosuppression in the setting of checkpoint blockade 
is the presence of intratumoral regulatory T-cells (Tregs).  Tregs are a subset of CD4+ T cells that 
are required to restrain excessive immune responses to foreign pathogens and restrain tissue 
damage and autoimmunity.  However, these immunoregulatory properties may pathologically 
promote malignancy by inappropriately restraining effector responses.  This is best exemplified 
by the observed regression of established tumors in experimental models of Treg depletion 
(Klages et al., 2010; Li et al., 2010; Teng et al., 2010).  While the immunosuppressive targets of 
Tregs has most classically been tumor-infiltrating effector T-cells, recent work from Alexander 
Rudensky’s group has demonstrated that Tregs play a critical role in suppressing NK cell-
mediated killing of MHC class-I deficient targets (Gasteiger et al., 2013). 
 
There is strong evidence to suggest that lymphomas recruit Tregs to suppress anti-tumor 
immunity.  B-cell lymphomas have been shown to produce chemokines that serve as 
chemoattractants to induce Treg recruitment into the tumor microenvironment.  In particular, 
production of CCL22 (MDC) and CCL17 (TARC) has been resported in multiple lymphomas 
(Ghia et al., 2001; Takegawa et al., 2008; Niens et al., 2008).  These chemokines recruit Tregs 
through the chemokine receptor CCR4, a lymphocyte receptor expressed on Tregs (Tobinai et al., 
2012). Production of CCL17 and CCL22 in lymphomas has been shown to recruit CCR4+ Tregs 
into the tumor microenvironment (Yang et al., 2006).  The recruitment of Tregs to the tumor 
microenvironment may underlie ineffective NK cell cytotoxicity seen in DLBCL (Cox et al., 
2015). We have preliminary observed that patients progressing on anti-PD-1 therapy have a high 
proportion of Tregs within the tumor microenvironment, which may promote ongoing immune 
evasion in the presence of checkpoint blockade.  
 
This suggests that depletion of Tregs may be an effective therapeutic strategy to promote anti-
tumor immune responses.  Indeed, work by Jedd Wolchok’s group at MSKCC has demonstrated 
that many immunomodulatory therapeutic strategies (such as GITR agonists, indoleamine 2,3 
dioxygenase inhibitors, or anti-CTLA-4 antibodies) may operate through intratumoral Treg 
depletion (Schaer et al., 2013; Holmgaard et al., 2013; Simpson et al., 2013).  CCR4 is a highly 

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attractive strategy for therapeutic targeting of Tregs as it is preferentially expressed on activated 
regulatory T-cells, which exert a more potent immunosuppressive effect (Hirahira et al., 2006).  
Indeed, CCR4 antagonism in mouse models induced expansion of antigen-specific CD8 T cells 
and promoted anti-tumor immunity (Pere et al., 2011).  In a phase I/II study of subjects with 
relapsed adult T-cell leukemia/lymphoma (ATLL), a single treatment course of KW-0761 
(mogamulizumab) (8 weekly doses of 1 mg/kg) induced a marked depletion of FoxP3+ Tregs 
from the peripheral blood that persisted for 4 months after the final dose (Ishida et al., 2012; 
Sugiyama et al., 2013).  In CTCL patients, treatment with KW-0761 (mogamulizumab) 
effectively depleted CC4+ Tregs leading to an increase in CD8 and NK cell cytotoxicity (Ni et al., 
2015); similar results were seen in a phase Ia clinical trial of solid tumor patients in which KW-
0761 (mogamulizumab) depleted circulating Tregs and induced peripheral blood responses to 
cancer/testis antigens (Kurose et al., 2015). 
 
We propose that targeting regulatory T cells with the monoclonal antibody KW-0761 
(mogamulizumab), a humanized monoclonal antibody targeting the chemokine receptor CCR4 
that is highly expressed on Tregs, represents a mechanistically rational strategy to overcome 
resistance to checkpoint blockade and promote durable responses in relapsed and refractory 
diffuse large B-cell lymphoma. KW-0761 (mogamulizumab) has been safely administered to 
patients with T cell lymphomas (Duvic et al., 2015; Ogura et al., 2014; Zinzani et al., 2016; 
Yamamoto et al., 2010).  We propose that the combination of KW-0761 (mogamulizumab) and 
MK-3475 (pembrolizumab) will overcome immune evasion in DLBCL by promoting CD8 T-cell 
dependent effector responses in MHC-I expressing lymphomas while promoting NK cell-
dependent cytotoxicity in MHC-I deficient lymphomas. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Targeted genomic sequencing and fluorescence in-situ hybridization of formalin-
fixed, paraffin-embedded tumor samples 
 
2.4.1.1 Background 
The MSK-IMPACT platform is a CLIA-certified assay which routines assays for somatic 
mutations in clinical FFPE samples, achieving >500X coverage in almost all samples.  The 
Clinical Cytogenetics Laboratory has developed multiple FISH assays, including PD-L1, for 
clinical use. 
 
2.4.1.2 Hypotheses 
1) DLBCL tumors with somatic mutations in B2M and CD58 will be differentially 
associated with tumor-infiltrating CD8 and NK cells in response to KW-0761 
(mogamulizumab) and MK-3475 (pembrolizumab), with NK cell predominant 
responses in B2M-mutant DLBCL and CD8 T-cell predominant responses in CD58-
mutant DLBCL 
2) Genetic amplification of PD-L1 will predict for response to therapy 
2.4.1.3 Aims 
1) Determine the prevalence of somatic mutations in B2M and CD58 in patients treated 

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with KW-0761 (mogamulizumab) and MK-3475 (pembrolizumab) vs. MK-3475 
(pembrolizumab) alone and correlate with progression-free survival 
2) Determine the prevalence of PD-L1 amplifications by FISH and correlate with 
progression-free survival 
 
2.4.1.4 Methods 
DNA extracted from formalin-fixed, paraffin-embedded tissues will be evaluated for 
somatic mutations in established cancer-related genes using the MSK-IMPACT hybrid 
capture platform (Hyman et al., 2015, Cheng et al., 2015) which includes over 400 genes 
commonly mutated in hematologic malignancies including those listed above.  
Amplification of PD-L1 will be evaluated by fluorescence in-situ hybridization (Roemer et 
al., 2016) in the Clinical Cytogenetics Laboratory. 
 
2.4.2 Immunohistochemical analysis of the tumor and tumor microenvironment 
 
2.4.2.1 Background 
The MSK Pathology department has extensive 
expertise in performing Immunohistochemical 
assessment of CD3, CD4, CD8, MHC-I, MHC-
II, B2M, PD-L1, CCR4, and FoxP3.  
Association of expression levels of these 
proteins with outcomes in Hodgkin lymphoma 
was presented at the 2016 American Society of 
Hematology meeting. 
 
2.4.2.2 Hypotheses 
1) DLBCL tumors with loss of surface MHC-I 
expression will be associated with higher 
NK cell infiltration while tumors with 
surface loss of CD58 will be associated with higher CD8 T cell infiltration in response 
to therapy 
Depletion of tumor-infiltrating regulatory T-cells (marked by FoxP3 expression) will predict for 
response to therapy. 
 
2.4.2.3 Aims 
1) Determine expression levels of MHC-I, CD58, PD-L1, and FoxP3 at baseline and in 
response to therapy using Immunohistochemical analysis of FFPE samples obtained prior 
to and following 1 cycle of therapy, and correlate these results with progression-free 
survival. 
 
2.4.2.4 Methods 
Immunostaining of FFPE sections from pre-treatment biopsies will be performed as 
previously described; all targets have been validated and successfully used in patients with 
lymphoma (Vardhana et al., Blood 2016).  Expression of MHC-I, MHC-II, and CD58 will 
be scored in a binary fashion (positive vs. negative) while CD3, CD4, CD8, PD-L1 and 
Figure 1. Example of positive and negative 
staining for MHC-I, MHC-II, and B2M in 
Hodgkin lymphoma samples. 

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FoxP3 expression will be scored based on percent of total cells that are positive across 15 
high-powered fields.  Results will be independently corroborated by 2 pathologists. 
 
2.4.3  Immunophenotyping and functional 
characterization of circulating 
immune cells 
 
2.4.3.1 Background 
The Immune Monitoring Facility is a 
CLIA-certified laboratory with 
extensive experience in performing the 
assays mentioned below, as shown in 
Figure 2, demonstrating a significant 
reduction in circulating regulatory T 
cells (A) and increase in CD8 T cells 
(B) in the peripheral blood following 
treatment with KW-0761 
(mogamulizumab) in a phase I trial. 
 
2.4.3.2 Hypotheses 
1) KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab) will decrease regulatory 
T cells in the peripheral blood 
2) KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab) will result in an increase 
in the activation status and effector function of circulating T cells within the peripheral 
blood.  
2.4.3.3 Aims 
1) Determine the prevalence of circulating regulatory T-cells in the peripheral blood 
following treatment with KW-0761 (mogamulizumab) and MK-3475 (pembrolizumab) 
2) Determine the prevalence, activation status, and effector function of circulating T-cells in 
the peripheral blood following treatment with KW-0761 (mogamulizumab) and MK-3475 
(pembrolizumab) 
 
2.4.3.4 Methods 
Flow cytometry will be performed within the Immune Monitoring Facility at MSKCC. 
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, CCR4, CD45RA, CD45RO, 
LAG3, GARP, PD1, and CTLA4 (Figure 2). Activation markers such as CD44 and CD69, will 
also be examined.   
 
2.4.4  Evaluation of circulating serum cytokines at baseline and in response to therapy 
 
 
2.4.4.1 Background  
The Immune Monitoring Facility is a CLIA-certified laboratory with extensive experience 
Figure 2.  Depletion of regulatory T cells (A) and 
enhancement of CD8 T cells (B) in patients treated with 
mogamulizumab in a phase I trial.  Each number represents 
a separate patient. 

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in performing the assays mentioned above, and has published identical assays performed 
as part of early phase trials of ipilimumab and nivolumab in solid organ malignancies. 
 
2.4.4.2 Hypotheses 
An increase in the production of pro-inflammatory cytokines (IFN-g, IL-2, TNF-a) and a 
decrease in anti-inflammatory cytokines (IL-10) will be seen in response to therapy. 
2.4.4.3 Aims 
 
Determine levels of IL-2, IL-4, IL-6, IL-10, TNF-a, IFN-g, and IL-17a in patient serum 
following treatment with KW-0761 (mogamulizumab) and MK-3475 (pembrolizumab). 
 
2.4.4.4 Methods 
Cytokine measurements will be performed on serum by the Immune Monitoring Facility 
using a Human Th1/Th2/Th17 cytometric bead array (BD Biosciences).  Cytokines 
measured will include IL-2, IL-4, IL-6, IL-10, TNF-a, IFN-g, and IL-17a. 
 
 
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
23 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically confirmed diffuse large B-cell lymphoma. All subtypes 
of diffuse large B-cell lymphoma are eligible, including high-grade B-cell lymphoma 
(Swerdlow et al., 2016) and DLBCL that has transformed from a prior indolent B-cell 
Non-Hodgkin lymphoma. 
 
3.1.2 Patients must have measurable disease per 2014 Lugano Classification Criteria (Cheson et 
al., 2014) which is defined as at least one nodal lesion measuring >1.5cm in greatest 
diameter or at least one extranodal lesion measuring >1.0cm in greatest diameter.  
 
3.1.3 For phase 2: patients have received at least 2 prior lines of therapy and must have 
previously received, refused, or been deemed ineligible for autologous stem cell 
transplantation.  
 
3.1.4 Age ≥18 years. 
 
Because no dosing or adverse event data are currently available on the use of MK-3475 
(Pembrolizumab) in combination with KW-0761 (Mogamulizumab) in patients <18 years 
of age, children are excluded from this study, but will be eligible for future pediatric trials. 
3.1.5 ECOG performance status ≤ 1 (Karnofsky ≥ 80%, see Appendix A). 
 
3.1.6 Patients must have normal organ and marrow function as defined below: 
 
 
Absolute neutrophil count 
≥1,500/mcL (if neutropenia is related to bone 
marrow involvement with lymphoma, the absolute 
neutrophil count must be ≥1,000/mcL) 
Platelets 
≥75,000/mcL (if thrombocytopenia is related to 
bone marrow involvement with lymphoma, the 
platelet count must be ≥50,000/mcL) 
Hemoglobin 
≥9 g/dL (if anemia is related to bone marrow 
involvement with lymphoma, the hemoglobin must 
be ≥8 g/dL) 
Total bilirubin 
≤1.5x the institutional ULN or < 3x the ULN for 
indirect bilirubin in patients with Gilbert’s disease   
AST and ALT 
≤2.5x institutional upper limit of normal 
Creatinine OR measured or 
calculated creatinine 
clearance 
≤1.5x institutional upper limit of normal OR if 
creatinine >1.5x ULN then creatinine clearance 
≥40 mL/min/1.73 m2 as calculated by Cockcroft 
and Gault equation 
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
24 
 
3.1.7 Life expectancy of greater than 3 months 
 
3.1.8 The effects of MK-3475 (Pembrolizumab) in combination with KW-0761 
(Mogamulizumab) on the developing human fetus are unknown. For this reason, women 
of child-bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, for the duration of study 
participation, and 6 months after completion of MK-3475 (Pembrolizumab) in 
combination with KW-0761 (Mogamulizumab) administration. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately.  Men treated or enrolled on this 
protocol must also agree to use adequate contraception prior to the study, for the duration 
of study participation, and 6 months after completion of MK-3475 (Pembrolizumab) in 
combination with KW-0761 (Mogamulizumab) administration. 
 
Submit adequate archival tissue specimen (25+ unstained slides or 2 tissue blocks) from a 
biopsy performed after progression of disease on most recent therapy OR subject is willing 
to undergo a new core or excisional biopsy to obtain evaluable tumor tissue sample for 
immunohistochemical assessment and sequencing for B2M loss. Repeat samples may be 
required if adequate tissue is not provided, however, patients may still be considered for 
enrollment on a case by case basis following consultation with the PI. See Section 2.4 in 
protocol for an explanation.  
 
3.1.9 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.10 Subjects with prior history of chemotherapy-induced or radiation-induced pulmonary 
toxicity require confirmation of diffuse capacity of the lung for carbon monoxide (DLCO) 
over 60% (adjusted for hemoglobin) by a pulmonary function test prior to study 
enrollment.  
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had previous systemic anti-cancer therapy within 2 weeks or 5 half-
lives (the shorter of the two) of registration or those who have not recovered from adverse 
events due to agents administered previously. 
 
Note: Patients are considered enrolled on the study after protocol registration and not after 
signing consent. 
 
3.2.2 Patients who are receiving any other concurrent investigational agents. 
 
3.2.3 Patient is receiving systemic steroid therapy or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of trial treatment.  The use of physiologic 
doses of corticosteroids (e.g. prednisone <=20mg/d) may be approved after consultation 
with the study PI.  Topical or inhaled corticosteroids are allowed.  
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
25 
 
3.2.4 Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin 
that has undergone potentially curative therapy, or in situ cervical cancer. 
 
3.2.5 Patients with active cerebral or meningeal involvement by lymphoma should be excluded 
from this clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound evaluation of neurologic and 
other adverse events.  
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-3475 (Pembrolizumab) or KW-0761 (Mogamulizumab). 
 
3.2.7 Subject with active autoimmune disease. Subjects with vitiligo, eczema, alopecia, type I 
diabetes mellitus, psoriasis not requiring systemic treatment, or endocrine deficiencies 
(such as hypothyroidism) managed with replacement hormones, including physiologic 
corticosteroid replacement therapy are eligible.  
 
3.2.8 Has a history or currently active (non-infectious) pneumonitis that required steroids unless 
prior history of chemotherapy or radiotherapy induced pneumonitis meeting the eligibility 
criteria in 3.1.11 
 
3.2.9 Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the patient’s participation for the full 
duration of the trial, or is not in the best interest of the patient to participate, in the opinion 
of the treating investigator. 
 
3.2.10 Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 
antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or checkpoint pathways). 
 
3.2.11 Prior allogeneic SCT 
 
3.2.12 Patients who are planning to receive allogeneic SCT in the near future as preliminary 
reports suggest added toxicity in patients undergoing allogeneic stem cell transplantation 
after having received mogamulizumab. 
 
3.2.13 Autologous SCT ≤ 90 days prior to first dose of study drug  
 
3.2.14 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 

NCI Protocol #: 10106 
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26 
 
3.2.15 Pregnant women are excluded from this study because MK-3475 (pembrolizumab) is an 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with MK-3475 (pembrolizumab), breastfeeding should be discontinued if the 
mother is treated with MK-3475 (pembrolizumab).  These potential risks may also apply 
to KW-0761 (mogamulizumab). 
 
MK-3475 (pembrolizumab) and KW-0761 (mogamulizumab) may have adverse effects on 
a fetus in utero.  Furthermore, it is not known if MK-3475 (pembrolizumab) or KW-0761 
(mogamulizumab) has transient adverse effects on the composition of sperm.  Patients are 
excluded from this study if pregnant or breastfeeding or expecting to conceive or father 
children within the projected duration of the trial, starting with the screening visit through 
180 days after the last dose of trial treatment.   
 
See Section 5.7 for information on contraception and pregnancy. 
 
3.2.16 Patients with HIV are excluded if they have a detectable viral load, are not on a stable 
antiretroviral regimen, have a decreased CD4+ T-cell count (<500), or require 
prophylactic antibiotics for the prevention of opportunistic infections.  
 
3.2.17 Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority 
 
3.2.18 Has a known history of active tuberculosis (TB).  
 
3.2.19 Patients with significant cardiac disease (e.g., NYHA class III-IV congestive heart failure, 
unstable angina, recent myocardial infarction within the last 6 months, etc.).   
 
3.3 
Inclusion of Women and Minorities 
 
Both and women of all races and ethnic groups are eligible for this trial. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
2 
2 
2 
8 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
27 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
Native Hawaiian or 
Other Pacific Islander 
1 
1 
1 
1 
4 
Black or African 
American 
6 
6 
2 
2 
16 
White 
15 
15 
4 
4 
38 
More Than One Race 
3 
3 
2 
2 
10 
Total 
27 
27 
11 
11 
76 
   PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
 
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
28 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval Log (DTL). 
 
Additional information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
29 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
• Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can be approved to enroll patients.  Assignment of site 
registration status in the CTSU Regulatory Support System (RSS) uses extensive data to 
make a determination of whether a site has fulfilled all regulatory criteria including but not 
limited to:  
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not 
required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using 
the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an 
automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In order 
for the SSW approval to be processed, the Signatory Institution must inform the CTSU which 
CIRB-approved institutions aligned with the Signatory Institution are participating in the study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the [NCI protocol #] protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is 
restricted and is based on person and site roster data housed in the CTSU RSS.  To 
participate, Investigators and Associates must be associated with the Corresponding or 
Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MD017 and 
protocol #10106 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
30 
 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Requirements For 10106 Site Registration: 
  
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
• A Site initiation visit (SIV) is required for each participating site prior to 
activation. The local site PI must participate on the call as well as their research 
nurse, study coordinator, and pharmacist. To schedule a SIV, please email the 
Protocol Liaison and crocc@jhmi.edu and reference the protocol in the subject line 
of the email.   
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
31 
 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It is 
integrated with the CTSU Enterprise System for regulatory and roster data interchange and 
with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 Patient Enrollment Instructions   
 
Slot reservation will not be used when enrolling subjects. Slots are available on a first 
come, first serve basis.  
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
32 
 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk at 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 28 days. Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
33 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
As of 08/10/2019, we are using dose level (-1) due to limited feasibility of administering dose 
level 1.  
 
Dose Escalation Schedule 
Dose Level 
Dose 
MK-3475 [Pembrolizumab] 
(mg) 
KW-0761 [Mogamulizumab] 
(mg/kg) 
Level -1 
200mg IV day 1 every 21 
days 
Induction: 0.5 mg/kg IV weekly for 
3 weeks  
Maintenance: 1mg/kg IV day 1 
every 21 days  
Level 1 
200mg day 1 every 21 days 
Induction: 1 mg/kg IV weekly for 3 
weeks 
Maintenance: 1.5mg/kg IV day 1 
every 21 days 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
MK-3475 
(Pembrolizumab) 
N/A 
200 mg 
IV Piggyback 
(IVPB) over 30 
minutes.  
Every 3 
weeks 
(Day 1 of 
each cycle) 
21 days 
(3 
weeks) 
 
 
KW-0761 
(Mogamulizumab) 
Premedication with 
acetaminophen orally, 
diphenhydramine 
50mg IV (or 
equivalent), 
hydrocortisone 50mg 
IV before the first and 
second KW-0761 
(mogamulizumab) 
infusion. If a subject 
experiences an 
infustion-related 
reaction at any time 
during the study, pre-
According 
to assigned 
dose level* 
IVPB over 60 
minutes. After 
the first dose, a 
4-hour 
observation 
period is 
required. A 
minimum one-
hour post-dose 
observation 
period is 
required after 
Weekly for 
3 weeks 
(C1D1, 
C1D8, 
C1D15) 
then once 
every 3 
weeks 
(C2D1, 
C3D1, etc.) 

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
 
34 
 
medication is 
recommended prior to 
subsequent infusions.  
each infusion.  
 
*The dose of KW-0761 (mogamulizumab) will be as is appropriate for the assigned dose level in 
the phase I part of the study. In the phase II part of the study, KW-0761 (mogamulizumab) dose 
will be administered at the MTD / RP2D. 
 
In the phase I, the starting dose level is Level 1 (see Table above entitled Dose Escalation 
Schedule). Dose Level 1 consists of MK-4375 (pembrolizumab) given 200mg IV every 3 weeks 
and KW-0761 (mogamulizumab) 1mg/kg once weekly for 3 weeks (C1D1, C1D8, C1D15) and 
thereafter maintenance KW-0761 (mogamulizumab) 1.5mg/kg on day 1 of every 21-day cycle 
(C2D1, C3D1, etc). As of 08/10/2019, we are using dose level (-1) due to limited feasibility of 
administering dose level 1.  
 
For the randomized phase II, patients will be assigned to one of two treatment groups, Group 1 
(MK-3475 [pembrolizumab] and KW-0761 [mogamulizumab]) and Group 2 (MK-3475 
[pembrolizumab] alone). Patients will receive either MK-3475 (pembrolizumab) 200mg IV on 
day 1 of every 21-day cycle and KW-0761 (mogamulizumab) at the induction RP2D once weekly 
for 3 weeks (C1D1, C1D8, C1D15) and thereafter at the maintenance RP2D on day 1 of every 21-
day cycle (C2D1, C3D1, etc) (Group 1) or MK-3475 (pembrolizumab) alone (Group 2). 
 
5.1.1 MK-3475 (pembrolizumab) 
 
Trial treatment of MK-3475 (pembrolizumab) will be administered on Day 1 of each 3-week 
treatment cycle after all procedures/assessments have been completed.  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons (up to 5 days after randomization is permitted). 
 
MK-3475 (pembrolizumab) will be administered as a dose of 200 mg using a 30-minute IV 
infusion.  Infusion timing should be as close to 30 minutes as possible; however, a window of 
minus 5 minutes and plus 10 minutes is permitted (i.e., infusion time is 25 – 40 minutes).  Refer to 
section 6 for compatible infusion set materials including in-line filter. 
 
Administration: Mild infusion reactions can generally be treated with interruption of the infusion 
and medical intervention, including IV fluids, antihistamines, nonsteroidal anti-inflammatory 
drugs, acetaminophen, and narcotics as needed. More severe or life-threatening reactions may 
require vasopressors, corticosteroids, and epinephrine. In the case of severe or life-threatening 
reactions, subsequent doses of pembrolizumab should not be administered. 
 
5.1.2 KW-0761 (mogamulizumab) 
 
Trial treatment of KW-0761 (mogamulizumab) will be administered on Day 1, 8, and 15 of cycle 
1 and on Day 1 of all subsequent 21 day treatment cycles after all procedures/assessments have 
been completed.  Trial treatment may be administered up to 2 days before or after the scheduled 
date during cycle 1 and 3 days before or after the scheduled treatment date of each consecutive 
cycle due to administrative reasons (in order to ensure at least 5 days between doses).  

NCI Protocol #: 10106 
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35 
 
KW-0761 (mogamulizumab) will be administered as the dose that is appropriate per dose level 
during dose escalation or at the RP2D using a 60-minute IV infusion.  Infusion timing should be 
as close to 60 minutes as possible. KW-0761 (mogamulizumab) will be administered after MK-
3475 (pembrolizumab). After first dose of KW-0761 (mogamulizumab) (C1D1), patients will be 
monitored for a minimum of four hours to monitor for potential infusion reaction. Thereafter, 
patients will be monitored for one-hour after KW-0761 (mogamulizumab) administration.  
 
It is recommended that subjects be pre-medicated with acetaminophen 650 mg orally, 
diphenhydramine 50 mg IV (or equivalent), and hydrocortisone 50mg IV before the first and 
second  KW-0761 (mogamulizumab) infusion. If a subject experiences an infusion-related 
reaction at any time during the study, pre-medication is recommended prior to subsequent 
infusions. 
See section 6 for management of infusion reactions to KW-0761 (mogamulizumab). 
 
5.2 
Definition of Dose-Limiting Toxicity 
 
The DLT window of observation will be the first 2 cycles (6 weeks). 
The occurrence of any of the following toxicities will be considered a DLT, except those AEs that 
are clearly and incontrovertibly due to extraneous causes: 
 
 
1. Grade 4 hematologic toxicity lasting ≥7 days. Lymphopenia, a pharmacologic effect of the 
antibody treatment, will not be considered a DLT 
2. Any Grade 3 or 4 non-hematologic toxicity (not laboratory) of any duration. Exceptions 
include:  
• 
Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
• Grade 3 nausea, vomiting or diarrhea not requiring tube feeding, total parenteral 
nutrition, or requiring or prolonging hospitalization 
 
3. Any Grade 3 or Grade 4 nonhematologic laboratory value if: 
 
• 
Medical intervention is required to treat the patient, or 
• 
The abnormality leads to hospitalization, or 
• 
The abnormality persists for >72 hours. 
• 
The only exception for the above criteria is an isolated grade 3 increase in 
amylase or lipase not associated with clinical signs or symptoms of 
pancreatitis- this will not be considered a DLT.  
 
4. Febrile neutropenia Grade 3 or Grade 4. 
 
5. Grade 3 or 4 thrombocytopenia if associated with clinically significant bleeding.  
 
6. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 
 

NCI Protocol #: 10106 
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36 
 
7. Grade 5 toxicity. 
 
8. Patients meeting criteria for Hy's Law (ALT or AST >= 3x ULN and ALP <2x ULN and 
BIL >= 2x ULN) among patients with normal ALT, AST, ALP, and BIL measurements 
during the baseline period (30 days prior to initiation of study drug). Normal is defined as 
an ALT, AST, ALP, and BIL <1 times the upper limit of normal at baseline. ALT is alanine 
aminotransferase, AST is aspartate transaminase, ALP is alkaline phosphatase, and BIL is 
bilirubin. 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed according to the following scheme.  Dose-limiting toxicity (DLT) is 
defined above.  In this study, patients will be initially enrolled at dose level 1 and only if there are 
excessive DLTs will there be dose de-escalation.  
 
Number of Patients with DLT at a 
Dose Level 1 
Escalation Decision Rule 
0 out of 3 
Enter an additional 3 patients at dose level 1. If ≤1 out 
of 6 experience DLT, dose level 1 will be declared the 
RP2D. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, dose level 1 
will be declared the RP2D. 
• If 1 or more of this group suffer DLT, then dose 
level 1 will be declared the maximally administered 
dose.  Three patients will be entered at dose level -1. 
≥2 
Dose level 1 will be declared the maximally 
administered dose (highest dose administered).  Three 
patients will be entered at dose level -1. 
≤1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the RP2D 
 
Number of Patients with DLT at a 
Dose Level -1 
Escalation Decision Rule 
0 out of 3 
Enter an additional 3 patients at dose level -1. If ≤1 out 
of 6 experience DLT, dose level -1 will be declared the 
RP2D. 

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1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, dose level -1 
will be declared the RP2D. 
• If 1 or more of this group suffer DLT, then dose level 
-1 will be declared the maximally administered dose. 
The study will require amendment to test a lower 
dose level.    
≥2 
Dose level -1 will be declared the maximally 
administered dose (highest dose administered).  The 
study will require amendment to test a lower dose level. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of MK-3475 (Pembrolizumab) and KW-0761 
(Mogamulizumab) with other concomitantly administered drugs, the case report form must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any agent known to 
affect or with the potential for drug interactions. The study team should check a frequently-
updated medical reference for a list of drugs to avoid or minimize use of.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The investigator should discuss any questions regarding this with CTEP.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the patient's 
primary physician; however, the decision to continue the patient on trial therapy or vaccination 
schedule requires the mutual agreement of the Investigator, CTEP, and the patient. 
 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial treatment should 
be recorded for serious adverse events (SAEs). 
 
Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and Treatment 
Phase of this trial: 
− 
Antineoplastic systemic chemotherapy or biological therapy.  

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− 
Immunotherapy or immunosuppressants not specified in this protocol. 
− 
Chemotherapy not specified in this protocol. 
− 
Investigational agents other than MK-3475 (pembrolizumab) or KW-0761 
(mogamulizumab). 
− 
Radiation therapy - The use of palliative radiotherapy should be minimized given the 
potential of such treatment to confuse assessments of study drug safety and therapeutic 
effect. However, administration of limited-fraction radiotherapy is permitted after Cycle 1 
to control local tumor-related symptoms if irradiation is unlikely to induce major organ 
toxicity or affect target lesions being followed for tumor response and progression. 
− 
Live vaccines while participating in the trial.  Examples of live vaccines include, but are 
not limited to, the following:  measles, mumps, rubella, chicken pox, yellow fever, rabies, 
Bacillus Calmette–Guérin (BCG), and typhoid (oral) vaccine.  Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
− 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of suspected immunologic etiology.  The use of physiologic doses of corticosteroids may 
be approved after consultation with the study PI and CTEP.  
 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Patients may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to AE(s), treatment may continue for up to 2 years or until 
1 of the following criteria applies: 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
• 
Patient non-compliance 
 
• 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
 

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o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.5 
Criteria to Resume Treatment 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies. The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
5.6 
Contraception and Pregnancy  
 
5.6.1 Contraception 
 
MK-3475 (pembrolizumab) may have adverse effects on a fetus in utero. Furthermore, it is not 
known if MK-3475 (pembrolizumab) has transient adverse effects on the composition of sperm.   
 
KW-0761 (mogamulizumab) may have adverse effects on a fetus in utero. It has not been 
evaluated in pregnant or lactating women. 
 
For this trial, male patients will be considered to be of nonreproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).   
 
Female patients will be considered of nonreproductive potential if they are either:  
1. Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age, a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy.  In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR 
 
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR 
3. Has a congenital or acquired condition that prevents childbearing. 
 
Female and male patients of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 180 days after 
the last dose of study drug by complying with one of the following:   
1. Practice abstinence† from heterosexual activity;  

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OR  
2. Use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
Single method (1 of the following is acceptable): 
• intrauterine device (IUD) 
• vasectomy of a female patient’s male partner  
• contraceptive rod implanted into the skin 
Combination method (requires use of 2 of the following): 
• diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• cervical cap with spermicide (nulliparous women only)   
• contraceptive sponge (nulliparous women only)  
• male condom or female condom (cannot be used together) 
• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the patient’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and Ethics Review 
Committees (ERCs)/Institutional Review Boards (IRBs).  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for patients participating at 
sites in this country/region. 
 
Patients should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study, patients of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days 
prior to the initiation of study medication for oral contraception) throughout the study 
period up to 180 days after the last dose of trial therapy.   
 
If there is any question that a patient will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
 
5.6.2 Use in Pregnancy 
 
 If a patient inadvertently becomes pregnant while on treatment with MK-3475 
(pembrolizumab) or KW-0761 (mogamulizumab), the patient will immediately be 
removed from the study.  The site will contact the patient at least monthly and document 
the patient’s status until the pregnancy has been completed or terminated.  The outcome of 
the pregnancy will be reported without delay and within 24 hours if the outcome is a 

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serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or 
life-threatening complication to the mother or newborn).  The study investigator will make 
every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn.  If a male patient impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy reported and 
followed.  
 
5.6.3 Use in Nursing Women 
 
It is unknown whether MK-3475 (pembrolizumab) or KW-0761(mogamulizumab) is 
excreted in human milk.  Since many drugs are excreted in human milk, and because of 
the potential for serious adverse reactions in the nursing infant, patients who are breast-
feeding are not eligible for enrollment. 
 
5.7 
Treatment Beyond Progression 
 
Immunotherapeutic agents such as MK-3475 (pembrolizumab) may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with such 
an approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
 
A new response category called “indeterminate response” (IR) was developed based upon 
experience with checkpoint blockade therapy in which response assessment may be confounded 
by the delayed effect of these drugs, allowing for early tumor growth, or therapeutic immune 
activation that can manifest as growth of existing lesions or development of new lesions, resulting 
in delayed response or pseudo-progression. Please see the section entitled “Measurement of 
Effect” for the definition of IR. 
 
If radiologic imaging shows IR, tumor assessment may be repeated by the site ≥4 weeks later with 
the option of continuing treatment per below while awaiting clarification of response.  If repeat 
imaging shows a reduction in the tumor burden compared to the initial scan demonstrating IR, 
treatment may be continued as per treatment calendar.  If repeat imaging confirms true PD, 
patients will be discontinued from study therapy.  In determining whether or not the tumor burden 
has increased or decreased, investigators should consider all target lesions as well as non-target 
lesions.  The decision to continue study treatment after the 1st evidence of disease progression 
determined by radiologic imaging is at the Investigator’s discretion based on the clinical status of 
the patient as described in the table below.  
 
Patients may receive study treatment while waiting for clarification of response if they are 
clinically stable as defined by the following criteria: 
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 

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requiring urgent alternative medical intervention 
 
 
Clinically Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of IR 
Repeat imaging 
at ≥4 weeks to 
clarify response 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging 
at ≥4 weeks to 
clarify response 
per physician 
discretion only 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan 
shows SD, PR, 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
local site 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion 
 
5.8 
Discontinuation of Treatment Following Complete Response  
 
Discontinuation of treatment may be considered for patients who have attained a confirmed 
complete response (CR) that have been treated for at least 24 weeks with MK-3475 
(pembrolizumab) and had at least four cycles of treatment with MK-3475 (pembrolizumab) and 
KW-0761 (mogamulizumab) beyond the date when the initial CR was declared. 
 
5.9 
Treatment Up to 2 Years 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 2 
years with MK-3475 (pembrolizumab) (maximum 35 cycles) with or without KW-0761 
(mogamulizumab) (maximum 34 cycles) or until one of the following criteria applies: 
documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents 
further administration of treatment, investigator’s decision to withdraw the patient, patient 
withdraws consent, pregnancy of the patient, noncompliance with trial treatment or procedure 
requirements, or administrative reasons. 
 
 
 

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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Dose modifications and supportive care guidelines for drug-related adverse events 
with the combination of MK-3475 (Pembrolizumab) and KW-0761 
(Mogamulizumab).   
 
Adverse events (both non-serious and serious) associated with MK-3475 (pembrolizumab) and 
KW-0761 (mogamulizumab) exposure may represent an immunologic etiology. These AEs may 
occur shortly after the first dose or several months after the last dose of treatment. Study regimen 
must be withheld for drug-related toxicities and severe or life-threatening AEs as the table in 
Section 6.1.2. 
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays).  Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption.  The reason for interruption should be documented in the patient's study record. 
 
6.1.1 Supportive Care Guidelines 
 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are also outlined in the table in Section 6.1.2.  Where appropriate, these 
guidelines include the use of oral or IV treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.  Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased.  For each disorder, attempts should be made to rule out other causes 
such as progressive disease or bacterial or viral infection, which might require additional 
supportive care.  The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to MK-3475 (pembrolizumab) or KW-0761 
(mogamulizumab). 
 
Note:  If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of the evaluation of the event. 

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6.1.2 Dosing Modification and Toxicity Management 
 
Guidelines for Immune-mediated, Infusion Related, and Non Immune-mediated Reactions  
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune- 
related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation 
of study drug/study regimen based on CTC 
grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of 
≤10 mg of prednisone per day (or equivalent) 
within 12 weeks after last dose of study drug/study 
regimen 
• 
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of 
dosing 
Grade 1 No dose modification 
Grade 2 Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or 
Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes to Grade ≤1 after 
completion of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 
1) The event stabilizes and is controlled. 
2) The patient is clinically stable as per 
Investigator or treating physician’s 
clinical judgement. 
3) Doses of prednisone are at ≤10 mg/day 
or equivalent. 
Grade 3 Depending on the individual toxicity, study 
drug/study regimen may be permanently 
It is recommended that management of irAEs 
follows the guidelines presented in this table: 
• 
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, concomitant medications, and 
infections). 
• 
In the absence of a clear alternative etiology, all 
events should be considered potentially immune 
related. 
• 
Symptomatic and topical therapy should be 
considered for low-grade (Grade 1 or 2, unless 
otherwise specified) events. 
• 
For persistent (>3 to 5 days) low-grade (Grade 
2) or severe (Grade ≥3) events, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
• 
If symptoms recur or worsen during 
corticosteroid tapering (28 days of taper), 
increase the corticosteroid dose (prednisone dose 
[e.g., up to 2 to 4 mg/kg/day PO or IV 
equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid      
tapering at a slower rate (>28 days of taper). 
• 
More potent immunosuppressives such as TNF 
inhibitors (e.g., infliximab) (also refer to the 
individual sections of the irAE for specific type 
of immunosuppressive) should be considered for 
events not responding to systemic steroids. 
• 
Discontinuation of study drug/study regimen is 
not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit/risk analysis for that 
patient. 

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45 
 
 
Dose Modifications 
Toxicity Management 
discontinued. Please refer to guidelines 
below. 
Grade 4 Permanently discontinue study drug/study 
regimen. 
Note: For Grade ≥3 asymptomatic amylase or lipase 
levels, hold study drug/study regimen, and if complete 
work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: For Grade 3 and above asymptomatic amylase or 
lipase levels hold study drug/regimen and if complete 
work up shows no evidence of pancreatitis, may 
continue or resume study drug/regimen 
AE=Adverse event; CTC=Common Toxicity Criteria; CTCAE=Common Terminology Criteria for Adverse Events; irAE=Immune-related adverse event; 
IV=intravenous; NCI=National Cancer Institute; PO=by mouth 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6.2 
Specific Immune-mediated Reactions 
 
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after 
corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Add prophylactic 
antibiotics for 
opportunistic 
infections 
•  Monitor participants for 
signs and symptoms of 
pneumonitis 
•  Evaluate participants with 
suspected pneumonitis 
with radiographic imaging 
and initiate corticosteroid 
treatment 
Recurrent Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
•  Monitor participants for 
signs and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or 
without fever) and of 

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Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
equivalent) followed 
by taper 
bowel perforation (ie, 
peritoneal signs and ileus) 
•  Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and 
performing endoscopy to 
rule out colitis 
•  Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake 
is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2 a 
Withhold 
•  Administer 
corticosteroids (initial 
dose of 0.5 - 1 mg/kg 
prednisone or 
equivalent) followed 
by taper 
•  Monitor with liver 
function tests (consider 
weekly or more frequently 
until liver enzyme value 
returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer 
corticosteroids (initial 
dose of 1 - 2 mg/kg 
prednisone or 
equivalent) followed 
by taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
Withhold d 
•  Initiate insulin 
replacement therapy 
•  Monitor participants for 
hyperglycemia or other 

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hyperglycemia 
associated with 
evidence of -cell 
failure 
for participants with 
T1DM 
•  Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
signs and symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
•  Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
•  Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
•  Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
•  Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) followed 
by taper 
•  Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 

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49 
 
Myocarditis 
Grade 1 or 2 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other immune-
related AEs 
Persistent Grade 2 
Withhold 
•  Based on severity of 
AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x 
ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-
Johnson Syndrome and toxic epidermal necrolysis. 
 

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6.3 
Infusion-related Reactions 
 
Severity Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
Manage per institutional standard at the discretion of investigator. 
Monitor patients for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations  
in heart rate and blood pressure, dyspnea or chest discomfort, or skin 
rashes) and anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until 
resolution of the event. 
For Grade 2: 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution 
of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
Consider premedication per institutional standard prior to subsequent 
doses. 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
• 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV 
diphenhydramine and ranitidine, and IV glucocorticoid). 
CTCAE=Common Terminology Criteria for Adverse Events; IM=Intramuscular; IV=Intravenous; NCI=National Cancer Institute. 

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6.4 
Non-immune-mediated Reactions 
 
Severity Grade of the 
Event (NCI CTCAE 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs 
not deemed to be related to study treatment (e.g., 
events due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to 
≤Grade 1 
or baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to 
≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 14 
days, resume study drug/study regimen 
administration. Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
Discontinue study drug/study regimen (Note: For 
Grade 4 labs, decision to discontinue should be 
based on accompanying clinical signs/symptoms, the 
Investigator’s clinical judgment, and consultation 
with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Medical Monitor.” AE=Adverse event; CTCAE=Common Terminology Criteria for Adverse Events; 
NCI=National Cancer Institute. 
 
6.5 
Tumor lysis syndrome  
 
In the event a patient develops tumor lysis syndrome, the patient will be managed per institutional 
guidelines. 

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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Sections 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.  
 
7.1.1 CAEPRs for CTEP IND Agents 
 
7.1.1.1 
CAEPR for MK-3475 (pembrolizumab) 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MK-3475 (pembrolizumab, NSC 776864) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3793 patients. Below is the CAEPR for MK-3475 
(pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
    

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    Version 2.5, December 27, 20191 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
Lymph node pain2 
 
 
 
 
Thrombotic thrombocytopenic 
purpura2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypohysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - 
Other (acute graft-versus-host-
disease)2,3 
  
 
 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis)2 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation)2 
 
  
 
Immune system disorders - Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased2 
 
  
 
Blood bilirubin increased 
 
  
 
CPK increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  
 
 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Avascular necrosis2 
 
  
 
Back pain 
 
  
 
Joint effusion2 
 
  
 
Joint range of motion decreased 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(tenosynovitis)2 
 
  
 
Myalgia2 
 
  
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome)2 
  
 
 
Nervous system disorders - 
Other (neuromyopathy)2 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Nervous system disorders - 
Other (non-infectious 
encephalitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious 
meningitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious myelitis) 
  
 
 
Nervous system disorders - 
Other (polyneuropathy)2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pleuritic pain2 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (dermatitis)2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving MK-3475 
(pembrolizumab).  Adverse events potentially related to MK-3475 (pembrolizumab) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse 
reactions were reversible and managed with interruptions of MK-3475 (pembrolizumab), administration of 
corticosteroids and supportive care. 
 

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3Acute graft-versus-host disease has been observed in patients treated with MK-3475 (pembrolizumab) 
who received hematopoeitic stem cell transplants. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal 
hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; 
Rectal hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; 
Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general 
physical health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - Cholesterol high; Creatinine increased; Fibrinogen decreased; Lymphocyte count 
decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood cell 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: MK-3475 (pembrolizumab) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
 
 

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7.1.1.2 
CAEPR for KW-0761 (mogamulizumab) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
KW-0761 (mogamulizumab, NSC 791064) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 4759 patients. Below is the CAEPR for KW-0761 
(mogamulizumab).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER. If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.3, September 15, 20191 
 
 Adverse Events with Possible  
 Relationship to KW-0761 (mogamulizumab) 
 (CTCAE 5.0 Term) 
[n= 4759] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
CARDIAC DISORDERS 
  
 
 
Chest pain - cardiac 
  
 
 
Myocardial infarction 
  
 
 
Myocarditis2 
  
 
 
Restrictive cardiomyopathy 
  
GASTROINTESTINAL DISORDERS 
  
 
Nausea 
 
 Nausea (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Flu like symptoms2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
  
 
 
Anaphylaxis3 
  
 
 
Immune system disorders - 
Other (graft versus host 
disease)4 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction3 
 
 Infusion related reaction3 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2,6 
 
  

NCI Protocol #: 10106 
Protocol Version Date: 05/21/2020 
58 
 
 Adverse Events with Possible  
 Relationship to KW-0761 (mogamulizumab) 
 (CTCAE 5.0 Term) 
[n= 4759] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Alkaline phosphatase increased2,6  
  
 
Aspartate aminotransferase 
increased2,6 
 
  
 
Blood bilirubin increased2,6 
 
  
 
GGT increased2,6 
 
  
 
Lymphocyte count decreased2 
 
 Lymphocyte count decreased2 (Gr 2) 
 
Neutrophil count decreased2 
 
 Neutrophil count decreased2 (Gr 2) 
 
Platelet count decreased2 
 
 Platelet count decreased2 (Gr 2) 
 
White blood cell decreased2 
 
 White blood cell decreased2 (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthritis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Peripheral motor neuropathy2 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme2 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug eruption, 
toxic skin eruption)2 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis2 
  
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting  
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving KW-0761 
(mogamulizumab).  Adverse events potentially related to KW-0761 (mogamulizumab) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse 
reactions were reversible and managed with interruptions of KW-0761 (mogamulizumab), administration 
of corticosteroids and supportive care. 
 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of KW-0761 (mogamulizumab), may 
manifest as fever, chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during 
and immediately after administration of KW-0761 (mogamulizumab). 
 
4Acute graft-versus-host disease has been observed in patients treated with KW-0761 (mogamulizumab) 
who subsequently received hematopoeitic stem cell transplants. 
 
5Infection may include any of the infection sites under the INFECTIONS AND INFESTATIONS SOC. 

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6Symptoms of hepatic dysfunction may include Alanine aminotransferase increased, Alkaline 
phosphatase increased, Aspartate aminotransferase increased, Blood bilirubin increased, and GGT 
increased under the INVESTIGATIONS SOC. 
 
Adverse events reported on KW-0761 (mogamulizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that KW-0761 (mogamulizumab) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Disseminated intravascular coagulation; 
Febrile neutropenia; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrial fibrillation; Sinus tachycardia; Supraventricular tachycardia 
EYE DISORDERS - Retinal vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal pain; Cheilitis; Colitis2; Constipation; Diarrhea; 
Gastritis; Mucositis oral; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema 
limbs; Generalized edema; Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - Other (bile duct 
stone); Hepatobiliary disorders - Other (hepatitis) 
INVESTIGATIONS - Blood lactate dehydrogenase increased2; CPK increased; Lipase increased; Serum 
amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Anorexia; Dehydration; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other (diabetes mellitus) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Flank pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (tendonitis); Myositis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Depressed level of consciousness; Encephalopathy; Headache; 
Nervous system disorders - Other (altered state of consciousness); Nervous system disorders - Other 
(cerebellar syndrome); Paresthesia; Seizure 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Cough; Dyspnea; Hypoxia; Pleural effusion; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Erythroderma; Hyperhidrosis; 
Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Pruritus; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (lichenoid keratosis); Urticaria 
VASCULAR DISORDERS - Hypertension2; Hypotension2 
 
Note: KW-0761 (mogamulizumab) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 

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7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 

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other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium 
and perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 
event under the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEP-AERS recognizes this event as a patient death.  
 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 

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Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
Not applicable. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
The following paragraph only applies to trials using Medidata Rave; other trials may delete: 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 

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and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
7.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  
 
 
 

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8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 MK-3475 (pembrolizumab) (NSC 776864) 
 
Other Names: SCH 900475, pembrolizumab 
 
Classification: Anti-PD-1 MAb 
 
Molecular Weight: 148.9-149.5 KDa 
 
CAS Number: 1374853-91-4 
 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor 
expressed by T cells.  When bound to either of its ligands, PD-L1 or PD-L2, activated PD-1 
negatively regulates T-cell activation and effector function.  The pathway may be engaged by 
tumor cells to suppress immune control.  MK-3475 (pembrolizumab) blocks the negative 
immune regulatory signaling by binding to the PD-1 receptor, inhibiting the interaction between 
PD-1 and its ligands. 
 
Description: MK-3475 (pembrolizumab) is a humanized MAb of the IgG4/kappa isotype. 
 
How Supplied: MK-3475 (pembrolizumab) is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 100 mg vials containing a 
sterile, non-pyrogenic, clear to opalescent aqueous solution (25 mg/mL).  Proteinaceous particles 
may be present.  MK-3475 solution for infusion is formulated in 10mM histidine buffer, pH 5.2-
5.8, containing 7% sucrose and 0.02% polysorbate 80, supplied in Type I glass vials with a cap 
color of red, salmon, or blue. 
 
Preparation: MK-3475 (pembrolizumab) solution for infusion must be diluted prior to 
administration.  Do not shake the vials.  Do not use if opaque or extraneous particulate matter other 
than translucent to white proteinaceous particles is observed.  Do not use if discolored.  To prepare 
the infusion solution add the dose volume of MK-3475 (pembrolizumab) to an infusion bag 
containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.   
 
Gently invert the bag 10-15 times to mix the solution.  The final concentration must be between 
1 mg/mL to 10 mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, 
or PE lined polyolefin 
 

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Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from light by 
storing in the original box.   
 
If a storage temperature excursion is identified, promptly return MK-3475 (pembrolizumab) 
to between 2-8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going. 
 
Administer prepared solutions immediately after preparation.  If not administered immediately, 
prepared solutions may be stored refrigerated for up to 24 hours. MK-3475 (pembrolizumab) 
solutions may be stored at room temperature for a cumulative time of up to 6 hours.  This includes 
room temperature storage of liquid drug product solution in vials, room temperature storage of 
infusion solution in the IV bag, and the duration of infusion. 
 
Route of Administration: IV infusion only.  Do not administer as an IV push or bolus injection. 
 
Method of Administration: Infuse over approximately 30 minutes (range: 25 - 40 minutes) using an 
infusion set containing a low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone or 
polysulfone.  Infusion rate should not exceed 6.7 mL/min.  A central line is not required; however 
if a subject has a central venous catheter in place, it is recommended that it be used for the infusion.  
Do not co-administer other drugs through the same infusion line.  Following the infusion, flush the 
IV line with normal saline. 
 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-(2-
ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
 
Patient Care Implications: Refer to the protocol for information on evaluation and management 
of potential immune-related adverse events. 
 
Availability 
 
MK-3475 (pembrolizumab) is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
8.1.2 KW-0761 (NSC 791064) 
 
Other Names: Mogamulizumab, AMG 761, POTELIGEO® 
 
Classification: Anti-CC chemokine receptor 4 (CCR4) MAb 
 
Molecular Weight: ~149 kDa 
 
Mode of Action:  KW-0761 (mogamulizumab) selectively binds to and blocks the activity of CC 

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chemokine receptor 4 (CCR4), a G-coupled-protein receptor for C-C chemokines expressed on 
the surfaces of some types of T cells, endothelial cells, and neurons.  KW-0761 
(mogamulizumab) is a defucosylated, humanized, IgG1 MAb with lack of fucose resulting in 
enhanced antibody-dependent cellular cytotoxicity (ADCC) activity.  It may induce ADCC 
against CCR4-positive T cells and inhibit CCR4-mediated signal transduction pathways leading 
to chemokine-mediated cellular migration and proliferation of T cells, and chemokine-mediated 
angiogenesis. 
 
How Supplied: KW-0761 (mogamulizumab) is supplied by Kyowa Kirin Pharmaceutical 
Development, Inc. and distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI 
as single-use 20 mg vials containing a sterile, clear, colorless solution (4 mg/mL).  KW-
0761(mogamulizumab) solution for infusion is formulated in 2.1 mmol/L sodium citrate buffer, 
300 mmol/L glycine, and 0.2 mg/mL polysorbate 80 (Tween 80), pH 5.5, supplied in Type I 
glass vials. 
 
Preparation: KW-0761 (mogamulizumab) solution for infusion must be diluted prior to 
administration.  Do not shake the vials.  To prepare the infusion solution add the dose volume of 
KW-0761(mogamulizumab)  to an infusion bag containing 0.9% Sodium Chloride Injection, 
USP.  Non-PVC (polyolefin) IV bags must be used.  The final concentration of the infusion 
solution must be between 0.07 mg/mL to 1.44 mg/mL.   
 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze.  Protect from light by 
storing in the original box.   
 
If a storage temperature excursion is identified, promptly return KW-0761 
(mogamulizumab) to between 2-8°C and quarantine the supplies.  Provide a detailed report 
of the excursion (including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going.  KW-0761 (mogamulizumab) infusion 
solutions must be administered within 8 hours of preparation and stored at room temperature. 
 
Route of Administration: Intravenous (IV) infusion 
 
Method of Administration: Infuse over at least 1 hour using an infusion set containing a low-
protein binding 0.2 to 0.22 µm in-line filter.  Do not co-administer other drugs through the same 
infusion line.  Following the infusion, flush the IV line with normal saline. 
 
Patient Care Implications: Refer to the protocol for information on evaluation and management 
of infusion related reactions. 
 
Availability: KW-0761 (mogamulizumab) is an investigational agent supplied to investigators 
by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 

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8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application.  Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time.  Refer to the PMB’s 
website for specific policies and guidelines related to agent management.   
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.4 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB Coordinator 
via email. 
 
8.1.5 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 

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https://ctepcore.nci.nih.gov/OAOP/  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/index.jsp 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
 
 

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Biospecimen collections will be performed in accordance with the Schedule of Procedures detailed 
in the study calendar (Section 10). All specimens should be processed, packaged and shipped 
according to Section 10 and Appendix C.  Memorial Sloan Kettering (PI: Anas Younes, MD) will 
act as the receiving sites for biomarker specimens as outlined below.  
 
Archival and/or Fresh Tumor Tissue:  
Fresh pretreatment (screening) and/or archival tumor tissues with sufficient material (25 unstained 
slides or 2+ tissue blocks) are mandatory for disease confirmation, genomic sequencing, and IHC 
analysis. However, patients with insufficient biopsy material may still be considered for 
enrollment on a case by case basis following consultation with the PI. 
On-treatment biopsies are mandatory for all patients. 
Post-progression biopsies are optional but strongly encouraged for all patients. 
 
Archival tumor samples should be provided in the form of a formalin-fixed paraffin-embedded 
block. Alternatively, 25 unstained slides (5 micrometers in thickness, on charged, unbaked slides 
without coverslips) should be provided. Bone metastases, final needle aspirates, cytology 
specimens and alcohol-fixed specimens are not suitable. 
 
For fresh biopsies, a total of 4 cores should be obtained.  2 cores should be formalin-fixed and 
paraffin-embedded (FFPE).  2 cores should be snap-frozen in OCT media and shipped on ‘dry 
ice’.   
 
Peripheral blood mononuclear cells (PBMCs):  
Serial blood samples will be obtained as per section 10 and Appendix C. PBMCs will be isolated 
and viably cryopreserved at all time points. Samples are to be shipped on ‘dry ice’. 
 
Serum for cytokine analysis:  
Serum will be isolated from serial blood samples obtained as per section 10 and Appendix C. Sera 
will be frozen, shipped on ‘dry ice’ and stored at -80oC. 
 
9.1 
Integrated and Exploratory Correlative Studies 
 
9.1.1 Targeted genomic sequencing and fluorescence in-situ hybridization of formalin-
fixed, paraffin-embedded tumor samples  
 
9.1.1.1 
Collection of Specimen(s) 
Pre-treatment FFPE biopsy tissue will be obtained and shipped as described in section 
9.2 
 
9.1.1.2 
Site(s) Performing Correlative Study 
DNA extraction from FFPE tissue and next generation sequencing will be performed 
within MSKCC’s Center for Molecular Oncology (CMO).  MSK uses a custom, 
hybridization-based capture panel to detect single nucleotide variants, small indels, 

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copy number alterations, and structural variants from matched tumor-normal 
sequence data. Specimens are reviewed by a pathologist to ensure tumor cellularity of 
at least 10%. Tumors are sequenced to an average unique depth of coverage of 
approximately 750X. Reads are aligned using BWA, flagged for duplicate read pairs 
using GATK, and locally realigned using ABRA. Sequence mutations are called 
using MuTect and reported for >5% allele frequency (novel variants) or >2% allele 
frequency (recurrent hotspots). Copy number alterations are called using a custom 
pipeline and reported for fold-change >2. Structural rearrangements are called using 
Delly. All somatic mutations are reported without regard to biological function.  
 
9.1.2 Immunohistochemical analysis of the tumor and tumor microenvironment 
 
9.1.2.1 
Collection of Specimen(s) 
Pre-treatment and on-treatment FFPE biopsy tissue will be obtained and shipped as 
described in section 9.2 
 
9.1.2.2 
Site(s) Performing Correlative Study   
Immunostaining of FFPE sections from pre-treatment biopsies will be performed as 
previously described under supervision of the Hematopathology Service in the 
Department of Pathology.  All targets have been validated and successfully used in 
patients with lymphoma (Vardhana et al, Blood 2016).  Expression of MHC-I, MHC-
II, and CD58 will be scored in a binary fashion (positive vs. negative) while CD3, 
CD4, CD8, PD-L1, CCR4 and FoxP3 expression will be scored based on percent of 
total cells that are positive across 15 high-powered fields.  Results will be 
independently corroborated by 2 pathologists. 
 
9.1.3 Immunophenotyping and functional characterization of the circulating immune 
cells 
 
9.1.3.1 
Collection of Specimen(s) 
Peripheral blood will be collected, PBMCs will be isolated (as described in Appendix 
C) and shipped (as described in section 9.2) at the timepoints described in Section 10. 
 
9.1.3.2 
Site(s) Performing Correlative Study   
Flow cytometry will be performed within the Immune Monitoring Facility at 
MSKCC.  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, CCR4, CD45RA, CD45RO, LAG3, GARP, PD1, and 
CTLA4. Activation markers such as CD44 and CD69, will also be examined.  
 
 
 
 

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9.1.4 Evaluation of circulating serum cytokines at baseline and in response to therapy  
 
9.1.4.1 
Collection of Specimen(s) 
Peripheral blood will be collected, serum will be isolated and shipped as described in 
Appendix C and section 9.2 at the timepoints described in Section 10. 
 
9.1.4.2 
Site(s) Performing Correlative Study  
Cytokine measurements will be performed on serum by the Immune Monitoring 
Facility using a Human Th1/Th2/Th17 cytometric bead array (BD Biosciences).  
Cytokines measured will include IL-2, IL-4, IL-6, IL-10, TNF-a, IFN-g, and IL-17a. 
 
9.2 
Collection, Handling and Shipping of biomarker specimens to sites performing 
correlative studies  
 
Required Specimen 
Collection Time Point 
Ship To 
Pre-treatment and on-treatment 
biopsy specimens (B01) 
25 unstained slides or 2+ 
tissue blocks 
 
As per Section 10 
Pre-treatment biopsy is mandatory if 
adequate archival tissue is unavailable. 
However, patients with insufficient biopsy 
material may still be considered for 
enrollment on a case by case basis 
following consultation with the PI. 
 
Memorial Sloan Kettering Cancer 
Center 
ATTN: Santosha Vardhana 
430 E 67th Street, RRL-469  
New York, NY, 10021 
646-888-3285 
Archival tumor specimen 
(B02) 
As per section 10 
Not required if  B01is submitted 
Memorial Sloan Kettering Cancer 
Center 
ATTN: Santosha Vardhana 
430 E 67th Street, RRL-469  
New York, NY, 10021 
646-888-3285 
 
On-treatment biopsy 
specimens (B01) – 4 cores 
 
2 cores should be formalin-
fixed and paraffin-embedded 
(FFPE).   
2 cores should be snap-frozen 
in OCT media – send on ‘dry 
ice’ 
As per Section 10 
 
Memorial Sloan Kettering Cancer 
Center 
ATTN: Santosha Vardhana 
430 E 67th Street, RRL-469  
New York, NY, 10021 
646-888-3285 

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Peripheral blood 
mononuclear cells (PBMC-
01, PBMC-02…) 6 mL of 
blood per CPT tube x 2 tubes. 
Process prior to shipping as 
per Appendix C. Send on 
‘dry-ice’  
As per section 10. 
 
 
Memorial Sloan Kettering Cancer 
Center 
Hematologic Oncology Tissue Bank 
(HOTB)  
ATTN: Annie Slingerland 
408 E 69th Street, Z-2013  
New York, NY, 10021 
646-888-3227 
 
PI: James Young 
 
Peripheral blood serum (S-01, 
S-02…) 6 mL of blood per 
SST tube x 1 tubes. 
Process prior to shipping as 
per Appendix C. Send on ‘dry 
ice’ 
As per section 10. 
 
 
Memorial Sloan Kettering Cancer 
Center 
Hematologic Oncology Tissue Bank 
(HOTB)  
ATTN: Annie Slingerland 
408 E 69th Street, Z-2013  
New York, NY, 10021 
646-888-3227 
 
PI: James Young 
 
 
9.3 
Shipping 
 
All samples will be labeled with the following elements prior to shipping. FFPE samples should 
be sent in room temerature. All other samples should be shipped on dry ice. Prior to shipping 
samples, please email MSKCC HOTB (zzPDL_SKI_Hematology_HOTB_Lab@mskcc.org) and 
Dr. Vardhana (vardhans@mskcc.org) with sample manifest and shipment tracking number (if 
available). 
 
• 
NCI 10106 
• Study ID 
• Time point 
• Date collected 
• Sample type 
 

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10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy. Laboratory assessments on study 
should be completed +/- 2 days from treatment. In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy. 
 
 
Pre-Study 
C1 
D1 
C1 
D8 
C1 
D15 
C2  
D1 
C2  
D8 
C2  
D15 
C3  
D1 
C4-C34  
D1 
Off 
Treatmentj 
Windows 
 
 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
 
MK-3475 (Pemrolizumab) 
 
A 
 
 
A 
 
 
A 
A 
 
KW-0761 (Mogamulizumab) 
 
B 
B 
B 
B 
 
 
B 
B 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
 
 
X 
 
 
X 
X 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
X 
X 
Vital signs 
X 
X 
 
 
X 
 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
X 
X 
Performance status 
X 
X 
 
 
X 
 
 
X 
X 
X 
CBC w/differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TFTs (TSH, T3, FT4)b 
X 
X 
 
 
X 
 
 
 
X 
X 
EKGc 
X 
X 
X 
X 
X 
 
 
X 
X  
 
Pulmonary Function Testd 
X 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor assessments (CT CAP 
±PET and)e 
X 
 
 
 
 
 
 
X 
Xe 
 
B-HCGf 
X 
 
 
 
 
 
 
 
 
 
Fresh Pre-Treatment Biopsyg 
X 
 
 
 
 
 
 
 
 
 
On-Treatment Biopsyh 
 
 
 
X 
 
 
 
 
 
 
Immune cell phenotypingi 
 
X 
 
 
X 
 
 
 
X 
X 
Serum cytokine assessmenti 
 
X 
 
 
X 
 
 
 
X 
X 
A: MK-3475 (Pembrolizumab): 200mg IV on Day 1 of a 21-day cycle  
B: KW-0761 (Mogamulizumab): For all Phase 1 patients and Phase II Group 1 patients:  Dose as assigned; weekly for first 3 
weeks (C1D1, C1D8, C1D15) and then once every 3 weeks (C2D1, C3D1, etc.)  
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, 
uric acid. potassium, total protein, SGOT [AST], SGPT [ALT], sodium (to be completed +/- 2 days from treatment). 
b: Thyroid function tests. Patients receiving MK-3475 (Pembrolizumab) should be monitored for changes in thyroid function (at 
screening, periodically during treatment, post-treatment, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders. 
c:   Pre and post mogamulizumab infusion EKG will be performed every 3 cycles from C4 onward (C4, C7, C10, etc). 
d: If prior history of chemotherapy or radiation therapy induced pulmonary toxicity.  
e: Tumor measurements by CT CAP with contrast are initially performed after 2 cycles (6 weeks +/- 7 days) and after every 3rd 
cycles of treatment thereafter (i.e. every 9 weeks +/- 7 days from the end of C5). PET is required at baseline, after C2 and 
EOT. Documentation (radiologic) must be provided for patients removed from study for progressive disease.   
f: Serum pregnancy test (women of childbearing potential). 
g: Archived formalin fixed paraffin embedded (FFPE) tissue (25+ unstained slides or 2 tissue blocks) or Pre-Treatment biopsy 
specimen (4 cores, allocated as per section 9). For patients with insufficient archival material, a pre-treatment biopsy is 
requested, however, patients may still be considered for enrollment on a case by case basis following consultation with the 
PI. 
h: Mandatory on-treatment biopsy, Window:C1 D15-21 (4 cores, allocated as per section 9) 
i: Peripheral blood samples on C1D1, C2D1, C4D1, C6D1, and EOT: 3 tubes from which PBMCs and serum will be extracted 

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and stored. 
j. Off treatment visit will be done 4 weeks ± 3 days from the last treament. 
 
 
 

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11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of the phase I part of the study, patients with 
measurable disease will be assessed by standard criteria.  
 
All patients in the phase II portion of the study will be assessed by standard criteria.  
 
For the purposes of this study, patients should be re-evaluated initially after 2 cycles of treatment 
(after 6 weeks) and then after every 3 cycles of treatment (every 9 weeks).  
 
11.1 
Antitumor Effect – Solid Tumors 
 
The response criteria developed by “The Lugano Classification” for response assessment in 
lymphoma will be used to define complete response, partial response, and progression of disease 
in this study. (Cheson et al., 2014) Definitions are detailed in the table below.  
 

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A new response category called “indeterminate response” (IR) was developed based upon 
experience with checkpoint blockade therapy in which response assessment may be confounded 
by the delayed effect of these drugs, allowing for early tumor growth, or therapeutic immune 
activation that can manifest as growth of existing lesions or development of new lesions, 
resulting in delayed response or pseudo-progression.(Cheson et al. 2016)  
 
A subject will be considered to have IR in 1 or more of the 3 following circumstances:  
 
1. Increase in overall tumor burden (as assessed by sum of the product of the diameters [SPD]) of 
≥50% of up to 6 measurable lesions in the first 12 weeks of therapy. 
2. Appearance of new lesions or growth of one of more existing lesion(s) ≥50% at any time 
during treatment; occurring in the context of lack of overall progression (<50% increase) of 
overall tumor burden, as measured by SPD of up to 6 lesions at any time during the treatment.  
3. Increase in FDG uptake of 1 or more lesion(s) without a concomitant increase in lesion size or 
number.  
 
As detailed in section “treatment beyond progression,” if radiologic imaging shows IR, tumor 
assessment may be repeated by the site ≥4 weeks later with the option of continuing treatment 
while awaiting clarification of response. 
 
Progression free survival (PFS) will be calculated from the time of initiation of therapy.  
 
 
 

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12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
Enrollment to the Phase 2 portion of this trial will not begin until a protocol amendment has been 
submitted which summarizes the Phase 1 results, the recommended Phase 2 dose, and the 
rationale for selecting it.  The amendment must be reviewed and approved by CTEP before 
enrollment to the Phase 2 portion can begin. 
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave. Access to the trial 
in Rave is granted through the iMedidata application to all persons with the appropriate roles 
assigned in the Regulatory Support System (RSS). To access Rave via iMedidata, the site user 

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must have an active CTEP IAM account (check at https://ctepcore.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Rave Read-Only, Rave CRA (Lab Admin), Rave SLA or 
Rave Investigator) on either the LPO or participating organization roster at the enrolling site. To 
the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP 
registration type. To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.  
  
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
For studies assigned for CTMS Comprehensive Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted three times annually (one annual site visit and two data 
audits).  For CTMS monitored studies, after users have activated their accounts, please 
contact the Theradex Help Desk at (609) 799-7580 or by email at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 

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than once every 2 weeks. The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis. For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received. Queries will be issued by CTMS directly within Rave. The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve. Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP. Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D) and a description of any dose-limiting toxicities 
(DLTs). CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will 
be included when appropriate to meet unique study requirements. The PI is encouraged to 
review the eCRFs, working closely with CTMS to ensure prospectively that all required 
items are appropriately captured in the eCRFs prior to study activation. CTMS will 
prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex. CDUS submissions are performed by Theradex 
on a monthly basis. The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
12.3 
CTEP Multicenter Guidelines 
 
N/A  
 
 
 

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12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 

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Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5 
Genomic Data Sharing Plan 
 
N/A 
 
 
 

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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Primary Objectives 
 
13.1.1.1 
For phase I, to determine the MTD or RP2D of KW-0761 (mogamulizumab) when 
administered in combination with MK-3475 (pembrolizumab) in patients with 
relapsed, refractory lymphomas.  
13.1.1.2 
For phase I, to assess the safety and tolerability of KW-0761 (mogamulizumab) when 
administered in combination with MK-3475 (pembrolizumab) in patients with 
relapsed, refractory lymphomas. 
13.1.1.3 
For phase II, to assess the progression-free survival of KW-0761 (mogamulizumab) 
when administered in combination with MK-3475 (pembrolizumab) compared to 
MK-3475 (pembrolizumab) alone in patients with relapsed and refractory diffuse 
large B-cell lymphomas. 
 
13.1.2 Statistical Considerations for Primary Objectives  
 
The primary endpoint for the phase I portion is to determine the MTD or RP2D of KW-0761 
(mogamulizumab) in combination with MK-3475 (pembrolizumab). A standard 3+3 design will 
be used to find the MTD or RP2D for the combination of MK-3475 (pembrolizumab) and KW-
0761 (mogamulizumab). Three patients will be treated at dose level 1. If none or one of the 
initial 3 patients experience DLT by the end of cycle 1, 3 additional patients will be treated at the 
same dose level. If none or one of the 6 patients treated at dose level 1 experience DLT, it will be 
declared as the MTD. If more than one of the initial 3 or the 6 patients treated at dose level 1 
experience DLT, dose level will be de-escalated to -1. The same procedure will be carried out at 
dose level -1. If none or one of the 6 patients treated at dose level -1 experience DLT, it will be 
declared as the MTD. If more than one of the first 3 or the 6 patients treated at dose level -1 
experience DLT, the study will stop and other potential dose levels will be considered.  
 
Escalation will continue only if there is no additional DLT observed. If 2 or more patients 
experience DLT at any dose level, the previous dose will be declared the MTD. Should 2 or 
more patients experience DLT at dose level 1, the study will stop and the treatment regime will 
be re-evaluated. If only 3 patients are treated at a dose declared to be the MTD, 3 additional 
patients will be enrolled and treated at that dose to confirm the MTD. Therefore, at the 
completion of the phase I portion, 6 patients will have been treated at the MTD. The target 
probability of DLT for this regimen is 15%. Patients who withdraw before completing the 4 
weekly treatments of KW-0761 (mogamulizumab) for reasons other than development of a DLT 
will be replaced.  
 
The primary endpoint for the phase II portion is progression-free survival. Patients will be 
randomized to either MK-3475 (pembrolizumab) plus KW-0761 (mogamulizumab) group or 
MK-3475 (pembrolizumab) alone group at 1:1 ratio. We assume the 12-month PFS rate is 30% 
and 10% for the combination and MK-3475 (pembrolizumab)-alone group, respectively. With a 

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one-sided log-rank test assuming proportional hazards and administrative censoring only, a total 
of 58 patients (29 per group) will be need to provide 80% power and 0.1 type-I error rate. The 
expected total number of progression or death events is 45. 
 
To protect patients from exposing patients to unacceptable rate of toxicity, a toxicity-based 
stopping rule will be applied.  
 
For 30% unacceptable toxicity rate, stop recruitment if ≥5 toxicity events (grade 4 or higher 
serious adverse events) in the first 15 patients or ≥7 toxicity events (grade 4 or higher serious 
adverse events) in the 29 patients in each arm.This stopping rule has the following operating 
characteristics: 
 
True toxicity rate: 0.1, 0.14, 0.18, 0.22, 0.26, 0.30 
 
Probability of stopping recruiting: 0.091, 0.256, 0.472. 0.675, 0.826, 0.919 
 
To protect patients from exposing to potentially non-efficacious treatment, an interim futility as 
well as efficacy analysis will be performed when half of the expected number of events has 
occurred. We will consider stopping the trial for futility if the hazard of progression/death 
(estimated by Kaplan-Meier method) is lower in the MK-3475 (pembrolizumab)-alone group 
than in the combination group. This futility rule gives 50% chance of stopping the trial early 
when the combination treatment is no better than MK-3475 (pembrolizumab) alone. (Wieand et 
al. 1994) We will also stop the trial for efficacy if the one-sided logrank test comparing the two 
groups using the first half of the sample size gives a p value <=0.0025, which provides strong 
evidence for the superiority of the combo treatment. 
 
The patients with relapsed, refractory diffuse large B-cell lymphoma treated at MTD in the phase 
I will be included in the combination group of the phase II portion. Patients withdrawn from the 
study or lost to follow-up before 12 months will be counted as events. Patients randomized to the 
MK-3475 (pembrolizumab)-alone group will be allowed to cross-over to the combo group after 
they progress on the treatment. 
 
Of note, for patients who progress on MK-3475 (pembrolizumab)-alone arm, cross-over to the 
combination will be allowed.  
 
Progression-free survival (PFS) is defined as the time from C1D1 to the first date of recurrence, 
progression, or death due to any cause, whichever comes first. Patients who are alive, without 
evidence of disease will be censored at the date of last follow-up. The Kaplan Meier method will 
be used to estimate the median PFS. 
 
13.2 
Sample Size/Accrual Rate 
 
Proposed Sample Size Minimum: 70 Maximum: 76 
 
Projected accrual rate is 2 patients per month. Thus total accrual will occur over approximately 3 

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85 
years.  
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
2 
2 
2 
8 
Native Hawaiian or 
Other Pacific Islander 
1 
1 
1 
1 
4 
Black or African 
American 
6 
6 
2 
2 
16 
White 
15 
15 
4 
4 
38 
More Than One Race 
3 
3 
2 
2 
10 
Total 
27 
27 
11 
11 
76 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.3 
Stratification Factors 
 
N/A 
 
13.4 
Analysis of Secondary Endpoints 
 
13.4.1 Secondary Objectives 
 
13.4.1.1 
To assess the overall response rate (ORR), complete response rate, partial response 
rate, and duration of response of KW-0761 (mogamulizumab) and MK-3475 
(pembrolizumab) compared to MK-3475 (pembrolizumab) alone in patients with 
relapsed and refractory diffuse large B-cell lymphomas. 
 
The ORR, CR, and PR rates will be calculated along with exact 95% confidence intervals. The 
duration of response will be summarized by Kaplan-Meier method in patients who achieve CR or 
PR.  
 

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Exploratory Correlative Analysis  
 
Correlative studies will be performed and summarized using descriptive statistics and graphical 
displays at pre and post treatment time points.  
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with KW-
0761 (Mogamulizumab) and MK-3475 (Pembrolizumab).  
 
13.5.2 Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).   
 
However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis 
should be clearly reported.  The 95% confidence intervals should also be provided.  
 
 
 

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Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol.   
34: 2698-2704. 
 
Li X, Kostareli E, Suffner J, et al. (2010) Efficient Treg depletion induces T-cell infiltration and 
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Ni X, Jorgensen JL, Goswami M, et al. (2015). Reduction of regulatory T cells by 
Mogamulizumab, a defucosylated anti-CC chemokine receptor 4 antibody, in patients with 
aggressive/refractory mycosis fungoides and Sezary syndrome. Clin Cancer Res. 21:274-85.  
 
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patients: highly increased levels of CCL17 and CCL22. Br J Haematol. 140:527-36. 
 
Ogura M, Ishida T, Hatake K, et al. (2014) Multicenter phase II study of mogamulizumab (KW-
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peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 32:1157-63. 
 
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Riley, J.L.  (2009).  PD-1 signaling in primary T-cells.  Immunol Rev.  229:114-125. 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 

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APPENDIX B       PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drugs, KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab).  This 
clinical trial is sponsored by the National Cancer Institute.  This form is addressed to the patient, 
but includes important information for others who care for this patient.  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab) may interact with other drugs 
which can cause side effects. For this reason, it is very important to tell your study doctors of any 
medicines you are taking before you enroll onto this clinical trial.  It is also very important to tell 
your doctors if you stop taking any regular medicines, or if you start taking a new medicine 
while you take part in this study.  When you talk about your current medications with your 
doctors, include medicine you buy without a prescription (over-the-counter remedy), or any 
herbal supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an 
updated medication list with you. 
 
Many health care providers can write prescriptions. You must tell all your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical 
trial.  
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine. Your study doctor’s name is ______________________ and he or she can be 
contacted at ______________________. 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drug KW-0761 (Mogamulizumab) and MK-3475 (Pembrolizumab). 
This clinical trial is sponsored by the NCI.  KW-0761 
(Mogamulizumab) and MK-3475 (Pembrolizumab) may interact with 
drugs that are [processed by your liver, or use certain transport 
proteins in your body or affects the electrical activity of your heart].  
Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
➢ Tell all your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is ____________________________ 
and can be contacted at _______________________________. 

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APPENDIX C       PBMC ISOLATION PROCEDURE 
 
Objective and Scope:   
 
This procedure describes viable freezing and thawing procedure for blood and marrow 
mononuclear cells (MNCs), snap freezing (nonviable) and thawing of granulocytes, and 
freezing/thawing of plasma and serum. All activities will be performed at the site of collection 
under clean and sterile conditions as indicated, and sent to the Hematologic Oncology Tissue 
Bank on ‘dry ice’ for short-term storage prior to correlative studies.   
 
Materials and Reagents:   
 
1. RPMI 1640, Media Lab SKI 
2. 25% Human Serum Albumin, Alpine Biologics, NDC 63546-251-05, pharmaceutical 
grade  
3. Dimethyl sulfoxide (DMSO), cell-culture grade (Fisher EC 200-664-3 or similar).  Store 
at room temperature.  DMSO must be fresh and sterility maintained.  Reagent may be 
aliquoted in small amounts to help preserve sterility.  Certificate of Analysis is provided 
with each lot and maintained on file. 
4. HyClone Trypan Blue Solution, 0.2µm filtered (ThermoScientific SV30084.01); or 0.4% 
Trypan Blue Solution (Sigma).  Store at room temperature.  Observe manufacturer’s 
expiration date. 
5. Hemacytometer and cover slip 
6. Sterile 50ml polypropylene tubes 
7. Sterile freezing vials, 1-2ml capacity (e.g., Sarstedt, Nalgene, Nunc) all graded for liquid 
N2 storage.   
8. Alcohol 70% and/or 70% alcohol prep pads 
9. Sterile serological pipets 
10. Freezer box suitable for –80oC and/or liquid N2 
11. Water Bath 
12. Refrigerated and room temperature preparatory centrifuges 
13. Controlled rate freezer for subsequent liquid N2 storage 
14. Alcohol- and freeze-resistant marking pen 
15. Normal pooled or autologous human serum and/or plasma, or fetal calf serum (FCS), 
depending on the particular needs/uses of a given investigator for the thawed cells.   
 
Procedures:   
 
Freezing Procedure for VIABLE cryopreservation (applies only to marrow and blood 
MNCs and their subsets. 
1. Prepare “Freezing Medium A” for initial resuspension of cells by diluting 100mL of 25% 
HSA in 100mL RPMI for final 12.5% HSA. NOTE that Freezing Medium A does NOT 
contain any DMSO.  You may scale up or down for different total final volumes.   
2. Prepare “Freezing Medium B” by diluting 40mL DMSO, 100mL of 25% HSA stock, and 
60mL RPMI.  This gives a final volume of 200mL and final concentration of 20% DMSO 

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and 12.5% HSA.  Again, you may scale up or down for different total final volumes. 
3. Count viable cells to be frozen using trypan blue exclusion.   
4. Final cell concentrations for freezing are as follows, but initial suspensions will be 2x (in 
Freezing Medium A – see below table), to which an equal volume of Freezing Medium B 
will be added, after which the final correct concentration is achieved.   
 
 
 
5. Determine the number of vials needed and label freezing vials with  the following 
elements as per section 9.2:  
a. NCI 10106 
b. Study ID 
c. Time point 
d. Date collected 
e. Sample type 
Sample Type 
Treatment 
Total Viable Cell 
Number  
Number of Vials 
Mononuclear cells 
from the Ficoll 
interface (blood 
OR marrow) 
Isolated by density gradient 
centrifugation & viably 
cryopreserved in 10% DMSO (final). 
≥5x106 cells 
1-10 vials:  Maximum of 10 
vials at 5-30 (preferred; max 
50) x106 final per mL per vial 
<5x106 cells 
1 vial at 2.5-5 x106 final per 
mL per vial; anything <2.5 x 
106, min final volume should 
be 500uL 
Blastic acute 
leukemia, newly 
diagnosed or 
relapsed 
(consider 
predominantly 
CD34+ based on 
%blasts on 
differential) 
Isolated by density gradient 
centrifugation & viably 
cryopreserved in 10% DMSO (final). 
>1-10x106 blasts 
No maximum # vials, each 
vial at 1-10 x106 final per mL 
per vial;  
<1x106 blasts 
1 vial at 0.5-1 x106 final per 
mL per vial; anything <0.5 x 
106, min final volume should 
be 500uL 
Granulocytes 
(PMNs) 
Contained within RBC pellet after 
gradient centrifugation 
 
N/A because pellet 
will be snap frozen 
with or without 
RBC lysis for 
eventual recovery 
of DNA from this 
WBC source 
Eyeball pellet, resuspend in 
small volume, and divide 
among vials.  No cell count.  
Put immediately in -80 freezer 
(no controlled rate, no liquid 
N2 storage). 
Plasma 
Isolated from above the MNC 
interface after density gradient 
centrifugation of anticoagulated 
whole blood 
N/A 
No less than (2) 1 mL 
aliquots; Maximum (4) 1 mL 
aliquots 
Sera 
Isolated by direct centrifugation of 
clotted whole blood.  density 
gradient separation 
N/A 
No less than (2) 1 mL 
aliquots; Maximum (4) 1 mL 
aliquots 

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6. Place vials to be frozen in -80oC REVCO for 20-30 mins.   
7. Also place DMSO-containing freezing medium as well as the medium for resuspending 
the cells on ice for a minimum of 10 minutes.   
8. Remove freezing vials from the –80oC freezer, but keep vials cold. 
9. Resuspend viable cells in the “Freezing Media A” (12.5% HSA/RPMI solution, NO 
DMSO) at HALF the final volume determined by cell concentration, which would be 
TWICE the desired final cell concentration per mL . 
10. To this 2x cell suspension, add an equal volume of the DMSO containing freezing 
medium (Freezing Medium B), dropwise, while swirling the tube of cells continuously.  
This gives a 1:1 ratio of Freezing Media A and B.  The final concentration is 10% DMSO 
and 12.5% HSA.  The reaction is exothermic, so it is imperative to keep all vials and 
materials cold.   
11. Aliquot this cell suspension in vials.   
12. Work quickly to avoid prolonged exposure of cells to DMSO before freezing. 
Place labeled vials in controlled rate freezer.  Proceed with controlled rate freezing and transfer 
to vapor phase liquid N2 for storage. 
Thawing Procedure for VIABLE recovery (applies only to marrow and blood MNCs and 
their subsets.   
1. Prepare 5-10% normal human plasma or serum/RPMI.  Individual investigators may 
alternatively elect to use FCS instead, depending on their subsequent uses and needs for 
these cells.  For any clinical use of these cells or their progeny, you should use 
AUTOLOGOUS plasma or serum. 
2. Place 10ml of 5-10% plasma/serum RPMI into a 15 mL  polypropylene tube and place in 
waterbath at 37oC for about 30 minutes.  
3. Remove vial(s) to be thawed and place directly on dry ice.   
4. As it is imperative to thaw rapidly to avoid development of intracellular ice crystals, 
which will rupture and lyse the cells, and to work quickly so as not expose thawed cells 
too long to DMSO, it is best to thaw no more than 2 cryovials at a time.   
5. Place cryovials into waterbath, shaking continuously and ensuring the lid is not 
submerged. Thaw until approximately half of the medium in the vial is liquid. 
6. Dry off outside and open vial under hood using alcohol wipe at same time 
7. Place thawing contents of 1 mL vial into 15ml polypropylene tube with 10ml warm 
RPMI.  Optional rinse of the cryovial and transfer of additional contents to the same 
polyproylene tube.   
8. Spin for 10 minutes at 330 x g in the room temperature centrifuge.  Optional additional 
wash(es) x 1-2 are recommended if nonspecific cell loss will not compromise cell yield 
needed.   
9. After centrifugation and optional wash(es) remove supernatant.   
10. Resuspend.   
 
Snap Freezing PMNs/granulocytes (NOT viably cryopreserved):   
PMNs/granulocytes sediment with the RBCs in a pellet below Ficoll after density centrifugation.  
Aspirate off Ficoll.  Pellet will be snap frozen with or without RBC lysis for eventual recovery of 
DNA from this WBC source.  Eyeball pellet, resuspend in small volume of RPMI or comparable 
medium, and divide among vials.  No cell count.  Put immediately in -80 freezer (no controlled 

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rate, no liquid N2 storage) 
 
 
 
Thawing frozen PMNs/granulocytes:  
No special instructions.  Thaw at RT or in water bath.  Normally used as a source of DNA from 
WBCs.   
 
 
Freezing Plasma or Serum:   
Aliquot 1mL/vial, no less than 2 vials, max 4 vials.   
 
Thawing Plasma or Serum:   
No special instructions.  Thaw at RT or in water bath.