Conditions: Acute Myeloid Leukemia
Keywords: AML
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
AML is the most common acute leukemia in adults. Most patients can undergo allogeneic stem cell transplantation as a possible cure; however, many patients are not candidates for allogeneic transplant due to age, overall health, psychosocial factors, and/or lack of available donors. Therefore, these patients are unable to receive the therapeutic benefits of the "graft-versus-leukemia" effect of donor immune cells. The aim of this study is to hopefully break immune tolerance to AML cells to provide better outcomes in patients with non-favorable risk AML.

Detailed description:
Non-favorable risk AML patients will undergo a preparative regimen of lymphodepletion of Flu/Mel followed by autologous transplantation. Anti-PD-1 therapy of pembrolizumab will begin on Day +1 following stem cell transplantation and will be administered every 3 weeks for a total of 8 doses. According to the literature, the risk of 2-year relapse is estimated to be 60-80% in patients with non-favorable risk AML in CR-1. With this protocol, investigators hypothesize that following lymphodepleting chemotherapy and pembrolizumab, the 2-year relapse risk will decrease to less than or equal to 35%. The one-sided Wald test at 5% significance level will be used to test the hypothesis. The size of 20 patients yields the power of 90.5% assuming that the actual 2-year leukemia-free survival is 60%.

Arms:
arm 1: Fludarabine \& Melphalan followed by autologous stem cell transplantation. Pembrolizumab will begin on Day +1.

Interventions: intervention 1: Fludarabine intervention 2: Melphalan intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
 
12/12/17 
 
 
 
 
SPONSOR:    
 
Merck 
 
TITLE:  
Phase II trial of Lymphodepletion and Anti-PD-1 blockade to 
reduce relapse in high risk AML patients who are not eligible 
for allogeneic stem cell transplantation 
 
IND NUMBER:  
 
129899 
 
 
 
 
Merck IND 118604 
 
Protocol History 
Original 
 
 
May 4, 2015 
Revisions 
 
 
October 20, 2015 
 
 
 
 
December 29, 2015 
 
 
 
 
March 22, 2016 
 
 
 
 
March 25, 2016 
 
 
 
 
March 29, 2016 
 
 
 
 
September 9, 2016 
 
 
 
 
November 11, 2016 
 
 
 
 
January 16, 2017 
 
 
 
 
December 12, 2017 
 
 
 
 
July 6, 2021 
 
Principal Investigator  
Scott R. Solomon, MD 
Co-Investigators 
 
H. Kent Holland, MD 
 
 
 
 
Lawrence E. Morris, Jr, MD 
 
 
 
 
Asad Bashey, MD, PhD 
 
 
 
 
Melhem Solh, MD 
Investigative Site 
 
Blood and Marrow Transplant Program at Northside Hospital 
5670 Peachtree Dunwoody Rd. NE Suite 1000 
Atlanta, GA  30342 
404-255-1930 


 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Lymphodepletion and Anti-PD-1 blockade in AML 
Trial Phase 
Phase II 
Clinical Indication 
high risk AML patients not eligible for allogeneic stem cell transplantation 
Trial Type 
Single arm 
Type of control 
Historical 
Route of administration 
intravenous 
Trial Blinding 
none 
Treatment Groups  
Single arm 
Number of trial subjects 
20 
Estimated enrollment period 
20 months 
Estimated duration of trial 
48 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design:  
Eligible patients: 
1) Diagnosis of non-M3 AML 
2) In CR1 with non-favorable risk disease (appendix 1) or subsequent CR defined as 
no evidence of residual leukemia by morphology, flow cytometry, cytogenetics, or 
FISH studies. 
3) Completed at least one cycle of consolidation chemotherapy 
4) Collection of at least 2x10e6/kg CD34+ cells, with negative immunophenotypic 
studies (no evidence of leukemia contamination by flow cytometric analysis) of the 
product  
5) 18 - 78 years of age,  
Preparative regimen / lymphodepletion: 
Fludarabine 30mg/m2/d x 3 days, days -4 to -2, and  
Melphalan 180mg/m2 (age 18-60 years) or 140mg/m2 (age 61-75 years), day -1  
PBSC infusion Day 0 
Anti-PD1 therapy: 


 
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Beginning day +1, pembrolizumab 200mg/dose will be administered q3weeks x 8 
doses. 
 
2.2 
Trial Diagram 
 
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
(1) Objective: To estimate the 2-yr relapse risk 
Hypothesis:  In patients with non-favorable risk AML in CR1 who are not candidates for 
allogeneic transplant, the risk of 2-yr relapse is estimated to be 60-80%.  We hypothesize 
that following lymphodepleting chemotherapy and pembrolizumab, the 2-yr relapse risk 
will decrease to ≤35%. 
3.2 
Secondary Objective & Hypothesis 
(1) Objective:  To assess the safety of pembrolizumab in patients with AML following 
lymphodepleting chemotherapy 
 
3.3 
Exploratory Objective 
(1) Objective: To assess the generation of anti-leukemic T cell responses in AML patients 
receiving pembrolizumab.  Research blood samples will be drawn prior to lymphodepleting 
chemotherapy, prior to pembrolizumab dosing on each antibody dosing day, at 12 month, 
18 month and 24 months following autologous transplantation (12 total samples). 


 
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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Acute myeloid leukemia (AML) is the most common acute leukemia in adults.  Treatment 
with modern chemotherapy regimens often induces complete remission, but a majority of 
patients will ultimately relapse and die of their disease.  Results with conventional cytarabine-
based post-remission therapy are unsatisfactory for the three-quarters of AML patients that do not fall 
in the favorable cytogenetic/molecular risk category.  Five-year cumulative incidence of relapse 
following high-dose cytarabine is over 60% in intermediate risk AML and 90% in poor risk AML3.   
For many years, it has been recognized that allogeneic stem cell transplantation can be 
curative for some patients with AML1,2, and as a result it remains the recommended 
consolidation approach for non-favorable risk AML patients in CR1 who are young, healthy and have 
suitable donors.  The major therapeutic effect of allogeneic transplant is derived from the 
“graft-versus-leukemia” effect of allogeneic immune cells from the donor.  Unfortunately, 
many patients with AML are not candidates for this procedure due to factors such as age, 
overall health, psychosocial limitations, or lack of an available donor.  Therefore, cancer 
immunologists have sought approaches to stimulate anti-leukemic immunity within the host 
to promote immune-mediated elimination of AML. 
 
In patients without an available donor, post-remission therapy with high-dose chemotherapy 
and autologous transplant has been utilized in an attempt to improve outcomes.  Autologous 
transplant has consistently resulted in a significant reduction in relapse risk when compared 
with conventional chemotherapy, leading to improved event-free survival in a large number of 
clinical studies4-9.  This has unfortunately not translated into improved overall survival in these 
patients, likely due to the ability to salvage relapse with allogeneic transplant in a subset of 
patients. 
Cancer cells can express tumor antigens, rendering them susceptible to recognition and 
killing by cytotoxic T cells.  However, spontaneous rejection of established cancers is a rare 
occurrence, in part due to negative regulatory mechanisms used by the tumor and its 
microenvironment.  One such inhibitory mechanism is up-regulation of programmed death-
ligand 1 (PD-L1) expressed on tumor cells which binds to programmed death-1 (PD-1) on 
activated T cells10.  A wide variety of tumor cells express PD-L1, including AML cells11.  
PD-1/PD-L1 engagement results in diminished antitumor T cell responses and correlates with 
poor outcome in murine and human solid cancers12-18.  The PD-1 molecule has been 
recognized as a hallmark for cell exhaustion, and PD-1 expressing antigen-specific T cells 
are dysfunctional in cytokine production and proliferation upon antigen restimulation19.   
 
Regulatory T cells (Tregs) are naturally occurring immunosuppressive T cell populations 
which are increased in frequency in cancer patients and have been correlated with cancer 
outcomes in some studies17, 20-22.  Furthermore, depletion of Tregs in a number of 
transplantable cancer models results in significantly enhanced anti-tumor immune responses 
and control of tumor progression.  In AML, several groups have observed elevated Treg 
frequencies in the blood and marrow of AML patients, and this appears to correlate 
negatively with chemotherapy response and survival20-21.  In murine AML models, depletion 


 
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of Tregs alone or in combination with PD-L1 blockade resulted in enhanced anti-leukemic T 
cell responses23-24. 
 
Therefore, the obstacles of successful anti-leukemia immune responses in the clinical setting 
may include both suppressive factors in tumor environment that inhibit the function of a 
sufficient immune response (i.e. Tregs), as well as defeated immune effector components that 
are unable to control tumor growth (i.e. PD-1 expressing T cells).  We propose to overcome 
these obstacles through a combination of lymphodepletion (high-dose chemotherapy and 
autologous transplantation) and anti-PD1 blockade.  Chemotherapy-induced lymphodepletion 
may enhance the effectiveness of immunotherapy though several different mechanisms 
including increased availability of immune stimulatory cytokines and the creation of an 
environment conducive to disruption of T cell tolerance.25  Adoptive cellular therapy after 
lymphodepleting chemotherapy is known to cause regression of established tumors in murine 
models.26-28 More recently adoptive cellular therapy following nonmyeloablative 
conditioning has been shown to produce significant responses in patients with metastatic 
melanoma and have demonstrated the importance of modulating the host environment 
through lymphodepletion.29-30   
 
In this study, we will be utilizing a high-dose chemotherapy approach rather than traditional 
consolidative therapy in order to achieve both maximal myeloablation and lymphodepletion.  
We believe appropriate myeloablation is important for optimally reducing the leukemic 
burden, which may be critical given the slower kinetics of response to immune checkpoint 
inhibitors31-34.  Furthermore, high-dose chemotherapy is predicted to provide optimal 
lymphodepletion.  A lymphopenic environment can be caused by irradiation or chemotherapy 
drugs including cyclophosphamide, fludarabine, and melphalan35-37. After lymphodepletion, 
lymphocytes undergo spontaneous, antigen-independent expansion called homeostatic 
proliferation that restores the pre-lymphodepletion lymphocyte compartment. In addition to 
endogenous lymphocytes, adoptively transferred T cells undergo homeostatic proliferation 
when placed in a lymphopenic environment38.  Lymphodepletion also disrupts immunologic 
tolerance mechanisms, thus favoring the induction of anti-tumor immune responses39-41. 
In non-favorable risk AML patients that don’t receive allogeneic transplant, the vast majority 
of patients will relapse and die of their disease.  In such a context, exploration of effective 
adjuvant therapies that may reduce this high relapse risk is appropriate.  We hypothesize that 
immune checkpoint blockade with the PD-1 inhibitor, pembrolizumab, will decrease the risk 
of relapse in high risk AML patients.  In an analogous approach, the FDA recently expanded 
the approval of ipilimumab (Yervoy), another immune checkpoint inhibitor, in melanoma to 
include adjuvant treatment of patients with stage III melanoma with pathologic involvement 
of regional lymph nodes >1 mm who have undergone complete resection including total 
lymphadenectomy.    
 


 
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4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) 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+ Tregs seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, Tregs and natural killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL).  
This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 


 
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PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Clinical Trial Data 
In a prospective phase I study, 411 patients with advanced melanoma were treated with 
pembrolizumab on one of three dose schedules (10 mg/kg every two weeks, 10 mg/kg every 
three weeks, or 2 mg/kg every three weeks)42. Seventy-seven percent of patients had received 
prior systemic therapies for metastatic disease. The study included 190 patients who were 
ipilimumab naïve (46 percent) and 221 who had been previously treated with ipilimumab (54 
percent). Included in the study was a cohort of 276 patients who were randomly assigned to 
either 2 or 10 mg/kg given every two weeks43. Results from this study were updated at the 
2014 ASCO meeting.  The overall response rate using RECIST criteria and central review was 
34 percent, including 40 percent in those who were ipilimumab naïve and 28 percent in those 
who had been treated with ipilimumab. Similar response rates were seen using immune-related 
response criteria.  On multivariate analysis of the entire study population, there were no 
significant differences in outcomes between the three dose schedules; however there was a 
trend to better responses in the q2week arm: 
IPI-N 
IPI-T 
2 Q3W 
n = 73 
10 Q3W 
n = 76 
10 Q2W 
n = 41 
Total 
n = 190 
2 Q3W 
n = 89 
10 Q3W 
n = 116 
10 Q2W 
n = 16 
Total 
n = 221 
RECIST 
ORR in pts with 
measurable 
disease, % 
37 
39 
46 
40 
26 
26 
57 
28 
Median PFS, wk 
(95% CI) 
36 
(12-NR) 
23 
(12-36) 
50 
(14-NR) 
24 
(16-48) 
22 
(12-36) 
17 
(12-24) 
NR 
(12-NR) 
23 
(14-24) 
24-wk PFS, % 
52 
46 
57 
51 
45 
40 
67 
44 
irRC 
ORR, % 
37 
41 
59 
43 
27 
30 
56 
31 
Median PFS, wk 
(95% CI) 
36 
(15-NR) 
28 
(13-NR) 
84 
(24-NR) 
37 
(24-84) 
31 
(22-48) 
30 
(24-NR) 
NR 
(12-NR) 
36 
(24-54) 
24-wk PFS, % 
57 
52 
61 
56 
57 
56 
73 
58 
 
Overall survival at 12 months was 69 percent and 62 percent at 18 months. The median 
progression-free survival was 5.5 months, and 45 percent of patients remained progression free 
at six months.  Treatment toxicity was manageable. The most common toxicities were fatigue, 
pruritus, rash, diarrhea, and arthralgia (36, 24, 20, 16, and 16 percent, respectively). Overall 


 
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12 percent of patients experienced grade 3 or 4 toxicity, the most common being fatigue (2 
percent), and there were no treatment-related deaths. There were similar safety profiles in those 
previously treated with ipilimumab and in those who were ipilimumab naïve.  
The phase II KEYNOTE-002 trial randomized 540 patients with ipilimumab-refractory 
advanced melanoma to pembrolizumab (2 mg/kg every three weeks), pembrolizumab (10 
mg/kg every three weeks) or chemotherapy (carboplatin plus paclitaxel, paclitaxel alone, 
dacarbazine, or temozolomide per institutional standard)44. Treatment continued on this 
schedule until progressive disease.  Progression-free survival assessed by central review, the 
primary endpoint of the trial, was significantly improved with both pembrolizumab treatment 
regimens compared with chemotherapy. The six-month progression-free rates were 34, 38, and 
16 percent for pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, and chemotherapy, 
respectively (pembrolizumab 2 mg/kg versus chemotherapy hazard ratio 0.57, 95% CI 0.45-
0.73, and pembrolizumab 10 mg/kg versus chemotherapy hazard ratio 0.50, 95% CI 0.39-0.64).   
The objective response rates (complete plus partial) were 21, 26, and 4 percent, respectively, 
for pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, and chemotherapy, respectively.  
Treatment was relatively well tolerated, with grade 3-5 adverse events reported in 11 and 14 
percent of the pembrolizumab treatment arms, and 26 percent of those managed with 
chemotherapy. The most common pembrolizumab-related adverse events were fatigue, 
pruritus, and rash. Grade 3 immune related toxicity was reported in two patients treated with 
pembrolizumab 2 mg/kg (hepatitis, hypophysitis), and in eight patients given pembrolizumab 
10 mg/kg (hepatitis, colitis, pneumonitis, and iritis or uveitis. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
We hypothesize that the use of high-dose chemotherapy to induce lymphodepletion followed 
by anti-PD-1 antibody therapy to further break immune tolerance to AML cells will improve 
outcomes in patients with non-favorable risk AML.  Historically, the vast majority of patients 
with non-favorable risk AML, who are not candidates for allogeneic transplant, relapse and die 
of their disease.  It is currently estimated that 60-80% of patients with non-favorable risk AML 
will have disease recurrence.  In this study, we hope to decrease the recurrence rate to 35% or 
less.  There is now increasing in vitro and pre-clinical in vivo data supporting an important 
role for PD1-PDL1 interactions in AML (see Background, section 4.1).   Although anti-PD1 
therapy has not been formally tested in AML, it has been successfully used in other 
hematologic malignancies with 53-87% response rate (CR + PR) seen in Hodgkin lymphoma45-
46, 36% and 40% in diffuse large B cell and follicular lymphoma, respectively47. 
Eligible patients must be deemed medically fit to undergo Melphalan-based high-dose 
chemotherapy, and therefore must meet all inclusion/exclusion criteria as defined in the study 
protocol.  Eligible patients must also be deemed “not eligible” for allogeneic transplant.  
Patients may meet this criteria for multiple reasons, including 1) lack of suitable donor (HLA-
matched related, HLA-matched unrelated, haploidentical, or cord blood unit), 2) patient refusal 
of allogeneic transplant, 3) lack of appropriate psychosocial support, or 4) perceived high risk 


 
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of treatment-related mortality with allogeneic transplant due to patient comorbidities or other 
factors.  
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first in human study of MK-3475 showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 
mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.   
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 


 
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fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
 
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. 
 
 
  
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be 18 - 78 years of age on day of signing informed consent. 
3. Diagnosis of non-M3 AML 
4. In CR1 with non-favorable risk disease (appendix 1) or subsequent CR defined as with 
no evidence of residual leukemia by morphology, flow cytometry, cytogenetics, or 
FISH studies. 
5. Not eligible for allogeneic transplant for any reason, including  
a.  lack of suitable donor 
b.  patient refusal of allogeneic transplant,  
c. lack of appropriate psychosocial support,  
d. perceived high risk of treatment-related mortality with allogeneic transplant due 
to patient comorbidities or other factors. 
6. Completed at least one cycle of consolidation chemotherapy. 
7. Collection of at least 2x106/kg CD34+ cells, with negative immunophenotypic studies 
on product. 
8. Have a Karnofsky performance status of 70% or greater. 


 
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9. Demonstrate adequate organ function as defined in Table 1.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Renal 
 
Serum creatinine OR 
Measured or calculated 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤2mg/dl OR 
 
≥40 mL/min for subject with creatinine levels > 
2mg/dl 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) ≤ 3 X ULN  
 
10. Female subject of childbearing potential (all women with a uterus <50 and women >50 
but <1 year without a menstrual cycle) should have a negative urine or serum pregnancy 
within one week prior to receiving the first dose of study medication.  If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
11. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
12. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Hypersensitivity to pembrolizumab or any of its excipients. 
3. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 


 
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4. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
5. Has known active central nervous system (CNS) involvement.   
6. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
7. Has an uncontrolled infection.  
8. Has a known history of active TB (Bacillus Tuberculosis). 
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 subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
10. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
11. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
13. Has a history of Human Immunodeficiency Virus (HIV). 
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
is detected). 
15. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start 
of study therapy. Administration of killed vaccines is allowed.  
16. Ejection fraction less than 40% or NYHA class II symptoms or higher 
17. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/interstitial lung disease 
 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below: 


 
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Preparative regimen / lymphodepletion: 
Fludarabine 30mg/m2/d x 3 days, days -4 to -2, and  
Melphalan 180mg/m2 (age 18-60 years) or 140mg/m2 (age 61-75 years), day -1  
 PBSC Infusion Day 0  
Anti-PD1 therapy: 
Beginning day +1, pembrolizumab 200mg/dose will be administered q3weeks x 8 
doses. 
5.2.1 Chemotherapy Dosing:   
All chemotherapy should be dosed based on ideal body weight (IBW) for patients who weigh 
100-130% of their IBW.  For patients who weigh less than 100% of their IBW, dosing should 
be based on actual body weight (ABW).  For patients who weigh more than 130% of their 
IBW, dosing should be based on the adjusted ideal body weight (AIBW).   
1.  Ideal Body Weight (IBW) Formulas: 
 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
 
Females IBW = 45.5 + 2.3 kg/inch over 5 feet 
 
 
For patients less than 5 feet, subtract 2.3 kg/inch 
 
2.  Adjusted Ideal Body Weight (AIBW) Formula: 
 
 
AIBW = IBW + [(0.25) x (ABW – IBW)] 
 
Doses of Fludarabine will be adjusted as needed according to creatinine clearance: 


 
12/12/17 
 
 
 
Creatinine Clearance = (140-Age) x IBW ( x 0.85 for females) 
                                    72 x Serum Creatinine 
 
 
 
 
 
 
 
5.2.2 Stem Cell Collection 
Peripheral blood stem cells (PBSC) are to be collected within 30 days of study treatment 
initiation.  Peripheral blood stem cells will be collected by standard apheresis techniques 
following either chemotherapy-based or growth factor-based mobilization regimens per 
institutional standards.  An acceptable PBSC product will contain a minimum of 2 x 106 
CD34+ cells/kg body weight and have no evidence of leukemia contamination by flow 
cytometric analysis of the product. 
5.2.3 Pembrolizumab Dose Modifications 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 2 below. See Section 5.4.1 
for supportive care guidelines, including use of corticosteroids. 
 
CHEMOTHERAPEUTIC 
AGENT 
 
Calculated Creatinine 
Clearance (measured or 
calculated) 
30-60 
 
Fludarabine 
 
80% of total dose 


 
12/12/17 
 
 
 
Table 2 
Dose Modification Guidelines for Immune Related Adverse Events Associated with Pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor 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 
• 
 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 


 
12/12/17 
 
 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
• 
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 / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
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 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other 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 
discontinue1  
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 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 


 
12/12/17 
 
 
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 
Neurological 
Toxicities 
Grade 2 
Withold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grace 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   


 
12/12/17 
 
 
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). Subjects should 
be placed back on study therapy within 1 week of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record. 
5.2.4 Timing of Dose Administration 
Each dose of pembrolizumab should be administered after all procedures/assessments have 
been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Beginning day +1, pembrolizumab 200mg/dose will be administered q3weeks x 8 doses. 
5.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.   
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  


 
12/12/17 
 
 
• Systemic glucocorticoids for any purpose other than (1) as an antiemetic prior to 
chemotherapy or (2) to modulate symptoms from an event of clinical interest of 
suspected immunologic etiology.  The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 
Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or intravenous 
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 metastatic 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 pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the 
case of prolonged steroid administration. 


 
12/12/17 
 
 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience 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.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, felt related to study drug, that persists > 1 week, 
administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, felt related to study drug, that persists > 3 
days, treat with intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 


 
12/12/17 
 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, felt related to study drug, monitor liver function tests more 
frequently until returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, felt related to study drug, treat with intravenous 
corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Acute kidney injury: 
o For Grade 2 events, felt related to study drug, administer oral corticosteroids. 
o For Grade 3-4 events, felt related to study drug, treat with 
intravenous steroids followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 3 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
None 
Grade 2 
Stop Infusion and monitor 
symptoms. 
Subject may be 
premedicated 30 min (± 30 


 
12/12/17 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 
subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
minutes) prior to infusion of 
pembrolizumab (MK-3475) 
with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration. 
 
 


 
12/12/17 
 
 
5.5 
Other Considerations 
5.5.1 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥50 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor and to Merck.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
5.5.2 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 


 
12/12/17 
 
 
5.5.3 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.6 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed disease progression if clinically stable or clinically improved. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 


 
12/12/17 
 
 
5.7 
Subject Replacement Strategy 
If a subject is unable to complete at least 4 doses of pembrolizumab due to any reason (i.e. 
disease progression, toxicity, noncompliance, etc.), then accrual will be increased accordingly 
to replace these patients.  We will replace a maximum of 5 patients which is equal to 25% of 
the total study enrollment.  
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
Non-relapse mortality (NRM): 
The incidence of NRM following autologous transplantation for patients with AML is 
predicted to be 5% or less. Consequently, an incidence of NRM convincingly greater than 10% 
would raise concerns for excessive toxicity and would trigger early trial termination. This 
trigger would be met if NRM occurs in 2 of the first 5 patients, 3 of the first 10 patients, 4 of 
the first 15 patients, and 5 of the first 20 patients.  
Drug-related grade ≥3 adverse events (AEs): 
The incidence of drug-related grade ≥3 AEs following treatment with pembrolizumab is 
predicted to be 15% or less. Consequently, an incidence of drug-related grade ≥3 AEs 
convincingly greater than 20% would raise concerns for excessive toxicity. This trigger would 
be met if a grade ≥3 AE, deemed to be related to study drug, occurs in 3 out of the first 5 
patients, 5 of the first 10 patients, 6 of the first 15 patients, or 8 of the first 20 patients. If this 
stopping criterion is met, accrual to the trial will be temporarily halted, until a decision 
regarding either modification or termination of the trial could be made.


 
12/12/17 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
 
Treatment weeks 
End of 
Treatment 
Post-Treatment 
 
Screening 
Visit 
Within 24 
hours of 
high-dose 
chemo 
0 
 
 
 
1 
 
 
 
2 
3 
6 
9 
12 
15 
 
18 
 
21 
 
24 
 
 
 
Scheduling Window (Days): 
-28 to -5 
 
Day 
+1 
 
 
Days 
2-7 
 
 
Days 
8-14 
Days 
15-21 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
At time of 
Discontinu
ation 
30 days 
post 
discontinu
ation 
Post-BMT 
month 12, 
18, and 24  
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
 
 
x 
 
 
x6 
x 
x 
x 
x 
x 
x 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
X 
Review Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Full Physical Examination 
x 
 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
 
 
 
 
Directed Physical Examination 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
x 
 
X 
Vital Signs and Weight 
x 
 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Karnofsky Performance Status 
x 
 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
 
 
 
X 
Pregnancy Test – Serum β-HCG 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
x 
x 
x1 
x 
x 
X 
x 
x 
x  
x 
x 
x 
x 
x 
 
X 
Comprehensive Serum Chemistry 
Panel 
x 
x 
x1 
x 
x 
X 
x 
x 
 x 
x 
x 
x 
x 
x 
 
X 
Urinalysis 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
12/12/17 
 
 
Trial Period: 
 
Treatment weeks 
End of 
Treatment 
Post-Treatment 
 
Screening 
Visit 
Within 24 
hours of 
high-dose 
chemo 
0 
 
 
 
1 
 
 
 
2 
3 
6 
9 
12 
15 
 
18 
 
21 
 
24 
 
 
 
Scheduling Window (Days): 
-28 to -5 
 
Day 
+1 
 
 
Days 
2-7 
 
 
Days 
8-14 
Days 
15-21 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
 
At time of 
Discontinu
ation 
30 days 
post 
discontinu
ation 
Post-BMT 
month 12, 
18, and 24  
PT/PTT/INR 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
Bone Marrow Biopsy 
X2 
 
 
 
 
X4 
X4 
 
X4 
 
x 
 
X4 
 
 
X4 
Bone Marrow Collection 
 
 
 
 
 
X4 
X4 
 
X4 
 
 
 
 
 
 
 
Correlative Studies Blood 
Collection3 
 
x 
X 
 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
Stem Cell Collection5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1CBC, chemistry, vital signs & physical examinations will be done according to standard of care treatment following autologous stem cell transplant 
2Screening & disease restaging will consist of bone marrow biopsy, aspirate, cytogenetics, flow and molecular studies and will be done according to institutional 
standards pre-transplant, at 3, 6, 12 and 24 months post-transplant.  
3Research blood samples (30-60ml) will be drawn prior to lymphodepleting chemotherapy, prior to pembrolizumab dosing on each antibody dosing day, and at 12, 
18 and 24 months following autologous transplantation. 
4 A bone marrow biopsy will be performed for research purposes only at one and two months post autologous transplant.  Additional research marrow samples will 
be also collected at standard disease assessment times (3, 6, 12, 18 and 24 months post-transplant) 
5Stem cells will be collected per institutional standard within 30 days of study treatment initiation 
6Week 3 treatment administration will be given on Day 21 + 3 days 
 
 


 
12/12/17 
 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator or designee must obtain documented consent from each potential subject prior 
to participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB approval in advance of 
use.  The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements. 
 


 
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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior Medications  
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.5 
Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
7.1.1.6 
Assignment of Study Number 
Patients will be assigned a study number in chronological order including the IRB number -
001, 002, 003, etc along with the patient’s initials.  


 
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7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0.  Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs); see the separate ECI guidance document in Appendix 4 regarding the 
identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess Karnofsky performance status (see Section 
11.1) at screening, prior to the administration of each dose of trial treatment and 
discontinuation of trial treatment as specified in the Trial Flow Chart.   


 
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7.1.2.6 Assessment of Disease 
Assessment of AML disease status will be performed at the following time points after 
autologous transplant: 3 months, 6 months, 12 months, 18 months and 24 months.  A bone 
marrow biopsy will be performed and evaluated by morphology, flow cytometry, cytogenetics, 
and FISH studies (when applicable).  Complete remission (CR) is defined by the absence of 
residual leukemia in the bone marrow (less than 5% blasts by morphology and no definitive 
evidence of disease by flow cytometry), absence of extramedullary disease and adequate 
peripheral blood counts (absolute neutrophil count >1,000/microL and platelet count > 
100,000/microL).  Patients fulfilling the criteria for CR, but who do not achieve adequate 
peripheral blood counts, will be denoted as CR with insufficient hematologic recovery (CRi).  
Relapse is defined as the reappearance of leukemia blasts in the peripheral blood; or > 5% 
blasts in the bone marrow not attributable to another cause (e.g., recovery of normal cells 
following chemotherapy-induced aplasia); or appearance or reappearance of extramedullary 
disease. 
7.1.2.7 Correlative Studies Blood and Marrow Sampling 
Research blood samples (30-60ml) will be drawn prior to lymphodepleting chemotherapy, 
prior to pembrolizumab dosing on each antibody dosing day, and at 12, 18 and 24 months 
following autologous transplantation (12 total samples).  From each blood sample, peripheral 
blood mononuclear cells (PBMCs) and serum will be collected and cryopreserved for 
correlative studies.  A bone marrow biopsy will be performed for research purposes only at 
one and two months post autologous transplant.  Additional research marrow samples will be 
also collected at standard disease assessment times (3, 6, 12, 18 and 24 months post-transplant; 
7 total samples).  From each marrow sample, cells will be processed and cryopreserved for 
correlative studies. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   


 
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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal 
results are noted)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
 
Thyroid stimulating hormone (TSH) 
 
Blood Urea Nitrogen 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Creatinine 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
 
 
 
† Perform on women of childbearing potential only.   
 
 
 


 
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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
7.1.4 Other Procedures 
Bone marrow biopsy, using standard techniques, will be performed at the following time points 
post-transplant: 1, 2, 3, 6, 12, 18, and 24 months. 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  After discontinuing treatment, these subjects should return to the site for a 
Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up 
Period of the study (described in Section 7.1.5.4). 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1  Screening 
 
The screening visit will occur between 28 and 5 days prior to the start of high dose 
chemotherapy in preparation for stem cell transplantation.  The screening procedures will 
include standard pre-bmt workup and are fully outlined in Section 6.0 Trial Flow Chart.  
7.1.5.2  Treatment Period 
 
The treatment period may continue every 3 weeks for up to 8 doses.  If a subject 
withdraws from the trial early, end of study evaluations will occur.  Refer to the Trial Flow 
Chart for specific study related evaluations.   
7.1.5.3  Post-Treatment Visits 
 
The patient will be evaluated 30 days after the discontinuation of treatment and then at 
12, 18 & 24 months post-transplant.  Refer to the Trial Flow Chart for specific post-treatment 
evaluations.   
7.1.5.3.1  Safety Follow-up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 


 
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comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1, until the beginning of a new anti-neoplastic therapy, or until 30 days after the last dose of 
trial treatment, whichever occurs first.  SAEs that occur within 90 days of the end of treatment 
or before initiation of a new anti-cancer treatment should also be followed and recorded.   
7.1.5.1 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed according to institutional standards.  Every 
effort should be made to collect information regarding disease status until the start of new anti-
neoplastic therapy, disease progression, death, end of the study.     
7.1.5.1.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 


 
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Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
All adverse events will be recorded from the time the first dose of study drug is administered 
through 30 days following cessation of treatment and at each examination on the Adverse 
Event case report forms/worksheets. The reporting timeframe for adverse events meeting any 
serious criteria is described in section 7.2.3.1. 
7.2.1 Definition of an Overdose for this Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 


 
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missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  


 
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Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology.   
 
 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 


 
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which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


 
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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 


 
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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


 
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7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRBs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Patient Recruitment  
Accrual will continue until 20 patients are transplanted. It is estimated that one patient will be 
enrolled per month and about 20 months of accrual will be necessary to reach the required 
sample size. 
8.2 
Sample Size Calculation  
The objective of this study is to show that the 2-year cumulative incidence of relapse is less 
than 70%. Experience from the literature, suggests that following chemotherapy-based 
consolidation for high-risk AML, the rate of relapse is approximately 60-80%.  It is hoped that 
under this protocol, this rate will be at most 35%. The 2-year cumulative incidence of NRM is 
about 5%. The 2-year leukemia-free survival (LFS) is the primary endpoint and tested against 
the reference value 25%. We frame the objective to the hypotheses H0: S(t)=0.25 versus Ha: 
S(t)>0.25 for t = 2, where S(t) denotes the LFS probability at t. The Kaplan-Meier method and 
Greenwood’s formula are used to estimate the LFS probability and its precision. The one-sided 
Wald test at 5% significance level is used to test the hypotheses and we determine to analyze 
the data at the 3 years since the first patient is transplanted. The size of 20 patients yields the 
power of 90.5% assuming that the actual 2-year LFS is 60%. 
The power was estimated based on 5000 simulated replicates. Assume that LFS time follows 
the exponential distribution. Under the condition that the 2-year LFS is 60% the hazard rate is 
calculated to be 0.255. The LFS time was generated from exponential with rate=0.255. The 
censoring time was generated by the accrual estimate of one per month and the duration of 
study of 3 years. The following table shows the estimated powers for a few sizes. 
Sample size 
Test 
N=20 
N=23 
N=26 
Estimated power 1-sided 
0.905 
0.915 
0.924 
Estimated power 2-sided 
0.840 
0.863 
0.876 
 
8.3 
Analysis Plan  
The primary endpoint is 2-year LFS and the secondary endpoints include 2-year overall 
survival (OS), cumulative incidences of relapse and NRM. We decided the duration of study 
to be 3 years since the first transplant. The analysis will be performed when the study ends. 
The duration of 3 years was chosen to ensure sufficient follow-up of the participants so that 


 
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we can precisely estimate the 2-year survival outcomes. For N=20, the duration of 3 years leads 
to a median follow-up of 2.2 years given that censoring is caused by administrative loss-to-
follow up only. 
The Kaplan-Meier method will be used to estimate LFS and OS. Their precisions will be 
evaluated by the Greenwood’s formula. Relapse and NRM are considered as competing risks 
for defining LFS. The cumulative incidences of relapse and NRM will be estimated to 
accommodate competing risks. For each endpoint, the one-sample test for the 2-year outcome 
will be evaluated by the one-sided Wald test of 5% significance level. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   


 
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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1     Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and Investigator’s Brochure.  Essential clinical 
documents will be maintained to demonstrate the validity of the study and the integrity of the 
data collected.  Master files should be established at the beginning of the study, maintained 
for the duration of the study and retained according to the appropriate regulations.   
10.2 
    Ethical Considerations 
The study will be conducted in accordance with applicable regulatory requirement(s) and will 
adhere to GCP standards.  The IRB/IEC will review all appropriate study documentation in 


 
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order to safeguard the rights, safety and well-being of the patients.  The study will be 
conducted only at sites where IRB/IEC approval has been obtained.  The protocol, 
Investigator’s Brochure, informed consent form, advertisements (if applicable), written 
information given to the patients (including diary cards), safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB/IEC by the 
investigator.   
10.3 Investigator Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  .  
The IRB/IEC may provide, if applicable regulatory authority(ies) permit, expedited review 
and approval/favorable opinion for minor change(s) in ongoing studies that have the approval 
/favorable opinion of the IRB/IEC.  The investigator will submit all protocol modifications to 
the regulatory authority(ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.5 Data Management 
Data will be collected per standard of care for patients enrolled on this study. Shadow charts 
will be kept by the research administration team and will contain data specific to the clinical 
trial including screening and eligibility source documents, treatment information, adverse 
event/serious adverse event information and restaging/disease evaluation.  Routine stem cell 
transplantation information including laboratory results, medications and hospitalization 
information will be house in the BMT application, Northside Hospital medical record and 


 
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BMTGA electronic medical record. This information is available to the research and clinical 
teams and can be viewed upon request.  
 
10.6 References  
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versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in 
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4.  
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5. 
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6. 
Nathan PC, Sung L, Crump M, Beyene J. Consolidation therapy with autologous bone 
marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer 
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7. 
Oliansky DM, Appelbaum F, Cassileth PA, Keating A, Kerr J, Nieto Y, et al. The role 
of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute 
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2008 Feb;14(2):137-80. 
8. 
Pfirrmann M, Ehninger G, Thiede C, Bornhauser M, Kramer M, Rollig C, et al. 
Prediction of post-remission survival in acute myeloid leukaemia: a post-hoc analysis of the 
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9. 
Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen 
JJ, et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. 
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Chen X, Liu S, Wang L, Zhang W, Ji Y, Ma X. Clinical significance of B7-H1 (PD-
L1) expression in human acute leukemia. Cancer Biol Ther. 2008;7(5):622-627. 


 
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12. 
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infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 
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13. 
Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with 
tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin 
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14. 
Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-
H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating 
lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10(15):5094-5100. 
15. 
Liu J, Hamrouni A, Wolowiec D, et al. Plasma cells from multiple myeloma patients 
express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR 
ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood. 2007;110(1):296-304. 
16. 
Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed 
death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and 
disease progression. Blood. 2009;114(8):1528-1536. 
17. 
Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S. FOXP3+ 
Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast 
cancer patients: Implication for immunotherapy. BMC Cancer. 2008;8:57. 
18. 
Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-
infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl 
Acad Sci U S A. 2007;104(9):3360-3365. 
19. 
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receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. 
J Exp Med. 2000;192(7):1027-1034. 
20. 
Shenghui Z, Yixiang H, Jianbo W, et al. Elevated frequencies of CD4(+) CD25(+) 
CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid 
leukemia. Int J Cancer. 2011;129(6):1373-1381. 
21. 
Szczepanski MJ, Szajnik M, Czystowska M, et al. Increased frequency and suppression 
by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res. 
2009;15(10):3325-3332. 
22. 
Wang X, Zheng J, Liu J, et al. Increased population of CD4(+)CD25(high), regulatory 
T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid 
leukemia patients. Eur J Haematol. 2005;75(6):468-476. 
23. 
Zhou Q, Bucher C, Munger ME, et al. Depletion of endogenous tumor-associated 
regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine 
acute myeloid leukemia. Blood. 2009;114(18):3793-3802. 
24. 
Zhou Q, Munger ME, Highfill SL, et al. Program death-1 signaling and regulatory T 
cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in 
advanced acute myeloid leukemia. Blood. 2010;116(14):2484-2493. 
25. 
Shvets A, Chakrabarti R, Gonzalez-Quintial R, Baccala R, Theofilopoulos AN, 
Prud'homme GJ. Impaired negative regulation of homeostatically proliferating T cells. Blood. 
2009;113(3):622-625. 
26. 
Bracci L, Moschella F, Sestili P, et al. Cyclophosphamide enhances the antitumor 
efficacy of adoptively transferred immune cells through the induction of cytokine expression, 
B-cell and T-cell homeostatic proliferation, and specific tumor infiltration. Clin Cancer Res. 
2007;13(2 Pt 1):644-653. 


 
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27. 
Wrzesinski C, Paulos CM, Gattinoni L, et al. Hematopoietic stem cells promote the 
expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. 
2007;117(2):492-501. 
28. 
Wrzesinski C, Paulos CM, Kaiser A, et al. Increased intensity lymphodepletion 
enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J 
Immunother. 2010;33(1):1-7. 
29. 
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in 
patients 
after 
clonal 
repopulation 
with 
antitumor 
lymphocytes. 
Science. 
2002;298(5594):850-854. 
30. 
Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following 
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-2357. 
31. 
Joseph RW, Elassaiss-Schaap J, Wolchok JD, Joshua AM, Ribas A, Hodi FS, et al. 
Baseline tumor size as an independent prognostic factor for overall survival in patients with 
metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Oncol 
(Meeting Abstracts). 2014 May 20, 2014;32(15_suppl):3015-. 
32. 
Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer 
Therapy. J Clin Oncol. 2015 Jun 10;33(17):1974-82. 
33. 
Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events 
and kinetics of response with ipilimumab. J Clin Oncol. 2012 Jul 20;30(21):2691-7. 
34. 
Yang YF, Zou JP, Mu J, Wijesuriya R, Ono S, Walunas T, et al. Enhanced induction 
of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the 
effect is manifested only at the restricted tumor-bearing stages. Cancer Res. 1997 Sep 
15;57(18):4036-41. 
35. 
Condomines M, Veyrune JL, Larroque M, Quittet P, Latry P, Lugagne C, et al. 
Increased plasma-immune cytokines throughout the high-dose melphalan-induced 
lymphodepletion in patients with multiple myeloma: a window for adoptive immunotherapy. 
J Immunol. 2010 Jan 15;184(2):1079-84. 
36. 
Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. 
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of 
adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005 Oct 3;202(7):907-12. 
37. 
Wallen H, Thompson JA, Reilly JZ, Rodmyre RM, Cao J, Yee C. Fludarabine 
modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells 
in patients with metastatic melanoma. PLoS One. 2009;4(3):e4749. 
38. 
Goldrath AW, Sivakumar PV, Glaccum M, Kennedy MK, Bevan MJ, Benoist C, et al. 
Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory 
CD8+ T cells. J Exp Med. 2002 Jun 17;195(12):1515-22. 
39. 
Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, et al. Disabling 
immune tolerance by programmed death-1 blockade with pidilizumab after autologous 
hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an 
international phase II trial. J Clin Oncol. 2013 Nov 20;31(33):4199-206. 
40. 
Chung DJ, Pronschinske KB, Shyer JA, Sharma S, Leung S, Curran SA, et al. T-cell 
Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of 
Immunotherapy. Cancer Immunol Res. 2016 Jan;4(1):61-71. 
41. 
Rezvani K, Yong AS, Mielke S, Savani BN, Jafarpour B, Eniafe R, et al. 
Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-


 
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antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid 
leukemia undergoing WT1 peptide vaccination following chemotherapy. Cancer Immunol 
Immunother. 2012 Jul;61(7):1125-36. 
42. 
Ribas A. Efficacy and safety of the anti-PD1 monoclonal antibody MK-3475 in 411 
patients with melanoma. J Clin Oncol. 2014;32(5s):Abstr LBA9000. 
43. 
Hamid O. Randomized Comparison of two doses of the anti-PD1 monoclonal antibody 
MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naive (IPI-N) melanoma. J Clin Oncol. 
2014;32(5s):Abstr 3000. 
44. 
Dummer R, Daud A, Puzanov I, et al. A randomized controlled comparison of 
pembrolizumab and chemotherapy in patients with ipilimumab-refractory melanoma. J Transl 
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45. 
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Refractory Hodgkin Lymphoma - Preliminary Safety, Efficacy and Biomarker Results of a 
Phase I Study. Vol. 124; 2014. 
46. 
Moskowitz CH, Ribrag V, Michot J-M, et al. PD-1 Blockade with the Monoclonal 
Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after 
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47. 
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Vol. 124; 2014. 
 
 
 
 


 
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10.7  Appendices  
Appendix 1: Favorable Cytogenetic/Molecular Risk Abnormalities   
Favorable cytogenetic/molecular risk abnormalities: 
1. T(15;17) 
2. T(8;21) with wild-type c-kit 
3. Inversion 16 with wild-type c-kit 
4. Normal cytogenetics with mutated NPM-1 and wild-type FLT3 
5. Normal cytogenetics with mutated CEBPA and wild-type FLT3 
 
 


 
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Appendix 2: Karnofsky Performance Status Scale 
Index 
Specific Criteria 
General 
100 
Normal, no complaints, no evidence of 
disease. 
 
Able to carry on normal activity; 
no special care needed. 
90 
Able to carry on normal activity, minor signs 
or symptoms of disease. 
80 
Normal activity with effort, some signs or 
symptoms of disease. 
70 
Care for self, unable to carry on normal 
activity or to do work. 
Unable to work, able to live at 
home and care for most personal 
needs, 
varying 
amount 
of 
assistance needed. 
60 
Requires occasional assistance from others 
but able to care for most needs. 
50 
Requires considerable assistance from others 
and frequent medical care 
40 
Disabled, 
requires 
special 
care 
and 
assistance. 
Unable to care for self, requires 
institutional or hospital care or 
equivalent, disease may be rapidly 
progressing. 
 
30 
Severely disabled, hospitalization indicated, 
but death not imminent. 
20 
Very sick, hospitalization necessary, active 
supportive treatment necessary. 
10 
Moribund 
0 
Dead