Clinical trial NCT03286114
Conditions: Myelodysplastic Syndromes Acute Myeloid Leukemia Acute Lymphoblastic Leukemia
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2017-12-21; Completion date: 2021-04-28
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm, open-label, Phase 1b study of pembrolizumab for patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) whose disease has relapsed after receiving allogeneic hematopoetic stem cell transplant.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: 200mg IV every 21 days

Protocol documents:
Prot_SAP_000.pdf: 
ID: UMCC 
2017.056 
    Augmentation of the Graft vs. Leukemia Effect Via 
Checkpoint Blockade With Pembrolizumab 
    NCT03286114 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
1 
SPONSOR:  John Magenau, M.D. (University of Michigan) 
UMCC 2017.056 
TITLE: Augmentation of the Graft vs. Leukemia Effect via Checkpoint Blockade with Pembrolizumab for 
Relapse of Primary Malignancy after Allogeneic Hematopoietic Stem Cell Transplant: A Feasibility 
Study. 
IND NUMBER: Exempt #136227 
Institution Name: University of Michigan 
Co-Principal Investigators Information: 
John Magenau, M.D.  
Assistant Professor of Internal Medicine  
Division of Hematology/Oncology, Department of Internal Medicine 
University of Michigan Medical School  
Address: University Hospital South, BMT Program, Room F4856  
1500 E. Medical Center Drive  
Ann Arbor, MI 48109, SPC 5271  
Phone: 734-936-8785; Fax: 734-232-4484  
Email: johnmage@med.umich.edu  
Pavan Reddy, M.D.,  
Moshe Talpaz Professor of Translational Oncology 
Division of Hematology/Oncology, Department of Internal Medicine 
University of Michigan Medical School 
Address: University Hospital South, BMT Program, Room F4856  
1500 E. Medical Center Drive  
Ann Arbor, MI 48109, SPC 5271  
Phone: 734-936-8785; Fax: 734-232-4484  
Email: reddypr@med.umich.edu  
Co-Investigators  
Brian Parkin, M.D. Assistant Professor of Internal Medicine 
Attaphol Pawarode, M.D. Assistant Professor of Internal Medicine 
Mary Riwes, D.O. Assistant Professor of Internal Medicine  
Sarah Anand, M.D. Assistant Professor of Internal Medicine 
Monalisa Ghosh, M.D. Assistant Professor of Internal Medicine 
Patrick Burke, M.D. Assistant Professor of Internal Medicine 
Sung Choi, M.D., Associate Professor of Pediatrics  
Challice Bonifant, M.D. Assistant Professor of Pediatrics 
David Frame, Pharm D 
Thomas Braun, Ph.D. Professor of Biostatistics  
Oncology Clinical Trials Support Unit (OCTSU) Study Coordinators:  
Nancy McCullough, CCRP  
Address  
NCRC, Clinical Trials Office, 2800 Plymouth Rd., Bldg. 300, Ann Arbor, MI 48109-2800 
Phone: 734-232-0758, 734-936-8538; Fax: 734-232-0744  


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
2 
E-mail:  
 
University of Michigan BMT Program Clinical Research Coordinators: 
Maggi Kennel  mkennel@med.umich.edu 
Lynne Bischoff   lloisros@med.umich.edu  
 
 
Contracting Person:  
Name: Tricia Haynes, Assistant Project Representative  
Address: ORSP, Wolverine Tower, Room 1024, 3003 South State Street,  
Ann Arbor, MI 48109-1274  
Phone no 734-615-8383  
Fax no 734-763-4053; 764-8510  
Email Address: phaynes@umich.edu  
 
Protocol version / date: v2.0 / May 16, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
3 
 
TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY .......................................................................................................... 4 
2.0 
TRIAL DESIGN............................................................................................................... 5 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES) ............................................................................ 5 
4.0 
BACKGROUND & RATIONALE .................................................................................... 6 
5.0 
METHODOLOGY ......................................................................................................... 11 
5.1 
INCLUSION/EXCLUSION CRITERIA .......................................................................... 11 
5.2  
TRIAL TREATMENTS………………………………………………………………………..15 
6.0 
TRIAL FLOW CHART…………………………………………………………………….......26    
7.0 
TRIAL PROCEDURES ................................................................................................. 29 
8.0 
STATISTICAL ANALYSIS PLAN ................................................................................. 46 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ..... 48 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS .................................................... 49 
11.0 APPENDICES............................................................................................................... 53 
12.0 REFERENCES ............................................................................................................. 56 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
4 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab for Relapsed Disease after Allogeneic 
Hematopoietic Stem Cell Transplant 
Trial Phase 
Phase 1b 
Clinical Indication 
Relapsed myelodysplastic syndrome, acute myeloid 
leukemia and acute lymphoblastic leukemia after allogeneic 
hematopoietic stem cell transplant 
Trial Type 
Single center, Investigator-Initiated 
Type of control 
N/A 
Route of administration 
IV 
Trial Blinding 
none 
Treatment Groups  
Single treatment group 
Number of trial subjects 
20 subjects 
Estimated enrollment 
period 
2 years 
Estimated duration of trial 3 years 
Duration of Participation 
14 months 
Estimated average length 
of treatment per patient 
12 months 
 
 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
5 
2.0 TRIAL DESIGN 
2.1 
Trial Design   
Single-arm open label phase 1b clinical trial of pembrolizumab (Merck) to the determine the 
feasibility and immunologic correlates for treating relapse of primary malignancy  after 
allogeneic stem cell transplantation. 
 
2.2    Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
3.1.1 Primary Objectives 
1) To establish the safety of delivering single agent pembrolizumab ± chemotherapy to patients with 
relapse of ALL, AML or MDS after allogeneic transplantation. 
 
 
2) To determine the overall response rate (ORR) to single agent pembrolizumab ± chemotherapy in 
patients with relapsed ALL, AML or MDS after allogeneic transplantation.  
 
 
3) To describe the incidence of Graft vs. Host Disease (GvHD) and/or other clinically significant 
immune mediated toxicities after pembrolizumab ± chemotherapy.  
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
6 
3.1.2 Hypotheses for Primary Objectives 
Blockade of PD-1 with pembrolizumab will enhance (induce) the Graft vs. Leukemia (GvL) effect 
resulting in objective clinical responses without excessive toxicity (GvHD) in patients who 
experience relapse of primary malignancy after allogeneic transplantation.  
3.2 
Secondary Objective(s) & Hypothesis(es) 
3.2.1 Secondary Objectives 
 
1) Estimate the one-year overall and disease-free survival in patients administered pembrolizumab 
for relapse after HCT  
 
3.2.1.1 Exploratory Objectives 
 
1) Determine the immunologic correlates of response to checkpoint blockade in patients with 
hematologic malignancies who have relapsed after allogeneic transplantation via assessment of 
PD1-PDL1 axis with a well-defined focus on T and NK cell phenotypes, functions and leukemia 
specific responses. 
 
 
2) Determine the antigenic peptide repertoire of relapsed MDS and AML by whole exome 
sequencing (WES), bioinformatically nominate the most immunogenic antigens from the WES 
analyses and then functionally validate the top predicted peptides in silico and in vitro. 
 
3) Determine if PD-L1 expression at relapse serves as a biomarker for response to pembrolizumab 
in 
hematologic 
malignancies 
as 
has 
been 
reported 
in 
solid 
malignancies31.    
 
4) Identify responsive and resistant malignant clones and assess kinetics and depth of response to 
treatment with ultrasensitive mutation detection (droplet digital PCR [ddPCR] and single-
molecule/real-time sequencing [SMRT]) 
 
3.2.2 Hypotheses for Secondary and exploratory Objectives 
Blockade of PD-1 with pembrolizumab can reverse the putative immunobiologic mechanisms 
reported to play a significant role in contributing to relapse after allogeneic transplantation via the 
development of ‘adaptive resistance’ determined by analyses of immune peptide repertoire by WES 
and specific expression of PD-LI and other immune inhibitory markers on (Galectin 9, HVEM, CD48, 
CD155) leukemic cells and characterize the ‘senescent/exhausted’ CD8/4+ immunophenotype (PD1, 
LAG3, TIM3). 
4.0 BACKGROUND & RATIONALE 
Allogeneic stem cell transplantation provides the only modality with curative potential for many patients 
with life-limiting hematologic malignancies, particularly those with acute myelogenous leukemia (AML). 
 Relapse After Allo-HCT: According to the Center for International Bone Marrow Transplant Registry 
(CIBMTR), approximately 40% of mortality after allogeneic hematopoietic cell transplantation (HCT) 
occurs from relapse1. To our knowledge, there have been no successful approaches for reducing relapse 
after HCT. In AML, relapse rates range from 25% to 65% depending on HCT and disease specific risk 
factors including conditioning intensity, T cell depletion, cytogenetic profile and status of disease at the 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
7 
time of HCT. Refractory or relapsed AML, not in remission at time of HCT, has the highest relapse, 
approximately 60% or greater.  
Management of relapse has been unfortunately met with little success and the proportion of patients with 
long term survival after relapse HCT remains unacceptably low.  Although the use of Donor Lymphocyte 
Infusion (DLI), often in combination with chemotherapy has become a commonly utilized treatment 
approach, the long term outcomes remain poor and the incidence of Graft vs. Host Disease (GvHD) after 
DLI is a significant limitation to its overall success2-6. For example, 13% of patients with AML survived 
one-year if relapse occurred 6 months after HCT (Bejanyan et al. BBMT 2015).    
Although multi-factorial, one of the primary mechanisms by which HCT achieves anti-tumor control is via 
an immune-mediated ‘Graft vs. Leukemia’ (GvL) effect 2,7.  The mechanisms by which the host and donor 
hematopoietic and non-hematopoietic cells and tissues interact to achieve successful disease control 
and immune surveillance are complex and difficult to study in humans8-10.  Over the last decade, there 
has been extraordinary progress in our understanding of these mechanisms, not only those involved in 
the activation of the immune effectors to enhance cytotoxicity, but in particular, the numerous pathways 
involved in inhibition of the immune system that otherwise protect healthy tissues from autoimmune 
reactions, but can paradoxically lead to immune escape by malignant cells11, culminating in clinical 
relapse.  Included among the multiple negative regulatory mechanisms which appear to contribute to the 
inhibition of sufficiently primed anti-leukemic (tumor) T cell responses are 1) suppression of conventional 
T-cell function by regulatory T-cells12, 2) up-regulation of CTLA-4 on T-cells13, 3) tryptophan catabolism 
by IDO14-16,  4) T-cell anergy due to poor co-stimulation by tumor cells17, 5) functional senescence or 
exhaustion of antigen specific CD8+ T-cells after allotransplantation18 and 6) engagement of PD-1 on 
activated T-cells with PD-L1 [Figure 1]19,20. Although interfering with any one of these pathways might 
enhance the GvT effect, this proposal focuses on the latter via blockade of PD-1 with pembrolizumab in 
relapsed AML or MDS after HCT.    
Several murine and human studies have established that PD-1/PD-L1 interactions play a critical role in 
immune evasion21-27 and provide strong rationale for enhancing GvL via PD-1 blockade post-HCT.  
PD-L1 expression has been confirmed in several hematologic malignancies, including AML, providing 
the rationale for exploring both the impact of PD-1 blockade via pembrolizumab and the correlation of 
surface expression and response among disease subtypes. In addition, there are no published data 
exploring Pembrolizumab post allogeneic HCT in which a potentially ‘healthy’ immune effector system 
from the donor can be exploited to re-establish immune surveillance and cancer ‘immuno-editing’9.  A 
unique aspect of this study is that instead of ‘activating’ autologous T cells from a cancer patient with 
long-standing exposure to the tumor, the potential target are the ‘normal’ donor T-cells previously infused 
(and still persistent) after allogeneic HCT which have potentially become senescent/exhausted18.  
Although there is precedent for the ‘inhibition of inhibitory pathways’ via CTLA-4 blockade with 
ipilimumab, suggesting an enhancement in T-cell response against AML 28 without increasing GvHD  in 
the post-HCT setting29,30, this  trial will  focus on PD-1 blockade via pembrolizumab. 
By targeting established immunoregulatory pathways  with pembrolizumab, we postulate that we can 
overcome  inhibition mediated by PD-1 binding with PD-L1 and PD-L2, thereby inducing or restoring the 
immune-mediated GvL effect without undue toxicity in a patient population with very limited treatment 
options. 
When compared to the extensive data regarding the potential role of checkpoint blockade in solid tumors, 
there has been a relative paucity in hematologic malignancies. This proposal will investigate  PD-1 based 
check-point blockade (pembrolizumab) in the post-HCT setting, and will provide an important ‘proof of 
principle’ for understanding  key mechanisms of immune escape after HCT, reversal of 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
8 
senescence/exhausted immunophenotype, and 
potential impact on re-establishing  GvL and 
leukemic response. If successful, these clinical 
and laboratory data would provide compelling 
rationale for further definitive lines of investigation 
of pembrolizumab in this or related settings.    
FIGURE 
1. 
Immune 
checkpoint 
blockade 
as an 
immunotherapeutic modality. T-cell receptor binding to an 
human leukocyte antigen/peptide complex is a central event 
in cytotoxic T lymphocyte (CTL) mediated elimination of 
leukemia cells as it induces an activation signal within the 
CTL. Immune checkpoints refer to a number of inhibitory 
pathways that are crucial for maintaining self-tolerance and 
modulating the duration and amplitude of immune responses 
in peripheral tissues in order to minimize collateral tissue 
damage. It is well described that tumors use different immune 
checkpoint pathways as a major mechanism of immune 
resistance against leukemia-specific CTL. PD-1 is mainly 
expressed on antigen-experienced memory T cells in 
peripheral tissues (effector phase). Leukemia cells use this 
regulatory mechanism to evade a leukemia-directed CTL response by upregulating PD-L1, which is the ligand for PD-1, on its 
surface. Blocking monoclonal antibodies (orange squares) directed at the inhibitory immune receptors CTLA-4, PD-1 and PD-
L1 have all emerged as promising novel treatment approaches for cancer patients. Figure and caption from MH Andersen, 
Leukemia 2014.  
4.1 
Pharmaceutical and Therapeutic Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
Pembrolizumab (MK-3475). 
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+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control.  
The normal function of PD-1, expressed on the cell surface of activated 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, T regs 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 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
9 
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, 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. Keytruda is also approved for patients with metastatic 
NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have disease 
progression on or after platinum-containing chemotherapy.  
4.2 
 Rationale 
4.2.1 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 (KeytrudaTM, pembrolizumab). 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. Recent data from other clinical studies within the MK-3475 program has shown 
that a lower dose of MK-3475 and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
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 Q3W dosing schedule in this study.   
 
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 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
10
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 
was 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 current study will employ pembrolizumab at a fixed dosage of 200mg every 3 weeks, which is the 
FDA approved standard dosing. 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. 
 
4.2.2 Rationale for Endpoints 
4.2.2.1 Efficacy Endpoints 
This feasibility study addresses a cohort of patients with established resistance to chemotherapy and 
HCT by virtue of having relapsed after HCT.  We are seeking to identify a signal for clinical benefit by 
assessing the ORR to pembrolizumab ± chemotherapy while providing additional insights into the 
mechanisms of check-point inhibition in the immune biology of post-HCT relapse. These efficacy 
endpoints will be assessed by serial CBC, bone marrow biopsies / aspirate, assessing peripheral blast 
percentages, absolute blast counts (ABC), and marrow blasts.  
The time to response in this disease cohort is unknown.  The first marrow assessment of disease 
response will be at day 35 after initiation of study treatment. If disease is stable (SD) or improved (CR or 
PR) at day 35, clinicians will continue single agent therapy every 3 weeks for a total of 4 doses. A second 
marrow assessment will be performed on day 77. If CR or PR is attained subjects may proceed to phase 
II (maintenance) (see section 5.2).  
 
If there is a concern for rapid disease progression or clinical instability, chemotherapy may be added per 
investigators discretion after the day 35 marrow results (two doses of pembrolizumab) (See section 
5.2.1.2).. Subjects may continue study drug in the absence of toxicity attributable to pembrolizumab per 
Table 3.   
 
Primary objective endpoints: 
Efficacy: 
- ORR at days 35  and 77 in subjects receiving pembrolizumab monotherapy  
- ORR at day 77 in subjects receiving pembrolizumab ± standard induction chemotherapy 
- Clinical Benefit Rate (CBR) at days 35 and 77 in subjects receiving pembrolizumab monotherapy 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
11
Safety: 
-  Incidence and severity of GvHD after administration of pembrolizumab 
- Grade 3-5 Regimen-related toxicities (RRT) per CTCAE v4 
- Incidence of immune mediated toxicities attributable to pembrolizumab  
Secondary objective endpoints: 
 - Estimate overall survival (OS) and disease-free survival (DFS) at one year in patients who receive 
pembrolizumab for relapse after allogeneic HCT. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Please refer to section 5.1.2. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) or Myelodysplastic Syndrome 
(MDS) in confirmed relapse based on bone marrow examination after allogeneic HCT. Biopsy 
confirmed myeloid sarcoma or extramedullary AML may also be considered.  
2. Confirmation of ‘measurable disease’ by blast % will be defined as a marrow blast percentage of > 
5% by morphologic assessment on bone marrow examination. This criterion does not apply to 
myeloid sarcoma, or extramedullary leukemia, which must also show measurable lesion by CT, MRI, 
PET/CT or photograph (i.e. Leukemia cutis). If marrow blasts of ≤ 5% blasts are enumerated the 
patient may be eligible only if there is clear (probable or definite) flow cytometric, cytogenetic or 
molecular aberrations (e.g. FLT3-ITD, NPM1, etc.) documenting relapse of the leukemia associated 
clone defined prior to HCT.  
3. Patient may not have received definitive salvage chemotherapy for their post-transplant relapse within 
the past 21 days. Use of hydroxyurea is permitted.  
 
4. Be willing and able to provide written informed consent/assent for the trial 
5. Be ≥ 18 years of age on day of signing informed consent 
6. Be willing to provide tissue from bone marrow biopsies   
7. Have a performance status of 0, to 1 on the ECOG Performance Scale. For purposes of HCT, this 
will correspond to a Karnofsky Performance status of ≥ 80% 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
12
8. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed 
within 10 days of treatment initiation   
 
 
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN 
AST (SGOT) and ALT (SGPT) 
≤ 5 X ULN for subjects 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
Pulmonary 
Pox >90% on Room Air 
aCreatinine clearance should be calculated per institutional standard. 
Hematology (Blood Counts): Must have an absolute blast count (ABC) of < 15 K/ul in the peripheral blood 
prior to initiating study treatment. Use of hydroxyurea to control blast counts prior to initiating study 
treatment is acceptable.  
 
9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 
hours 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.   
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 – Contraception,  for the course of the study through 120 
days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
11. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of 
contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
13
1. 
Has had relapse prior to primary neutrophil engraftment or ≤21 days post HCT. 
2. 
Has received >1 line of chemotherapy or other treatment directed towards post-transplant relapse 
prior to study entry 
3. 
Rapidly progressive relapse requiring urgent chemotherapy as determined by treating physician 
4. 
Is currently participating and receiving study therapy of an investigational agent and received 
study therapy within 2 weeks of the first dose of treatment. This 2 week washout period would not apply 
to investigational food ingredients.   
5. 
Has a diagnosis of active GvHD (≥ Grade I). Patients with prior active GvHD that is quiescent 
(Grade 0) at time of entry may be considered. 
6. 
Receiving systemic steroid therapy of > 10mg prednisone daily or equivalent*  
7. 
Has received GM-CSF within 14 days of first dose of pembrolizumab 
8. 
Has a known history of active TB (Bacillus Tuberculosis)Hypersensitivity to pembrolizumab or 
any of its excipients 
9. 
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier 
10. 
Has had prior chemotherapy within 21 days, or radiation therapy within 14 days 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 
a. 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for 
the study. 
b. 
Note:  If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.   
11. 
Has a known additional (secondary) 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. 
12. 
Has known or suspected active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with suspected CNS disease should have lumbar puncture performed to exclude this 
possibility. Subjects with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain 
metastases, and are not using steroids for at least 7 days prior to trial treatment.  This exception does 
not include carcinomatous meningitis which is excluded regardless of clinical stability.   
13. 
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.  


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
14
14. 
Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis 
15. 
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.   
16. 
Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial 
17. 
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 
18. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
19. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) 
20. 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected) 
21. 
Has received a live vaccine within 30 days of planned start of study therapy 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
*Note:                                                                                                                                                                 
a. Corticosteroid use on study after Cycle 1 for management of adverse events, 
serious adverse events, and events of clinical interest, as a premedication for IV 
contrast allergies/reactions, or if considered necessary for a subject’s welfare is 
allowed. 
b. Subjects who receive daily steroid replacement therapy are an exception. Daily 
prednisone at doses of 5 to 7.5 mg is an example of replacement therapy. 
c. Equivalent hydrocortisone doses are also permitted if administered as replacement 
therapy. 
 
 
Subject Screening and Registration Procedure 
Subject registration for this study will be centrally managed by the Oncology Clinical Trials Support Unit 
(OCTSU) of The University of Michigan Comprehensive Cancer Center as described below: 
 
All potential study subjects who are screened for  the study and have signed the Informed 
Consent document will be assigned a study number. 
 
It is the responsibility of the local site investigator to determine subject eligibility prior to submitting 
subject registration request to the OCTSU. After subject eligibility has been determined, the patient 
will be enrolled by the OCTSU study coordinator. The informed consent and eligibility checklist must be 
completed before subjects can receive the first study treatment of MK-3475 (pembrolizumab®). 
 
Subjects found to be ineligible for participation after being consented will be considered screen failures, 
and documented as such. These subjects will not will not receive study treatment. 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
15
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 (see also Trial Diagram in section 2.2). 
Table 2  Trial Treatment  
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
(Phase I: Induction) 
200 mg 
Every 3 
weeks 
IV infusion 
Day 1 of each 3 week 
cycle x 4 doses 
Experimental 
Pembrolizumab 
(Phase II: 
Maintenance) 
200 mg 
Every 3 
weeks 
IV infusion 
Day 1 of each 3 week 
cycle up to 13 doses 
Experimental 
 
Description of Trial Treatment: Eligible subjects will be initiated on pembrolizumab (phase I) for up to 
4 doses with response assessments at day 35 (after 2 doses) and day 77 (after 4 doses). Subjects who 
are tolerating therapy without drug related adverse events (Table 3) AND who have disease in PR or CR 
on day 77 response assessment may be continued on pembrolizumab maintenance (phase II). Phase II 
treatment will continue for up to an additional 13 doses or until either toxicity or progression of malignancy 
at which time the subject will be placed into follow-up.   
Subjects initiated on systemic induction chemotherapy: due to progression will receive no additional 
or concomitant phase I (induction) doses of pembrolizumab but may be considered for phase II 
maintenance pembrolizumab if disease assessment at day 77 (following chemotherapy) indicates PR or 
CR. Pembrolizumab may have synergistic effects with chemotherapy and/or facilitate augmention of GVL 
after reduction of high leukemic burden.  
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – Background and 
Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the Pharmacy 
Manual.   
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
After initiated study treatment, the use of chemotherapy prior to day 35 bone marrow biopsy (or two 
cycles of pembrolizumab) is discouraged.   
- 
Systemic Chemotherapy may be instituted in the following scenarios: 
• 
Evidence for progressive AML or MDS on day 35 bone marrow biopsy. Progression will 
be defined as a minimum of > 5% increase in the absolute marrow blasts from pre-
treatment biopsy. For example, increase in bone marrow blast from 10% on pretreatment 
biopsy to 25% on day 35 marrow examination OR 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
16
• 
At the discretion of the treating physician for impending rapidly progressive relapse (e.g. 
rapid increase in peripheral blast % or hematologic instability. These situations should be 
discussed in consultation with the study PIs OR 
• 
Alternatively, subjects with minimal progression may remain on monotherapy if deemed 
there may be potential for subsequent clinical response or deemed poor candidates for 
systemic chemotherapy. For example, a subject who is tolerating pembrolizumab at day 
35 of treatment with increase in bone marrow blasts to 15% at day 35 from 9% at pre-
treatment will be recorded as progression but may remain on monotherapy to complete 
four dose of induction (phase I) at investigator’s discretion.   
- 
The chemotherapy regimen will be at the discretion of the treating physician and may include 
hypomethylation therapy or cytotoxic chemotherapy including high dose ara-C (e.g. FLAG) and/or 
anthracycline-based regimens. Other investigational agents are not permitted or the subject will be 
removed from further pembrolizumab and placed into follow-up.   
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 weeks 
after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe 
or life-threatening adverse events (AEs) as per Table 3 below. Pembrolizumab must also be permanently 
discontinued in patients who develop ≥ Grade 3 acute GvHD requiring systemic corticosteroids. 
Pembrolizumab should be temporarily held if acute GVHD grade II occurs. Pembrolizumab may be re-
initiated once acute GVHD improves to < grade II.  See Section 5.4 for supportive care guidelines, 
including use of corticosteroids. 
 
 
Table 3. Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence 
of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
17
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite adequate 
premedication 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
 
Permanently discontinue 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or 
equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative 
to baseline and lasts for at least 1 week then patients should be discontinued. 
b 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; – 
Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 
weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related 
to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). 
Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle 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. 
Pembrolizumab 200 mg (flat dose) will be administered as a 30 minute IV infusion every 3 weeks x 4 
doses.  Every effort should be made to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment 
administered. 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
18
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 
Patients may receive hydroxyurea at the discretion of their treating hematology physician as a temporary 
bridge to chemotherapy.  All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes 
occur during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF. 
All concomitant medications received within 14 days before the first dose of trial treatment and 30 days 
after the last dose of trial treatment should be recorded. Concomitant medications administered after 30 
days after the last dose of trial treatment should be recorded for SAEs and ECIs as defined in Section 
7.2. 
FLT-3 inhibitors and tyrosine kinase inhibitors which are resumed as part of usual care after HCT are 
permissible.  
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this trial: 
• 
Immunotherapy not specified in this protocol 
• 
No GM-CSFwill be used during the trial 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Radiation therapy  
• 
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.  
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids (e.g. hydrocortisone for adrenal replacement or premedication for blood 
transfusion) or continuation of low dosages of corticosteroids as specified in the protocol eligibility 
(≤ 10mg prednisone / day).   


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
19
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. 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 does not need to 
follow the treatment guidance (as outlined below). 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.  
• 
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. 
• 
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, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose 
oral steroids.   


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
20
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. 
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, 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, 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. 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
21
o For Grade 3-4 events, treat with systemic corticosteroids. 
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 4 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 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
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. 
Subject may be 
premedicated 1.5h (± 30 
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., 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
No subsequent dosing 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
22
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
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. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
 
 
5.5 
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
5.5.2 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.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; 
in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal 
ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last dose of 
study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
23
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as 
the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods 
of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable 
method of contraception for subjects participating at sites in this country/region. 
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 subjects 
of childbearing potential must adhere to the contraception requirement (described above) from the day 
of study medication initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of trial therapy.  If there is any question 
that a subject of childbearing potential will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
5.5.3 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. 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
24
5.5.4 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. 
• 
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 
• 
Administrative reasons 
 
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. 
5.7 
Subject Replacement Strategy 
Subjects receiving less than 2 doses of pembrolizumab may be replaced but will be monitored for study 
specified outcomes. Subjects removed from the trial for toxicities / SAEs probably or definitely related to 
pembrolizumab will not be replaced.  
5.8 
Clinical Criteria for Early Trial Termination 
As a feasibility trial in which patients may receive the standard of care in addition to pembrolizumab 
therapy at the discretion of the treating physician, stopping rules for FUTILITY are not indicated. 
Stopping rules for TOXICITY are outlined in section 8 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
25
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided so that 
appropriate adjustments to subject treatment can be made. 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
 
 
 
26
6.0 TRIAL FLOW CHART 
Study Period: 
Screening Phase 
Treatment Cycles 
Phase I: Induction 
Response  
Post- 
Induction 
Treatment Cycles 
Phase II: Maintenance 
Response 
Post-
Maintenance  
Post-Treatment 
Treatment Dose/Title 
Day (D) 
Pre-
screening 
Main Study 
Screening  
1 
(D1) 
2 
(D22) 
3 
(D43) 
4 
(D64) 
 
 
(D77) 
Doses 5 – 17 
(D85 - D365)* 
 
End of Treatment 
(D365) 
Follow-up: 30 and 90 
Days After Treatment 
up to D455† 
Relapse‡ 
Scheduling Window (Days): 
Days 
-21 to -1 
 
Days 
-21 to -1 
 
± 3 
± 3 
± 3 
± 3 
 
±7 
± 3 
 
± 14 
± 14 
n/a 
 
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Subject Identification Card 
 
X 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
X 
 
 
 
 
X 
 
 
 
 
Study Treatment Administration 
 
 
X 
X 
X 
X 
 
X 
 
 
 
Post-study Therapy Response Status 
 
 
 
 
 
 
 
 
X 
 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Directed Physical Examination 
 
 
 
 
 
 
 
X 
X 
X 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG OR Karnofsky Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum b-HCG 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
PT/INR and aPTT 
 
X 
X 
X 
X 
X 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum Chemistry Panel‖ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDH and Uric acid 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Urinalysis 
 
X 
X 
X 
X 
X 
 
X 
 
 
 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
 
 
 
27
Study Period: 
Screening Phase 
Treatment Cycles 
Phase I: Induction 
Response  
Post- 
Induction 
Treatment Cycles 
Phase II: Maintenance 
Response 
Post-
Maintenance  
Post-Treatment 
Treatment Dose/Title 
Day (D) 
Pre-
screening 
Main Study 
Screening  
1 
(D1) 
2 
(D22) 
3 
(D43) 
4 
(D64) 
 
 
(D77) 
Doses 5 – 17 
(D85 - D365)* 
 
End of Treatment 
(D365) 
Follow-up: 30 and 90 
Days After Treatment 
up to D455† 
Relapse‡ 
Scheduling Window (Days): 
Days 
-21 to -1 
 
Days 
-21 to -1 
 
± 3 
± 3 
± 3 
± 3 
 
±7 
± 3 
 
± 14 
± 14 
n/a 
T3, FT4 and TSH 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Efficacy Measurements 
Bone Marrow Morphology§ 
 
 
 
D35 
(±5) 
 
 
X 
 
 
X 
 
 
X 
Bone Marrow Flow Cytometry§ 
 
 
 
D35 
(±5) 
 
 
X 
 
X 
 
X 
Bone Marrow Cytogenetics§ 
 
 
 
D35 
(±5) 
 
 
X 
 
X 
 
X 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Pre-transplant Bone Marrow Biopsy 
Specimen Collection 
 
X 
 
 
 
 
 
 
 
 
 
Correlative Studies: Bone Marrow 
Aspirate§ 
 
X 
 
D35 
(±5) 
   
 
X 
 
X 
 
X 
Correlative Studies: Blood Collection§,¶ 
 
X 
D14 
(+5) 
D35 
(±5) 
  D56 
(±5) 
 
X 
D168 (±7) 
D252 (±7) 
X 
D425 (±14)† 
X 
Correlative Studies: Buccal Swabs 
 
X 
 
 
 
 
 
 
 
 
 
Chimerism Analysis (VNTR) (Peripheral 
Blood)** 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
*Phase II Maintenance treatment: For subjects achieving CR / PR as determined by day 77 response post-induction without significant pembrolizumab related toxicity. Subjects without 
CR / PR at day 77, relapse / progression after day 77 or clinically significant toxicity during the treatment will be considered off treatment and will be placed into follow-up. 
†Follow up: Toxicity assessments will be for 30 days after last dose of pembrolizumab. Longer follow-up for up to 90 days, if applicable, based on continuing SAE / AE that was 
observed in the treatment period or an events of clinical interest (ECI). Follow up for survival will be up to 90 days after pembrolizumab or D455 (±14) for subjects completing 


Product:   Pembrolizumab 
Protocol/Amendment No.:  v2.0 
 
 
 
 
28
maintenance and a research blood collection will be obtained. Subjects not initiating or completing maintenance will complete 30 day toxicity assessments and then be followed only 
for survival (through D365 after initiating pembrolizumab). Subjects in CR/PR not completing maintenance for toxicity may have additional research specimens collected per 
investigators discretion (see below note). ‡ Relapse denotes collection of unplanned / unscheduled bone marrow aspirate, biopsy and correlative studies at time of clinical suspicion of 
relapse (if CR) or progression of malignancy at any time during treatment and follow-up periods.     
§Bone marrow morphology based on aspirate and/or core biopsy, flow cytometry and ± cytogenetics will be performed on day 35 (+5) after dose #2, day 77 (±7) after dose #4, day 365 
(±14) after completing maintenance. An end of treatment bone marrow may be performed prior to day 365 in subjects in CR/PR who do not complete full maintenance therapy due to 
toxicity. Subjects removed from further treatment due to documented relapse are not required to undergo further bone marrow studies for research purposes. Cytogenetic analysis may 
be omitted if there are not pre-treatment cytogenetic anomalies of clinical interest.    
‖Comprehensive Serum Chemistry Panel should include Magnesium and Phosphorus. 
¶ PK and anti-pembrolizumab Ab testing may be performed as a component of the research lab testing, as indicated.  These studies will be performed after collaboration with the 
sponsor (Merck) 
** Chimerism studies (lineage specific) when sent as part of routine care will be recorded as percentage of donor cells (CD3 and CD33).  
Note: Every effort will be made to collect bone marrow and blood samples for efficacy and correlative specimens for research purposes. Efficacy and correlative studies not obtained 
during the treatment and post-treatment for clinical reasons (e.g. intercurrent illness, leukemia progression receiving concomitant chemotherapy, myeloid sarcoma) will not constitute a 
protocol deviation. 


Product:   Pembrolizumab 
29 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
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 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 or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in advance of 
use.  The subject or his/her legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the trial.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor 
requirements. 
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.  


Product:   Pembrolizumab 
30 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
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.  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 and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the subject within 7 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.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during the trial.  
All medications related to reportable SAEs and ECIs should be recorded as defined in Section 7.2. 
7.1.1.5 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.  Once new anti-cancer therapy has been initiated the subject will move into 
survival follow-up.  
7.1.1.6 Assignment of Screening Number 
A screening number will be assigned to all subjected being screened. 
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 treatment and during the safety follow-up period (30 
days after the last dose of pembrolizumab) according to NCI CTCAE Version 4.0 (see Section 11.3. 
Adverse events in the post-treatment follow up period will not be recorded or reported unless they 
represent continuing adverse events from the treatment period related to pembrolizumab therapy. 


Product:   Pembrolizumab 
31 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
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 ECOG 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. As Karnofsky performance score is commonplace in BMT clinical practice and research, 
this scale is acceptable in place of ECOG (Appendix 11.2)   
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling   
See section 7.1.3.1.3 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below.  Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   


Product:   Pembrolizumab 
32 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
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)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


Product:   Pembrolizumab 
33 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
7.1.3.1 Pharmacokinetic/Pharmacodynamic  and Laboratory correlation Evaluations 
7.1.3.1.1 Blood Collection for Serum pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
The time points for PK blood sampling are described in Section 6 – Trial Flow Chart.  
7.1.3.1.2 Blood Collection for Anti-pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples will be provided in the Laboratory 
Manual. 
7.1.3.1.3  Laboratory Correlates 
The immunobiologic, neoantigen analyses, advanced studies for minimal residual studies, and flow and 
ex vivo studies will be performed in collaboration by Drs. Pavan Reddy’s and Brian Parkin’s labs with 
additional support from Dr. Arul Chinnaiyan’s lab.  
Lab correlates  
Assays 
Tissue/Body Fluid Tested 
and Timing of Assay 
Immune-antigen repertoire and inhibitory 
receptor analyses of AML cells and donor 
T cell exhaustion and functional analyses  
 
Whole exome sequencing of AML at 
relapse, 
Flow 
cytometry, 
tetramer 
analyses, cellular killing assays, MHC-
peptide binding affinity studies, PCR 
PBMC and BM: day 1 (pre-treatment),  ±14, 
35, 77, ±168, ±252, 365, ±425  , and at 
relapse/progression 
Functional T cell subtypes and cytokine 
profiles  
 
 
 
 
 
AML immune peptide repertoire analyses 
 
 
 
 
Characterization of T cell exhaustion 
Flow cytometry: Quantify activated and 
effector CD4+ and CD8+ cells, NK cells, 
senescent, exhaustion and regulatory T 
cells (CD45RA, CD45RO, CD127, CD25, 
CCR7, CD57, CD28, CD62L, CTLA4, 
LAG3 and Foxp3)  
Cytokine 
profiling: 
Intracellular 
IFN-γ 
(Th1), IL-4 (Th2), IL-17 (Th17), IL-2, and 
transcription factor profiling with Q-PCR 
for T-bet, Gata-3, RORγT, Foxp3  
• 
Whole exome sequencing (WES) of 
relapsed AML blasts 
• 
Characterize neoantigens 
• 
Bioinformatically 
nominate 
most 
immunogenic peptides 
• 
Functionally validate in silico the 
immunogenic 
potential 
of 
the 
peptides in the context of the donor 
MHC 
• 
Functionally validate in vitro the 
bioinformatically 
nominated 
PBMC and BM: day 1 (pre-treatment),  ±14, 
35, 77, ±168, ±252, 365, ±425  , and at 
relapse/progression 


Product:   Pembrolizumab 
34 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
 
Antigen specific T cell expansion 
 
Functional 
Antigen 
presenting 
cells 
subtypes and cytokine profiles  
 
immunogenic AML peptides by 
performing MHC-peptide binding 
affinity assays  
PD1, CTLA4, LAG3, TIM3, TIGIT 
Tetramer staining for leukemia specific 
(HLA-A2+ 
restricted 
WT1, 
PRAME, 
proteinase-3), hematologic cell specific 
minor antigen specific (HLA-B7 restricted 
LRH-1), and CMV (pp65). 
Quantify CD11c, CD1a, CD14, BDCA3, 
HLADR, 
CD40, 
CD80, 
CD86 
and 
intracellular IL-1β, TNFα, IL-10, IL-6 
 
T cell and NK cell cytotoxicity   
Plasma cytokines 
Intracellular CD107a, granzymeB (flow 
cytometry), flow cytometric analysis of 
tumor cell death  
TNFα, IL-6, IL-1β, IL-10, Reg3α, ST-2, 
TNFR1 
PBMC: day 1 (pre-treatment), ~d14 [before 
2nd dose of anti-PD-1], 35, 56, 77, ±168, 
±252, 
±365, 
±425 
and 
at 
relapse/progression 
Ex-vivo stimulation analyses 
Ex-vivo stimulation with specific peptides 
and DCs with ELISPOT, CFSE and 
CD107a  
PBMC: day 1 (pre-treatment), ~d14 [before 
2nd dose of anti-PD-1], 35, 56, 77, ±168, 
±252, 
±365, 
±425 
and 
at 
relapse/progression 
AML and MDS post-therapy clonal 
selection analysis 
High-sensitivity 
response 
assessment 
(genomic 
minimal 
residual 
disease 
detection)  
Droplet digital PCR (ddPCR) and single-
molecule/real-time (SMRT) sequencing of 
AML- and MDS-associated mutations in 
BM, PBMC, and cell-free DNA to: 
• Define and distinguish responsive 
and 
resistant 
AML 
clones 
via 
longitudinal analysis 
• Assess 
kinetics 
and 
depth 
of 
response 
to 
therapy 
at 
serial 
timepoints 
PBMC and BM: day 1 (pre-treatment),  ±14, 
35, 77, ±168, ±252, 365, ±425  , and at 
relapse/progression 
 
Sample collection: We will obtain 4 heparinized (green top) and 1 EDTA (purple top) blood samples (or 
approximately 35 mL total/sample) as well as bone marrow aspirates per schedule shown in the schema 
above. Buccal swabs will also be collected once prior to initiation of therapy for use as a normal DNA 
control for each patient. Plasma will be banked and frozen for analysis of anti-PD-1 antibody titers, 
cytokine analyses, and cell-free DNA as indicated. Leukocytes will be isolated by Ficoll gradient 
centrifugation and used for phenotypic and functional analyses described below. AML blasts will be 
analyzed for immune peptide repertoire analyses and as targets for ex vivo studies. For the purposes of 
this study, day 1 is defined as the first day of pembrolizumab.   
Statistics for correlative studies: The statistics will be descriptive in nature and hypothesis generating. 
However the analyses of leukemia from the bone marrow (BM) and both peripheral blood and BM derived 


Product:   Pembrolizumab 
35 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
T cells analyses at the time of relapse after allo-HSCT, post treatment with pembrolizumab at at 35, 77 
and 365 days will nonetheless serve as internal controls for assessing the impact of treatment on relapse, 
T cell functionality, immune neoantigen repertoire analyses, and depth and kinetics of response. 
However, the association of the laboratory values and percentage change of each variable and their 
relation to primary and secondary clinical outcomes will be descriptive and estimated with Cox regression 
(for response rate and PFS) and competing risks regression (TRM, relapse/progression).  
7.1.4 Other Procedures 
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.  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. 
7.1.4.2 Screening 
A subject will be considered to be in the “Screening” period from the time he/she signs consent until the 
date the subject is determined as either “eligible” or “ineligible” (screen failure) by PI or a Co-I. Patients 
may be consented to this study based on disease eligibility and other criteria at the time of consent, but 
later removed from the study if the change of disease status makes the subject “ineligible”. In the event 
that this occurs, the subject will be replaced.  
7.1.4.3 Treatment Period 
“Treatment Period” is defined as the first day of pembrolizumab through 30 days after the last dose of 
pembrolizumab – from 1st to 4th doses (or 17th dose if receiving maintnenance). The assessment and 
reporting period for adverse events (AE) related to the pembrolizumab will start from the first 
pembrolizumab administration until 30 days after the last pembrolizumab administration.  
“Follow-up Period” is defined as the first day the subject is no longer within the treatment period (e.g. 
31 days after last administration of pembrolizumab) until six months after date of initiating study treatment.  
 
7.1.4.4 Post-Treatment Visits 
7.1.4.4.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of 
trial treatment.  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 or until the beginning of a 
new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 30 days of the end of 
treatment or before initiation of a new anti-cancer treatment should also be followed and recorded.   


Product:   Pembrolizumab 
36 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
7.1.4.5 Follow-up Visits 
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 or if the subject begins retreatment with 
pembrolizumab as detailed in Section 7.1.4.5.1.   
Subjects in this trial will not be eligible for retreatment with pembrolizumab beyond the initial study phase.   
7.1.4.5.1 Survival Follow-up 
If a subject experiences a treatment related adverse event that necessitates their removal from further 
study treatment , starts a new anti-cancer therapy (non-protocol defined therapy), does not achieve after 
induction (phase I), develops progression during maintenance (phase II) or  or completes planned  
treatment phase the subject moves from treatment into the survival follow-up phase and will be followed 
at a minimum of every 8 weeks to assess for survival status until death, withdrawal of consent, or the end 
of the study (1 year after initiation of pembrolizumab or 90 days after last maintenance dose of 
pembrolizumab), whichever occurs first (please reference section 5.2.1.2 of this protocol regarding 
permitted chemotherapies on-protocol). These visits will be coordinated with routine BMT follow-up.  If 
follow-up is not feasible (e.g. patient leaves center) phone contacts will be made every 12 weeks.   
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 as prescribed 
in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after subject eligibility is confirmed but before treatment 
allocation/randomization must be reported by the investigator if they ultimately cause the subject to be 
excluded from initiating treatment on the trial, or are the result of a protocol-specified intervention, 


Product:   Pembrolizumab 
37 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of treatment, 
all non-hematologic grade ≥ III adverse events must be reported by the investigator. Investigators 
will monitor patients carefully for early evidence of transplant-related complications, such as 
hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile 
syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions. Such 
events will be recorded 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. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified procedure or 
intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first required to 
provide consent to the main study and AEs will be captured according to guidelines for standard AE 
reporting.  
 
7.2.1 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) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be excluded 
from the trial, or are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization through 120 
days following cessation of Sponsor’s product, or 30 days following cessation of treatment if the subject 


Product:   Pembrolizumab 
38 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator.  All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 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 an other important medical event  
• 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
Merck for collection purposes. 
o Is a new cancer (that is not a condition of the study); 
o Is associated with an overdose. 
Refer to Table 6 for additional details regarding each of the above criteria. For the time period beginning 
when the subject is enrolled until treatment is initiated, 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 
(reference Section 7.2.3.3 for additional details) 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. 
NOTE: for the purposes of this protocol planned hospitalizations solely for administration of protocol-
specified chemotherapy for tumor progression will not require expedited reporting.  For the time period 
beginning at treatment allocation/randomization through 30 days following cessation of treatment, 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 (reference Section 7.2.3.3 for additional details), whether or 
not related to the Merck product, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. 
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 following consent 
through the end of the specified safety follow-up period specified in the paragraph above, or at any time 
outside of the time period specified in the previous paragraph also must be reported immediately to the 
Sponsor and to Merck Global Safety. 


Product:   Pembrolizumab 
39 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
All subjects with serious adverse events must be followed up for outcome. 
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.  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. 
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.  When NOT deemed to be related to underlying leukemia, an elevated AST or ALT lab value that is 
greater than or equal to 5X 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 which changes CTCAE grade 


Product:   Pembrolizumab 
40 
Protocol/Amendment No.:  v2.0 
 
 
 
 
 
 
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. 


Product:   Pembrolizumab 
41 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
 
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 for an elective procedure to treat a pre-existing condition that has not worsened 
is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a 
Merck product and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 


Product:   Pembrolizumab 
42 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the 
Sponsor within 24 hours and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered 
a serious adverse event for collection purposes. 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 to the Sponsor and to Merck 
within 2 working days.. 
 
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 Merck product to be discontinued? 
Relationship 
to Merck 
Product  
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the AE; the 
greater the correlation with the components and their respective elements (in number and/or intensity), the more 
likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen? 


Product:   Pembrolizumab 
43 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
 
 
Time 
Course 
Did the AE follow in a reasonable temporal sequence from administration of 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 
 


Product:   Pembrolizumab 
44 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
 
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 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 Sponsor’s product; or (3) the trial is a single-dose 
drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge Was the subject re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO 
MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 
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. 


Product:   Pembrolizumab 
45 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
 
Record one of the 
following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative 
to the administration of Merck product is reasonable.  The AE is more likely explained by Merck 
product than by another cause. 
No, there is not a 
reasonable possibility of 
Merck product relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of Merck product is not reasonable OR the AE is more likely explained by another 
cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


Product:   Pembrolizumab 
46 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
 
 
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
The statistical plan for this feasibility study of pembrolizumab for relapse after HCT is primarily directed 
toward the primary objective of safety and feasibility after HCT. The trial will additionally estimate the 
proportion of patients responding to pembrolizumab monotherapy by overall response rate (ORR). The 
ORR (CR+PR) will also be estimated at day 35 and 77 for subjects receiving ≥ one dose of single agent 
pembrolizumab. If progression is noted subjects may receive standard induction chemotherapy. Subjects 
who are administered standard induction chemotherapy prior to day 77 (for any reason) will be considered 
non-responders for ORR of pembrolizumab monotherapy. However, we will perform a planned subset 
analysis to determine the ORR at day 77 for subjects receiving pembrolizumab followed by systemic 
chemotherapy.     
The incidence of grade 3-4 acute GvHD and significant (≥ grade 3) immune mediated toxicities will be 
estimated at the conclusion of the treatment period which is 30 days after the last dose of pembrolizumab. 
Overall survival (OS) and Disease Free Survival (DFS) at 12 months will be calculated by Kaplan Meier 
methods. The observation period for OS and DFS will begin at the confirmed date of relapse after HCT 
until death or last scheduled clinical follow up. These observations will assist in determining whether 
further investigations are warranted after HCT.     
8.2 
Statistical Analysis Plan 
8.2.1    As a phase 1b study, the analysis of results will be descriptive in nature. This study will estimate: 
- ORR at days 35 and 77 in subjects receiving pembrolizumab monotherapy  
- ORR at day 77 in subjects receiving pembrolizumab ± standard induction chemotherapy 
- Clinical Benefit Rate (CBR) at days 35 and 77 in subjects receiving pembrolizumab monotherapy 
Safety: 
-  Incidence and severity of GvHD after administration of pembrolizumab to include analysis of: 
a) incidence of severe acute GvHD events (grade 3-4) during induction treatment treatment and 
within 30 days of last pembrolizumab infusion during induction treatment (as described in 
sections 7.2 and 8.1). 
b) incidence of total GvHD events (acute GVHD grade 2-4, new onset chronic GVHD) that occur 
in subjects during treatment (both induction and maintenance) and in follow up through 90 days 
after last pembrolizumab infusion.  Subjects taken “off-study” will be censored if they receive 
other immune  therapies (e.g. DLI).   


Product:   Pembrolizumab 
47 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
- Grade 3-5 Regimen-related toxicities (RRT) per CTCAE v4 
- Incidence of immune mediated toxicities attributable to pembrolizumab  
 
8.2.2 Sample size estimate to assess if study drug is promising for further study 
Considering the highly refractory nature of the subjects to be enrolled in this study and our lack of 
understanding of the kinetics of response to pembrolizumab in the post HCT setting, the investigators 
will be cautious about the potential underestimation of response of this novel agent. In addition, several, 
but not all patients are expected to receive standard chemotherapy at some point during their on-study 
therapy, thereby potentially confounding interpretation of the response rate to study drug. Therefore, the 
following criteria will be used to assess if the study drug is promising for further study:  
(a) if ≥ 4 subjects demonstrate evidence of clinical benefit the drug will be considered promising. With 20 
subjects we would be 90% confident that the true clinical benefit rate (CBR) lies between 7% and 40%. 
The CBR  will be assessed on both day 35 and day 77 as determined by  the proportion of subjects who 
receive pembrolizumab monotherapy who achieve either stable disease (SD) or ORR prior to the addition 
of standard chemotherapy  
(b) the observation of any CRs seen in subjects not receiving standard chemotherapy will be considered 
promising.  
8.2.2.1 Definition of Response.  
For the purposes of this study, complete remission (CR) will be defined as achieving a morphologic 
leukemia free state by achieving all of the following criteria: bone marrow myeloblasts < 5% by 
morphologic assessment; AND absence of circulating blasts with phenotypic or morphologic features of 
leukemia (e.g. Auer rods) AND no evidence of extramedulary disease. For subjects with ≤ 5% blasts but 
possessing flow cytometric, cytogenetic or molecular aberration (Sec 5.1); CR will also require resolution 
(absence) of that aberration. Partial remission (PR) will be defined as a ≥ 50% reduction in bone marrow 
blast percentage to 5-25% or marrow blasts < 5% with persistent Auer rods, flow cytometric or cytogenetic 
disease. PR is not possible response designation for indivuals entering with ≤ 5% blasts. SD will be 
defined as ≤ 5% increase in blasts or decreased blast percentage in the bone marrow that does not meet 
the criteria for PR. Progression will be defined as >5% increase in bone marrow blast percentage from 
prior bone marrow aspirate. NOTE Given these patients have relapsed after allogeneic HCT blood count 
recovery is not considered at criteria for response in this protocol. 
8.2.3 Stopping rules for futility: Study subjects will receive pembrolizumab ± the addition of standard 
chemotherapy, therefore stopping rules for futility are not indicated. The primary endpoint of this study is 
safety and feasibility.  
8.2.4  Stopping rules for toxicity: Patients will be monitored closely for the development of immune-
mediated toxicity that may be attributable to pembrolizumab. For the purposes of this trial, we will consider 
the development of acute GvHD as a distinct entity from the known immune-mediated toxicity profile 
associated with PD1 blockade, though there may be clinical overlap. The impact of PD1 blockade on the 
development of acute GvHD following allogeneic HCT has not been studied in human subjects. 
Therefore, a rational approach will focus on whether there is an increase in the rates and severity of 


Product:   Pembrolizumab 
48 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
acute GvHD and other immune mediated toxicities over the expected baseline. The following 
assumptions will be used to assess potential toxicities associated with this trial: 
• 
All subjects will be inherently at risk for the development of GvHD as this study is limited to 
patients who have relapsed post-HCT. Although screening will exclude patients with active GvHD 
requiring immunosuppression, subjects will remain at risk independent of whether they receive 
study drug. The expected incidence of clinically significant grade 2 to 4 acute GvHD (requiring 
therapy) without Pembrolizumab is estimated to be 40-50%.  
• 
Patients who relapse (without GVHD present) may still be receiving standard immunosuppression 
post-HCT to reduce the risk of inciting GVHD. Immunosuppressive medications (IS)may be 
withdrawn or tapered per usual care. Because patients are at risk for the development of GVHD 
within several weeks after IS withdrawal tapering may occur during administration of 
pembrolizumab at a rate determined by the treating physician. Due to timing of IS withdrawal 
overlapping with the treatment period for pembrolizumab, potentially confounding its relationship 
to the study drug, an aggregate summary of toxicity will be used to determine whether PD1 
blockade is potentially associated with an increase in the severity of acute GvHD. 
• 
For the purposes of this study, toxicity will be deemed as excessive if 12 of 20 subjects (60%) 
develop severe acute GvHD (≥ grade 3-4) OR  ≥ grade 3 immune related adverse events that do 
not improve to grade 1 after systemic corticosteroid treatment for 14 days. This study specific 
stopping rule is intended to capture excessive rates of severe acute GvHD (grades 3-4) as an 
adverse safety signal.  We have set this threshold because some degree of GvHD is an 
anticipated consequence of usual withdrawal of immune-suppression and chemotherapy which 
is a current treatment standard for relapse.  Grade 2 GvHD is associated with less morbidity and 
mortality compared to grades 3-4 and may be a potential surrogate of a beneficial anti-leukemic 
response (GvL), thus grade 2 GvHD will be recorded but not included in the stopping definition.  
The occurrence of severe acute GvHD for this toxicity rule will be monitored during the induction 
treatment period until 30 days after the last induction treatment dose of pembrolizumab given for 
the induction phase (doses 1-4).  
• 
We will also make interim assessments after 10 and 15 patients have been observed for 30 days 
after the last induction dose of pembrolizumab. Specifically, further accrual will be halted if we 
observe at least 6 of 10 or 9 of 15 patients developing severe acute GvHD.  If the true rates of 
severe acute GvHD are 30%, 40%, 50% or 60%, the study has respective probabilities of 0.05, 
0.18, 0.43, and 0.71 of stopping early. 
• 
  
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. 
 


Product:   Pembrolizumab 
49 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
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.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the University of 
Michigan. 
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 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 Confidentiality 
Subject medical information obtained as part of this study is confidential, and must not be disclosed to 
third parties, except as noted below. The subject may request in writing that medical information be given 
to his/her personal physician. 
The Investigator will permit direct access to source data and documents by the FDA and/or other 
applicable regulatory authority. The access may consist of study-related monitoring, audits, IRB or Ethics 


Product:   Pembrolizumab 
50 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
Committee reviews, and FDA inspections. Release of research results should preserve the privacy of 
medical information and must be carried out in accordance with Department of Health and Human 
Services Standards for Privacy of Individually Identifiable Health Information, 45 CFR 164.508. 
10.2 Compliance with Financial Disclosure Requirements 
The sponsor, investigator and members of the study team will comply with all applicable regulations 
regarding financial disclosure requirements.  
10.3 Compliance with Law, Audit and Debarment 
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), the 
Declaration of Helsinki, Health Canada, any applicable local health authority, and Institutional Review 
Board (IRB) or Ethics Committee requirements. 
This study must have the approval of a properly constituted IRB or Ethics Committee. Before the 
investigational drug is shipped to the Investigator, the Investigator or designee will provide Merck with a 
copy of the IRB or Ethics Committee approval letter stating that the study protocol and any subsequent 
amendments and informed consent form have been reviewed and approved. 
The Investigator or designee will be responsible for obtaining annual IRB or Ethics Committee re-approval 
throughout the duration of the study. 
The Investigator is also responsible for notifying their IRB or Ethics Committee of any significant adverse 
events that are serious and/or unexpected. The Investigator is also required to notify the FDA in writing 
of any SAE that is both unexpected and related to the study drug, within 15 days of knowledge of the 
event, and within 7 days of a death related to the study drug. 
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 Quality Management System 
The following quality management systems at the University of Michigan will be performed in the conduct 
of this clinical trial.  
10.5.1  Data Safety Monitoring Plan 
The following are the procedures for data and safety monitoring of this clinical trial to be conducted at the 
University of Michigan Blood and Marrow Transplant program and sponsored by Merck, Inc. This is to 
ensure the safety of participants, the validity of research data, and the appropriate termination of studies 
for which significant benefits or risks have been uncovered or when it appears that the trial cannot be 


Product:   Pembrolizumab 
51 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
concluded successfully. This protocol will conduct a data and safety monitoring process as described in 
the plan below.  
10.5.2 Clinical Monitoring Plan 
This trial will be monitored in accordance with the NCI approved University of Michigan Comprehensive 
Cancer Center Data and Safety Monitoring Plan. 
 
The study team will provide continuous review of the data and patient safety and meet monthly or more 
frequently depending on the activity of the protocol. The discussion will include matters related to the 
safety of study participants (SAE/UaP reporting), validity and integrity of the data, enrollment rate relative 
to expectations, characteristics of participants, retention of participants, adherence to the protocol 
(potential or real protocol deviations) and data completeness. At these regular meetings, the protocol 
specific Data and Safety Monitoring Report form will be completed and signed by the Principal 
Investigator or by one of the co-investigators. 
 
Data and Safety Monitoring Reports will be submitted to the University of Michigan Comprehensive 
Cancer Center Data and Safety Monitoring Committee on a monthly basis for independent review. 
 
The University of Michigan Comprehensive Cancer Center Data and Safety Monitoring Committee can 
request a ‘for cause’ audit of the study if the committee identifies a need for a more rigorous evaluation 
of study-related issues. A “for cause” audit would be conducted by the Quality Assurance Review Core 
(QARC) of the University of Michigan Comprehensive Cancer Center.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its conduct 
or even after its completion. If an inspection has been requested by a regulatory authority, the site 
investigator must immediately inform the Clinical Trials Office that such a request has been made.  
10.5.3 Trained and Certified Personnel 
 
All of the research protocol personnel who will work with study subjects, study subject data or subjects’ 
research samples have completed training in the protection of human research participants per guidelines 
issued by the U. S. Department of Health and Human Services, Office of Human Research Protections. 
The documentation of completion of the certification is maintained in the Oncology Clinical Trials Support 
Unit (OCTSU). The investigator and designated associates have attended an IRB sponsored HIPAA 
research presentation in accordance with the policy of the study site. Each participant in this research 
trial will be listed by study specific numbers, without initials or date of birth; however, the date of transplant 
may be included when corresponding with the IRB or outside agencies. 
 
Designation of Responsibilities: The Principal investigator is solely responsible for the implementation, 
conduct and safety of human subjects enrolled in this trial. The principal investigator has however, 
designated associates to assist with the protocol implementation which includes but is not limited to the 
following: 
 
1. BMT Physicians – have been designated to assist with participant education, informed consent 
process, study implementation and compliance, recording of primary source documentation, AE 
assessment and reporting, adherence to all regulations. 


Product:   Pembrolizumab 
52 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
2.  BMT Research Nurse(s) - have been designated to assist with participant education, informed consent 
process, study implementation and compliance, recording of primary source documentation and 
adherence to all regulations. 
3. BMT Data Manager(s) - have been designated to assist with patient enrollment/eligibility, verification 
of protocol compliance, all data collection and recording from primary source, AE reporting, DSM reports 
and adherence to all regulations. 
4. BMT Clinical Team - The members of the BMT clinical team that have been designated to assist the 
investigator in any aspect of this protocol will be listed on the protocol specific designation log. 
5. The BMT program’s internal Data and Safety Monitoring Committee (BMT DSMC) will meet monthly 
to review the data, safety and monitoring reports and all SAEs that have been filed.  
 
Storage and Dissemination of Reports 
The Oncology Clinical Trials Support Unit (OCTSU) at the University of Michigan is responsible for 
collating all the Data and Safety Monitoring Reports and providing this information to Data Safety 
Monitoring Committee. The OCTSU will coordinate the reporting process between the Investigators, the 
Sponsor, the IRB and UMCCC DSMC as well as other applicable reporting agencies (FDA and study 
sponsors). Copies of all related correspondence and reporting documents will be maintained in a locked 
file by the OCTSU regulatory team and the research data file will be maintained in a file by the BMT data 
management team. 
 
Quality Assurance and Audits 
 
The Quality Assurance Review Committee (QARC) of the UMCCC performs quality assurance audits of 
investigator-initiated clinical trials. Audits provide assurance that trials are conducted in compliance with 
the protocol. Further, they ensure that study data are collected, documented and reported in compliance 
with Good Clinical Practices (GCP) Guidelines and regulatory requirements. A QARC audit of each 
clinical trial is conducted annually. All audit findings are reported by QARC to the UMCCC DSMB and 
the sponsor. The DSMB can also request QARC for a ‘for cause’ audit of the trial if the board identifies a 
need for a more rigorous evaluation of study-related issues. A regulatory authority (e.g. FDA) may also 
wish to conduct an inspection of the study, during its conduct or even after its completion. If an inspection 
has been requested by a regulatory authority, the investigator must immediately inform the OCTSU QA 
Team that such a request has been made. Audits of conduct of the clinical trial will also be conducted by 
the CRO to be determined by the sponsor. 
 
10.6 Data Management 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the web-based 
Velos data management system of the University of Michigan.  


Product:   Pembrolizumab 
53 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
11.0 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, 
J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern 
Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
11.2 KARNOFSKY PERFORMANCE SCALE (KPS)  
 
% 
Description 
100  
Normal, no complaints, no evidence of disease  
90  
Able to carry on normal activity, minor symptoms of disease  
80  
Normal activity with effort, some signs of symptoms of disease  
70  
Cares for self (consistent with age), unable to carry on normal activity or do active 
work/school/play  
60  
Requires occasional assistance (beyond age-appropriate care), but is able to care for 
most of their needs  
50  
Requires considerable assistance and frequent medical care  
40  
Disabled, requires special care and assistance  
30  
Severely disabled, hospitalization is indicated although death is not imminent  
20  
Hospitalization is necessary, very sick, active support treatment is necessary  
10  
Moribund, fatal processes progressing rapidly 
 
 
11.3 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
4.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 


Product:   Pembrolizumab 
54 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
12.0 REFERENCES 
1. 
Pasquini MC, Wang Z, Horowitz MM, Gale RP. 2010 report from the Center for International Blood 
and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell 
transplants for blood and bone marrow disorders. Clinical transplants 2010:87-105. 
2. 
Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 
2008;112:4371-83. 
3. 
Tomblyn M, Lazarus HM. Donor lymphocyte infusions: the long and winding road: how should it be 
traveled? Bone Marrow Transplant 2008;42:569-79. 
4. 
Warlick ED, DeFor T, Blazar BR, et al. Successful remission rates and survival after lymphodepleting 
chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic 
hematopoietic cell transplantation. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation 2012;18:480-6. 
5. 
Bishop MR. Donor lymphocyte infusion: beauty is in the eye of the beholder. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 
2013;19:849-50. 
6. 
Bar M, Sandmaier BM, Inamoto Y, et al. Donor lymphocyte infusion for relapsed hematological 
malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial 
CD3+ T cell dose. Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation 2013;19:949-57. 
7. 
Reddy P, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara JLM. A crucial role for antigen-
presenting cells and alloantigen expression in graft-versus-leukemia responses. Nature Medicine 
2005;11:1244-9. 
8. 
Toubai T, Mathewson N, Reddy P. The role of dendritic cells in graft-versus-tumor effect. Frontiers 
in immunology 2014;5:66. 
9. 
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer 
suppression and promotion. Science 2011;331:1565-70. 
10. Chakraverty R, Sykes M. The role of antigen-presenting cells in triggering graft-versus-host disease 
and graft-versus-leukemia. Blood 2007;110:9-17. 
11. Andersen MH. The targeting of immunosuppressive mechanisms in hematological malignancies. 
Leukemia 2014;28:1784-92. 
12. Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 
2014;27:1-7. 
13. Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and 
PD-1 pathways. Immunological reviews 2008;224:166-82. 
14. Johnson TS, Munn DH. Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor 
tolerance. Immunological investigations 2012;41:765-97. 


Product:   Pembrolizumab 
55 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
15. Munn DH. Blocking IDO activity to enhance anti-tumor immunity. Frontiers in bioscience (Elite 
edition) 2012;4:734-45. 
16. Munn DH. Indoleamine 2,3-dioxygenase, Tregs and cancer. Current medicinal chemistry 
2011;18:2240-6. 
17. Greaves P, Gribben JG. The role of B7 family molecules in hematologic malignancy. Blood 
2013;121:734-44. 
18. Beatty GL, Smith JS, Reshef R, et al. Functional unresponsiveness and replicative senescence of 
myeloid leukemia antigen-specific CD8+ T cells after allogeneic stem cell transplantation. Clinical 
cancer research : an official journal of the American Association for Cancer Research 2009;15:4944-
53. 
19. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews Cancer 
2012;12:252-64. 
20. Pen JJ, Keersmaecker BD, Heirman C, et al. Interference with PD-L1/PD-1 co-stimulation during 
antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene therapy 
2014;21:262-71. 
21. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-
tumor immunity. Curr Opin Immunol 2012;24:207-12. 
22. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. The New England journal of medicine 2012;366:2443-54. 
23. Norde WJ, Maas F, Hobo W, et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment 
in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer research 
2011;71:5111-22. 
24. 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;114:1528-36. 
25. Zhou Q, Munger ME, Veenstra RG, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell 
exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 
2011;117:4501-10. 
26. Munir S, Andersen GH, Met O, et al. HLA-restricted CTL that are specific for the immune checkpoint 
ligand PD-L1 occur with high frequency in cancer patients. Cancer research 2013;73:1764-76. 
27. Ahmad SM, Larsen SK, Svane IM, Andersen MH. Harnessing PD-L1-specific cytotoxic T cells for 
anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 
pathway. Leukemia 2014;28:236-8. 
28. Zhong RK, Loken M, Lane TA, Ball ED. CTLA-4 blockade by a human MAb enhances the capacity 
of AML-derived DC to induce T-cell responses against AML cells in an autologous culture system. 
Cytotherapy 2006;8:3-12. 


Product:   Pembrolizumab 
56 
Protocol/Amendment No.:  v2.0 
 
 
  
 
 
29. Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat relapse of 
malignancy after allogeneic hematopoietic cell transplantation. Blood 2009;113:1581-8. 
30. Fevery S, Billiau AD, Sprangers B, et al. CTLA-4 blockade in murine bone marrow chimeras induces 
a host-derived antileukemic effect without graft-versus-host disease. Leukemia 2007;21:1451-9. 
31. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 
(MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic 
correlates. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2010;28:3167-75. 
 

ICF_001.pdf: 
ID: UMCC 
2017.056 
    Augmentation of the Graft vs. Leukemia Effect Via 
Checkpoint Blockade With Pembrolizumab 
    NCT03286114 
 


Page 1 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
INFORMATION ABOUT THIS FORM
You may be eligible to take part in a research study.  This form gives you important information about the study. 
It describes the purpose of the study, and the risks and possible benefits of participating in the study.  
Please take time to review this information carefully.  After you have finished, you should talk to the researchers 
about the study and ask them any questions you have.  You may also wish to talk to others (for example, your 
friends, family, or other doctors) about your participation in this study.  If you decide to take part in the study, you 
will be asked to sign this form.  Before you sign this form, be sure you understand what the study is about, 
including the risks and possible benefits to you.
1. GENERAL INFORMATION ABOUT THIS STUDY AND THE RESEARCHERS
1.1 Study title: Augmentation of the Graft vs. Leukemia Effect via Checkpoint Blockade with Pembrolizumab for 
Relapse of Primary Malignancy after Allogeneic Hematopoietic Stem Cell Transplant: A Feasibility Study. (UMCC # 
2017.056)
1.2 Company or agency sponsoring the study: University of Michigan
1.3 Names, degrees, and affiliations of the researchers conducting the study:
John Magenau, MD
Division of Hematology/Oncology, Internal Medicine; University of Michigan
2. PURPOSE OF THIS STUDY
2.1 Study purpose:
Allogeneic stem cell transplantation, also known as bone marrow transplant or BMT, is an effective treatment of 
leukemia, even in advanced stages. Studies have shown, however, that in many patients their leukemia comes 
back after receiving a stem cell transplant. 
This research study is designed to test the safety and effectiveness of increasing immune system responses using 
the drug, pembrolizumab, to see whether pembrolizumab, can help patients with Acute Myeloid Leukemia (AML), 
Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) whose cancer has come back (relapsed) 
after allogeneic transplantation. 
Pembrolizumab is also known as Keytruda®. It was developed by the pharmaceutical company, Merck & Co., Inc., 
and has been approved by the United States Food & Drug Administration (FDA) for treatment in patients with 
many types of cancer, including skin, lung cancer, bladder cancer, and lymphoma. Pembrolizumab has not been 
approved for use in people with your type of cancer. It is an experimental drug in this research study because this 
is one of the first studies to evaluate pembrolizomab in this setting.
3. INFORMATION ABOUT STUDY PARTICIPANTS (SUBJECTS)
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  You may 
also leave the study at any time.  If you leave the study before it is finished, there will be no penalty to you, and 
you will not lose any benefits to which you are otherwise entitled. 
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 2 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
3.1 Who can take part in this study?
You are being asked to take part in this research study because you are at least 18 years of age and have Acute 
Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), or Myelodysplastic Syndrome (MDS) that has 
relapsed after you had a BMT.
3.2 How many people (subjects) are expected to take part in this study?
During this study, we expect to enroll about 20 people who will participate at the University of Michigan.
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
The study team will explain the research study and answer any questions you have about the study.  If you still 
want to participate in the study the study team will request you sign the consent form prior to any activities 
occurring that pertain to the study.  Once your consent is obtained, the study team will look through your medical 
chart, ask you questions, and begin scheduling tests and procedures to determine if you are eligible for the study.  
The study team will inform you of the types of tests and procedures required before the study begins.  
Once it is determined you are eligible to enter the study, tests and procedures done at your study visits as part of 
your regular cancer care will continue, but some may be done more often because you are participating in this 
research study.  Also, some of the tests or procedures may have to be repeated if, for example, they were done 
too long ago or the results are not normal. 
Some tests and procedures may be done that are not part of your regular cancer care and are being done only for 
this research study.  Tests and procedures that are performed more often or are not part of your standard cancer 
care will be identified below as “Research”.  
Study Procedures
Screening Phase: 
After you have signed this Informed Consent, you will have the following tests and procedures to determine 
whether you are eligible to take part in this research study.  These tests can be done up to 2 weeks (14 days) 
before your first dose of pembrolizumab. These tests are routinely performed in individuals who have 
experienced relapse after BMT.

Review of Medical History: You will be asked about previous diseases and surgeries that you have had 
and about your current disease and treatment. 

Review of Prior and Current Medications: You will be asked about medications you have taken or are 
currently taking including prescription and over the counter medication, vitamins, and herbal 
supplements.

Physical Examination

Vital Signs: Your temperature, pulse, respiratory rate, weight, blood pressure, and height will be 
measured.

Performance Status: You will be asked about your ability to perform everyday tasks.

Pulse Oximetry: Measuring the amount of oxygen in your blood by an easy and painless reading from 
your finger

Routine Blood Tests (approximately ½ tablespoon):
o
Hematology: tests for blood cell count, coagulation studies
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 3 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
o
Chemistry: tests for kidney and liver function
o
Thyroid: tests for thyroid function

Routine Urinalysis

Pregnancy Test (Women of child-bearing potential only): A serum or urine pregnancy test will be 
performed within 72 hours before your first dose of pembrolizumab.

Bone Marrow: A bone marrow biopsy and aspirate will be taken for disease assessment.

Research Blood Tests (approximately 1 tablespoon)
o
Pharmacokinetics (PK): to see what your body does to pembrolizumab
o
Correlative studies: to check the status of you and your donor’s immune system.

Research Buccal Swab: Your cheek will be swabbed.
Study Drug Dosing
All subjects in this research study will begin by receiving Phase I which is 200 mg of pembrolizumab intravenously 
(directly into a vein) over 30 minutes every 3 weeks for up to 4 cycles (12 weeks). Each study cycle is 21 days. 
Approximately 2 weeks after your 2nd dose (Day 35) of pembrolizumab, your response to the study drug will be 
assessed. If your disease is responding to the pembrolizumab, you will receive 2 more infusions. If your disease is 
not responding, you will not receive the two additional infusions of pembrolizumab in Phase I. Your doctor will 
discuss other treatment options at this time (e.g. chemotherapy).
About 2 weeks after your 4th dose or Day 77, your response to the study drug will be assessed. If you are 
tolerating the pembrolizumab and it is helping you by controlling your disease, you may continue to receive 
pembrolizumab every 3 weeks for up to an additional 13 doses (Phase II).
Phase I - Induction Phase
You will have the following tests and procedures on Day 1 of every study cycle performed during this phase of the 
study:

Review of Adverse Events

Physical Examination

Vital Signs: Your temperature, pulse, respiratory rate, weight, and blood pressure will be measured.

Performance Status: You will be asked about your ability to perform everyday tasks.

Routine Blood Tests (approximately ½ tablespoon) for blood cell counts, coagulation studies, and to 
assess kidney, liver, and thyroid function. 

Routine Urinalysis

Serum or Urine Pregnancy Test (Women of child-bearing potential only)

Bone Marrow Aspirate:  Approximately two weeks (Study Day 35) after your second infusion of 
pembrolizumab, you will have a bone marrow procedure to assess your disease.

Research Blood Tests (approximately 1 tablespoon): Study Days 14, 35, and 56
o
Pharmacokinetics (PK)
o
Correlative studies 

Pembrolizumab infusion: You can receive up to 4 doses of pembrolizumab during the induction phase, 
depending on the results of the bone marrow on Day 35. If your disease is responding to the 
pembrolizumab, you will receive 2 more infusions. If your disease is not responding, you will not receive 
any additional doses of pembrolizumab during this phase.
Response after Phase I (Induction)
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 4 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
On Study Day 77, or about two weeks after Cycle 4 of Phase I, you will have the following tests and procedures 
performed:

Review of Current Medications and Adverse Events

Physical Examination

Vital Signs: Your temperature, pulse, respiratory rate, weight, and blood pressure will be measured.

Performance Status: You will be asked about your ability to perform everyday tasks.

Routine Blood Tests (approximately ⅓ tablespoon) for blood cell counts and to assess kidney and liver 
function.

Pregnancy Test (Women of child-bearing potential only): A serum or urine pregnancy test will be 
performed within 72 hours of your first dose of pembrolizumab.

Bone Marrow Aspirate: for disease assessment

Research Blood Tests (approximately 1 tablespoon)
If you are tolerating the pembrolizumab and your bone marrow assessment shows it is helping you, you may 
continue to receive pembrolizumab every 3 weeks for up to an additional 13 doses or until either your disease 
progresses, you have an unacceptable toxicity, or you are removed from the study for another reason.
If your bone marrow assessment shows that the pembrolizumab is not helping you, you will not receive any 
additional doses of pembrolizumab and will enter the Follow-up Phase of the study described below.
If you only received 2 infusions of pembrolizumab during the Induction Phase (Phase I) but your bone marrow 
assessment shows that the study drug was helping you, you may be considered for additional doses of 
pembrolizumab. Your study doctor will discuss this with you.
Phase II – Maintenance Phase
If your disease assessment on Day 77 shows a response, you may continue to receive pembrolizumab. This is the 
Phase II or Maintenance Phase of this research study. During the Maintenance Phase, you will have the following 
tests and procedures performed:

Review of Adverse Events

Physical Examination

Vital Signs and Weight

Performance Status: You will be asked about your ability to perform everyday tasks.

Routine Blood Tests (approximately ⅓ tablespoon) for blood cell counts and to assess kidney, liver, and 
thyroid function.

Routine Urinalysis

Research Blood Tests (approximately 1 tablespoon): On Day 168 (Dose 9) and Day 252 (Dose 13)
o
Pharmacokinetics (PK)
o
Correlative studies 

Pembrolizumab infusion: You can receive up to 13 additional doses of pembrolizumab during the 
maintenance phase as long as you continue to tolerate the study drug and it continues to help you.
** You will not receive additional doses of pembrolizumab after you complete the Maintenance Phase.
Post-Maintenance
Approximately 2 weeks after your last dose of pembrolizumab, you will have the following tests and procedures:

Review of Adverse Events

Physical Examination
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 5 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020

Vital Signs and Weight

Routine Blood Tests (approximately ⅓ tablespoon) for blood cell counts and to assess kidney and liver 
function.

Bone Marrow Aspirate: for disease assessment

Research Blood Tests (approximately 1 tablespoon)
Follow-Up Phase
You will return to the University of Michigan Cancer Center 30 days and and 90 days after your last infusion of 
pembrolizumab for the following tests and procedures:

Review of Adverse Events

Physical Examination

Vital Signs and Weight

Routine Blood Tests (approximately ⅓ tablespoon for blood cell counts and to assess kidney and liver 
function.

Research Blood Tests (approximately 1 tablespoon)
Relapse
If your disease shows signs of progression any time while you are taking pembrolizumab or while you are in the 
follow-up phase, you will have a bone marrow aspirate and research blood samples (1 tablespoon) collected.
Research Studies
Tests will be performed on your blood and bone marrow samples to assess your disease and your immune 
response. Some of the testing may include genetic testing.  Genes carry information about features found in you 
and people who are related to you, such as eye or hair color. The researchers are interested in the way that genes 
affect how your body responds to the therapy at different time points. 
Your blood samples that are collected for correlative studies will be frozen and stored. All of the frozen samples 
will then be tested for the protocol specified testing at the same time at the end of the study. Samples will be 
identified with your subject study ID number. The University of Michigan study team will have access to the code 
linking your subject study ID number with your personal information. Your samples will not be shared with 
researchers outside of the University of Michigan.
Optional Studies
We would like your permission to store your blood and/or bone marrow samples leftover from the protocol 
specified testing noted above for future research. The future research may be similar to this study or may be 
completely different. You can take part in this study even if you do not agree to let us store your unused blood 
and/or bone marrow samples for future research. 
If you give us your permission, we will store your unused blood and/or bone marrow samples in at the University 
of Michigan for 10 years. Even if you give us your permission now to keep your unused samples, you can change 
your mind later and ask us to destroy them by telling your study doctor or a member of the study team. Keep in 
mind, however, that all protocol specified testing must be completed on your samples before they are destroyed. 
Also, the results of any non-protocol specific testing that has already been completed or is in progress at the time 
of your request will still be used to preserve the integrity of the research.
Your unused blood and/or bone marrow samples will not be shared with researchers outside of the University of 
Michigan.
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 6 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
For an explanation of the risks associated with this future research, please refer to Genetic Information 
Nondiscrimination Act (GINA) and Privacy and confidentiality risks in Section 5.1 below. 
You will not find out the results of future research on your unused blood and/or bone marrow specimens. 
Allowing us to store and use your samples for future research will not benefit you directly. 
The University of Michigan may benefit financially from future research on your blood and/or bone marrow 
samples.
You will make your choice about giving your permission to store your unused blood and/or bone marrow samples 
in Section 12 of this Informed Consent.
The table on the next page shows another way of looking at the tests and procedures you will have at each study 
visit.
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 7 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
Study Period
Screening
Phase I: Induction
Response 
Post-
Induction
Phase II: 
Maintenance1
Post-
Maintenance1
Follow-Up
Study Dose/Study Day (D)
Days 
-14 to -1
1 
(D1)
2 
(D21)
3 
(D42)
4 
(D63)
(D77)
Doses 5-17 
(D84-D365)
End of dosing 
(D365)
30 and 90 
Days after 
last dose
Relapse
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
Review Adverse Events
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
Vital Signs and Weight (Height measured at 
Screening only)
X
X
X
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
X
Pregnancy Test (urine or serum)
X
X
X
X
X
X
Routine Hematology Blood Tests
X
X
X
X
X
X
X
X
X
Routine Coagulation Blood Tests
X
X
X
X
X
Routine Chemistry Blood Tests
X
X
X
X
X
X
X
X
X
Routine Urinalysis
X
X
X
X
X
X
Routine Thyroid Function Blood Tests
X
X
X
X
X
X
Bone Marrow Biopsy and/or Aspirate
X
D35*
X*
X*
X
Research Blood Tests – PK and Correlative 
Studies
X
D35
X
D1682
D2523
X
D4254
X
Research Buccal Swabs
X
Study Drug Administration
X
X
X5
X5
X
Post- Study Therapy Response Status
X
Survival Status
X
X6
1: For subjects showing a response after Day 77. Subjects not showing a response will proceed to the Post-Dosing (Follow-up Phase).
2: Dose 9
3: Dose 13
4: 60 days after last dose of pembrolizumab
5: Only if D35 bone marrow showed pembrolizumab was helping you
6: Will continue for every 8 or 12 weeks
*Bone Marrow Aspirate
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 8 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
Subject Responsibilities
As a subject participating in this research study, you have the following responsibilities. You should: 

Follow directions from the study staff.

Make and keep study appointments.

Give blood samples and urine samples.

Tell the study staff about all of the medicines you take during the study.

Tell the study staff about any changes to your health during the study.

Not be part of any other research study while participating in this study.

If you are female, you should not get pregnant or breastfeed a baby while in this study and for at least 120 
days after your last dose of study drug.

If you are a female of child bearing potential, you must agree to the use of two highly effective methods 
of contraception while in this study and for at least 120 days after your last dose of study drug. Your study 
doctor will discuss acceptable methods of contraception with you.

If you are a male, you should not conceive a child with a female partner or donate sperm while in this 
study and for at least 120 days after your last dose of study drug.

If you are a male capable of conceiving a child with a female partner, you must agree to the use of two 
highly effective methods of contraception while in this study and for at least 120 days after your last dose 
of study drug. Your study doctor will discuss acceptable methods of contraception with you.
4.2 How much of my time will be needed to take part in this study? 
Visit
Number of Visits
Approximate Time of Visit
Screening
1
6 - 8 hours
Phase I: Induction
   Day 35 (bone marrow)
4
1
2 - 4 hours
1 - 3 hours
Response: Post-Induction
1
3 - 5 hours
Phase II: Maintenance
13
2 - 4 hours
Response: Post-Maintenance 
(End of Dosing)
1
3 - 5 hours
Follow-Up (30, 60, 90 days after 
last dose)
3
0.5 - 3 hours
Survival Follow-up clinic visit or
Phone call
Every 8 weeks
Every 12 weeks
1 - 3 hours
10 - 15 minutes
4.3 When will my participation in the study be over? 
After you have completed the study procedures described in Section 4.1, you will be followed approximately 
every 8 weeks as part of your routine bone marrow transplant follow-up. If you are no longer able to come to the 
clinic for your follow-up visits, you will be contacted by phone every 12 weeks to check on your health status. We 
will check on the status of your health until death, withdrawal of consent, or the end of the study. 
4.4 What will happen with my information and/or biospecimens used in this study?
Your collected information and biospecimens may be shared with others at Michigan Medicine. 
Your collected information and biospecimens may also be shared with other researchers, both here or 
around the world, or with companies. 
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 9 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
Additionally:

With appropriate permissions, your identifiable collected information and biospecimens may be 
shared, and/or,

Without your additional consent, your identifiable private information and identifiable 
biospecimens may be stripped of identifiers and used for future research studies or distributed to 
another researcher for future research studies
5.  INFORMATION ABOUT RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me against these 
risks?
Your study doctor and study staff will monitor you closely for side effects. Even with frequent blood tests and 
other examinations, taking the study drug involves risks, and some side effects cannot be predicted. Side effects 
can range from mild to severe and life-threatening. Many side effects will get better when you stop taking the 
study drug, but some may be long lasting or may never go away. Side effects may even cause death. You should 
tell your study doctor immediately about any side effects that you have or any change in how you feel while on 
this study. If you have side effects, your dose may have to be reduced, or you may have to stop taking the drugs 
and wait until you feel better before you start again. Your health care team may give you medicines or lower your 
dose of drugs to help lessen side effects.  If any side effect is intolerable, you may have to permanently stop taking 
the drugs.
 These risks will be minimized by:
We will minimize the risks by monitoring you carefully. We will provide the usual supportive care that would be 
routinely given to someone with your condition. If you have side effects from the investigational study treatment, 
we will make appropriate adjustments as defined by the study protocol. You may need to discontinue the 
investigational study treatment if the side effects are too serious.  If you have signs of infection, you will receive 
appropriate antibiotics.  If you have signs of bleeding you may need to receive transfusions of platelets, plasma, or 
red cells. If you start feeling sick to your stomach, you will be given medications to help reduce nausea. If you 
have vomiting, you may be given fluids through an IV.
Pembrolizumab:
Pembrolizumab/KEYTRUDA® is being studied by researchers and physicians at the University of Michigan to see if 
it is effective in treating various types of cancer, by itself or in combination with other therapies (e.g. 
chemotherapy) and to see what side effects are associated with its use.
As of 03–Sep-2016, pembrolizumab/KEYTRUDA® had been given to about 21,036 subjects with various cancers in 
clinical trials. Men and women with cancer were treated, some for up to approximately 2 years. Safety was 
studied across several cancers treated with different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 2 or 3 weeks, 
and 200 mg fixed dose every 3 weeks Which is the FDA approved dosage. The side effects seen were similar.
Very Common side effects seen in ≥20% of subjects who received pembrolizumab:

Itching of the skin

Loose or watery stools

Cough
Common side effects seen in ≥10% to 20% of subjects who received pembrolizumab:
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 10 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020

Joint pain

Fever

Back pain

Rash
Common side effects seen in ≥1% to <10% of subjects who received pembrolizumab:

Not enough thyroid hormone so you may feel tired, gain weight, feel cold, have infrequent or hard stools

Too much thyroid hormone so you may feel anxious, angry, can’t sleep, weak, tremble, sweat, tired, have 
loose and watery stools

Inflammation of the lungs so you may feel short of breath and cough. Rarely this might lead to death.

Inflammation of the bowels/gut that may cause pain in your belly with loose or watery stools

Inflammation of the skin so you may have peeling of the skin, itching, skin redness

Pain in your belly

Loss of skin color

Low level of salt in the blood that may cause you to feel tired, confused, headache, muscle cramps or sick 
to your stomach

Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or sick to your 
stomach at the time of receiving your infusion (IV) or just after, or pain at the site of infusion.
Common serious side effects seen in 1% to 4% of subjects who received pembrolizumab:

Inflammation of the lungs so you may feel short of breath and cough. Rarely this might lead to death

Inflammation of the bowels/gut that can cause pain in your belly with loose or watery stools

Fever
Immune-mediated serious side effects seen in <1.0% of subjects who received pembrolizumab:

Inflammation of the skin so you may have widespread peeling of the skin, itching, and skin redness.  More 
severe skin reactions may involve the inside of your mouth, the surface of your eye and genital areas, 
and/or may cause the top layer of your skin to peel from all over your body which can cause severe 
infection.  Rarely these reactions lead to death.

Inflammation of the liver that may cause a poor appetite, feeling tired, mild fever, muscle or joint aches, 
sick to your stomach and vomiting, pain in your belly, yellow eyes and skin, and dark urine

Inflammation of the pituitary gland (a gland in the head), which may cause headaches, sick to your 
stomach, changes in behavior, double vision, few to no menstrual cycles, weakness, vomiting and 
dizziness or fainting.

Adrenal glands (glands on top of the kidneys) may not make enough hormone causing tiredness, weight 
loss, muscle weakness, feeling faint, joint, muscle and abdominal aches, nausea, vomiting, loose or watery 
stools, fever, salt craving, and sometimes darkening of the skin like a suntan.

Inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, swelling and low 
back pain

Inflammation of the muscles so you may feel weak or pain in the muscles

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels) so you may have 
severe pain in the top part of your belly that may move to the back, sick to your stomach, and vomiting 
that gets worse when you eat

Inflammation of the eye so you may have redness of the eye, blurred vision, sensitive to light, have eye 
pain, see floaters or have headaches
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 11 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020

Too much sugar in your blood (diabetes), so you may feel thirsty, and are likely to need regular insulin 
shots

Inflammation of the nerves that may cause pain, weakness or tingling in the hands and feet, and may 
spread to the legs, arms and upper body leading to severe muscle weakness and possible temporary 
paralysis. 

Inflammation of the middle layer of your heart wall (myocarditis) that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of breath and 
swelling of the legs.  You may experience a fast or irregular heartbeat that may cause dizziness or fainting.  
Sometimes this condition can lead to death
Additional serious side effects seen in <1.0% of subjects who received pembrolizumab:

Dizziness or fainting (low blood pressure), flushing, rash, fever, shortness of breath or sick to your 
stomach at the time of receiving your infusion (IV) or just after, or pain at the site of infusion.
In addition to the above, the following side effect(s) have been seen in patients on pembrolizumab, but are still 
being evaluated to determine if they are related to the drug:
A condition where you will feel weakness and fatigue of your hip and thigh muscles and an aching back caused by 
your body’s immune system attacking your healthy cells and tissues.
Additional Risk:
Some patients have experienced neutropenia, immune-mediated skin adverse reactions including, Stevens-
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). 
Some of the symptoms listed in the sections above have been reported to occur simultaneously in patients treated 
with pembrolizumab. For example, Vogt-Koyanagi-Harada (VKH) syndrome is a grouping of symptoms including 
headache, loss of vision, eye pain, sensitivity to light, neck stiffness, hearing problems, and dizziness, that is 
caused by immune system activation against certain cells in the body. You should report any symptoms to the 
study team.
Potential Additional Risk
A potential added risk related to your transplant is the possibility that Pembrolizumab may increase your risk of 
graft-versus-host disease (GVHD) which could require treatment or be life threatening. You may develop GVHD 
anyway as a result of your transplant, as it is the most common, serious risk for your type of transplant. GVHD can 
occur in up to approximately 50% of patients after transplant and in severe cases that do not respond to 
treatment can result in death. GVHD has also been associated with less relapse of AML after transplant in some 
studies.
Risks of Study Procedures
Blood Draws
Collection of blood samples may cause pain, bleeding, bruising or infection. It is also possible that you may feel 
lightheaded or faint. Please tell your study doctor or the study nurse if you do not feel well after having your 
blood drawn at any time during your study participation.
Bone Marrow Aspiration
A bone marrow aspiration is a test involving a thin, hollow needle to withdraw a small amount of bone marrow, 
usually taken from the hip bone. Although the procedure includes the use of medications to decrease any pain 
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 12 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
associated with the test, you may still experience some pain or discomfort. A potential but uncommon risk is the 
development of infection of the skin or underlying bone.  You may also have some bleeding from the site.
Reproductive Risks
Women
If there is ANY chance that you can get pregnant, you must either agree to not have vaginal intercourse or you 
must use TWO types of birth control (one from each list below) AT THE SAME TIME. These birth control methods 
must be used from the time of enrollment, all during treatment including during temporary breaks from therapy, 
and for at least 120 days your last dose of study intervention. The following methods are considered acceptable 
birth control methods:
Primary forms 
Secondary forms
• tubal sterilization (tubes tied) 
•male latex condom with or without spermicide
• partner’s vasectomy 
•diaphragm with spermicide
• intrauterine device 
•cervical cap with spermicide
• hormonal contraceptives - (includes 
•vaginal sponge (contains spermicide)
transdermal patch, injectables, implantables)
Any birth control method can fail. The reports of birth control failing are more frequent for female patients who 
use only a single form of birth control. Using two forms of birth control at the same time greatly reduces the 
chances of pregnancy.
If you become pregnant while taking pembrolizumab, you will be removed from the study. Your pregnancy will be 
monitored until your pregnancy has been completed or terminated. The outcome of your pregnancy will be 
reported to Merck, the supplier of pembrolizumab.  
Men
Men must agree to either abstain from sexual activities that could result in pregnancy or use an acceptable form 
of birth control while taking part in the study and for at least 120 days your last dose of study intervention. 
Acceptable forms of birth control are male latex condom (with or without spermicide) or vasectomy. In addition, 
men should not donate sperm or semen while taking part in the study and for at least 120 days your last dose of 
study intervention.
If your partner becomes pregnant while you are taking pembrolizumab, you must notify the study doctor right 
away. The study doctor will request permission to follow the pregnancy to outcome. Your partner will be required 
to sign a separate pregnant partner consent before any information is collected.  
Genetic Information Nondiscrimination Act (GINA)
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic 
information.  This law does not protect you against genetic discrimination by companies that sell life insurance, 
disability insurance, or long-term care insurance.  Under this law:

Health insurance companies and group health plans may not request your genetic information that we 
obtain from this research

Health insurance companies and group health plans may not use your genetic information when making 
decisions regarding your eligibility or premiums
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 13 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020

Employers with 15 or more employees may not use your genetic information that we obtain from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment
GINA does not apply to the following groups, however these groups have policies in place that provide similar 
protections against discrimination:

Members of the US Military receiving care through Tricare

Veterans receiving care through the Veteran’s Administration (VA)

The Indian Health Service

Federal employees receiving care through the Federal Employees Health Benefits Plans
Privacy and confidentiality risks
There are also non-physical risks associated with taking part in this study, such as the risks associated with a loss 
of privacy or confidentiality. For example, if your identity as a participant in this research or your identifiable 
genetic or health information were disclosed to unauthorized persons, there is the possible risk of discrimination 
by employers or insurance providers. The researchers believe that the risks of such improper disclosure are very 
small because strict privacy and confidentiality procedures for this research have been adopted.
As with any research study, there may be additional risks that are unknown or unexpected.
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have problems or side 
effects, even when the researchers are careful to avoid them. Please tell the researchers listed in Section 10 
“Contact Information” (below) about any injuries, side effects, or other problems that you have during this study.  
You should also tell your regular doctors.
If you think you have an injury or illness that is related to your participation in this clinical trial, it is important that 
you tell your study doctor immediately.  If you have a clinical trial related injury or accident, the study staff will 
make sure that you get medical treatment.  
You will receive appropriate medical care for any side affects you have while participating in this study.  Your 
study doctor may also lower the drug dose or stop drug if you experience side effects.
You must inform your study doctor immediately if there are any changes in your health/condition, or if you have 
any concerns regarding the study. If for any reason you are seen by another healthcare provider or admitted to 
another hospital, you should make known your participation in this research study. These healthcare providers 
may wish to contact your study doctor to discuss your condition.  Your study doctor may need to contact your 
other doctors if you develop any potentially significant, unexpected diseases or conditions that may have been 
caused by the study intervention or procedures or are discovered during the study.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the risks to you.  
It may also affect the results of the studies.  You should not take part in more than one study without approval 
from the researchers involved in each study.  
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 14 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may not receive any direct personal benefits from being in this study. Taking part in this research study may 
not make your health better. Future AML, ALL, or MDS patients may benefit from knowledge obtained from the 
results of this research.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to stay in this 
study?
Yes, the researchers will tell you if they learn of important new information that may change your willingness to 
stay in this study. If new information is provided to you after you have joined the study, it is possible that you may 
be asked to sign a new consent form that includes the new information.
6.  OTHER OPTIONS
6.1 If I decide not to take part in this study, what other options do I have?
You may have standard chemotherapy agents (in consultation with your BMT physician or oncologist), palliative 
treatment (to relieve suffering and prolong quality of life, but not for sure), or no therapy at all. Your doctor can 
tell you more about these other treatments, their risks and their possible benefits.  You should have this 
discussion about the risks and benefits or other alternatives prior to making your decision about whether or not 
you wish to take part in this research study. 
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no penalty to 
you. You will not lose any benefits to which you may otherwise be entitled and this will not affect your future 
medical care in any way.  If you choose to tell the researchers why you are leaving the study, your reasons for 
leaving may be kept as part of the study record. If you decide to leave the study before it is finished, please tell 
your study doctor or one of the persons listed in Section 10 “Contact Information” (below).
You are free to partially or completely end your participation in the study. An example of partially ending your 
participation would be to discontinue receiving study intervention, while still allowing continuation of study 
follow-up procedures.
Please note that any information collected before you withdraw will be kept and used to complete the research.
Please note that even if you withdraw consent for further follow-up or contacts, if the study doctor becomes 
aware of additional safety information this will be reported to the sponsor in order to comply with legal or 
regulatory requirements.
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
You are free to leave the study at any time. If you leave the study before it is finished, there will be no penalty to 
you. This will not affect your future medical care in any way and you will not lose any benefits to which you may 
otherwise be entitled. Tell the study doctor if you are thinking about stopping or decide to stop. It is important to 
tell the study doctor if you are thinking about stopping so any risks can be evaluated by your doctor. He or she will 
also tell you how to stop safely and discuss what follow-up care and testing could be most helpful for you.  If you 
choose to tell the researchers why you are leaving the study, your reasons for leaving may be kept as part of the 
study record. If you decide to leave the study before it is finished, please tell your study doctor or one of the 
researchers listed in Section 10 “Contact Information” (below).
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 15 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  Some 
examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the study?  
The study will pay for research-related items or services that are provided only because you are in the study. 
Pembrolizumab will be provided at no cost to you.  If you are not sure what these are, see Section 4.1 above or 
ask the researchers for a list.  If you get a bill you think is wrong, call the researchers’ number listed in section 
10.1.
You or your health plan will pay for all the things you would have paid for even if you were not in the study, like:

Health care given during the study as part of your regular care

Items or services needed to give you study drugs or devices

Chemotherapy

Monitoring for side effects or other problems

Deductibles or co-pays for these items or services.
If you do not have a health plan, or if you think your health plan may not cover these costs during the study, 
please talk to the researchers listed in Section 10 below or call your health plan’s medical reviewer.
If you are injured or in the event of a medical emergency, dial 911 or visit your nearest Emergency Room. If you 
believe the study has made you sick or caused you injury, contact one of the people listed in section 10 of this 
document (Contact Information). If taking part in the study makes you sick or causes you injury, the study will not 
provide any compensation to you. You or your insurance provider will be billed for all costs of treatment for 
sickness or injury caused by the study. It is possible that your insurance will not cover these costs.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of being in this 
study.
8.2 Will I be paid or given anything for taking part in this study?
No. You will not be paid for taking part in this study.
8.3 Who could profit or financially benefit from the study results?
The company whose product is being studied: Merck and Co., Inc.
The University of Michigan and the researchers performing this study will receive no financial interest in the 
outcome of this study. Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, 
their organizations, and other entities, including companies, may potentially benefit from the use of the data or 
discoveries. You will not have rights to these discoveries or any proceeds from them. 
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 16 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study.
9.1 How will the researchers protect my privacy?
Your participation will occur at the University of Michigan medical center. 
Your data will be kept confidential, to the extent permitted by applicable laws, in the following manner:
• Your name will not be used in any reports about the study
• You will be identified only by a study code: a subject ID number, and initials
• Your identifying information will be kept secure
We will assign a code number to the study data and biological samples and may use your initials. Some study data 
may contain information that could be used (perhaps in combination with other information) to identify you (e.g., 
initials, date of birth). Only the study team at the University of Michigan will have access to the code linking your 
subject ID number with your personal information.
Study data (that does not directly identify you) may be published in medical journals or shared with others as part 
of scientific discussions.
9.2 What information about me could be seen by the researchers or by other people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you for this 
study, and is required in order for you to take part in the study.  Information about you may be obtained from any 
hospital, doctor, and other health care provider involved in your care, including:

Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.)

Mental health care records (except psychotherapy notes not kept with your medical records)

Alcohol/substance abuse treatment records

HIV/AIDS status

Sexually transmitted disease and/or other communicable disease status

Health plan/health insurance records

All records relating to your cancer, the treatment you have received, and your response to the treatment

Billing information

Demographic information

Personal identifiers
There are many reasons why information about you may be used or seen by the researchers or others during or 
after this study.  Examples include:

The researchers may need the information to make sure you can take part in the study.  

The researchers may need the information to check your test results or look for side effects.  

University, Food and Drug Administration (FDA) and/or other government officials, auditors, and/or the 
IRB may need the information to make sure that the study is done in a safe and proper manner.   

Study sponsors or funders, or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 17 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020

Insurance companies or other organizations may need the information in order to pay your medical bills 
or other costs of your participation in the study.

The researchers may need to use the information to create a databank of information about your 
condition or its treatment.

Information about your study participation may be included in your regular UMHS medical record.

Federal or State law may require the study team to give information to government agencies. For 
example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that would let 
others know who you are. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.
9.3 What happens to information about me after the study is over or if I cancel my permission?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it secure until it 
is destroyed.  Sometimes, it may be necessary for information about you to continue to be used or disclosed, even 
after you have canceled your permission or the study is over.  
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities  (This information would not 
include your name, social security number, or anything else that could let others know who you are.) 

To help University and government officials make sure that the study was conducted properly
As long as your information is kept within the University of Michigan Health System, it is protected by the Health 
System’s privacy policies.  For more information about these policies, ask for a copy of the University of Michigan 
“Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa. Note that once your information has been shared 
with others as described under Question 9.2, it may no longer be protected by the privacy regulations of the 
federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
9.4 When does my permission expire?  
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your permission at 
any time by writing to the researchers listed in Section 10 "Contact Information" (below).  
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 18 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
Principal Investigator: John Magenau, MD
Mailing Address: 
University Hospital South, BMT Program
1500 E. Medical Center Drive
Ann Arbor MI 48109
Telephone: 
734-615-5939
You may also express a concern about a study by contacting the Institutional Review Board listed below.
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies:  US Country Code: 001)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the name of the 
researcher, the IRBMED number (at the top of this form), and details about the problem.  This will help University 
officials to look into your concern.  When reporting a concern, you do not have to give your name unless you want 
to.
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
Your signature in the next section means that you have received signed and dated copies of all of the following 
documents:

This "Consent to be Part of a Research Study" document.  (Note: In addition to the copy you receive, 
copies of this document will be stored in a separate confidential research file and may be entered into your 
regular University of Michigan medical record.)
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 19 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
12.  SIGNATURES
Consent/Assent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential benefits, 
and my other choices with ________________________.  My questions so far have been answered.  I 
understand that if I have more questions or concerns about the study or my participation as a research subject, 
I may contact one of the people listed in Section 10 (above).  I understand that I will receive a copy of this form 
at the time I sign it and later upon request.  I understand that if my ability to consent or assent for myself 
changes, either I or my legal representative may be asked to re-consent prior to my continued participation in 
this study.
Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
For use only if required by sponsor: 
Date of Birth (mm/dd/yy): ____________________________
ID Number: ________________________________________
Consent/Assent for Participating in an Optional Sub-Study (Storage of unused blood/bone marrow samples 
for future research)
This project involves optional participation in a sub-study.  I understand that it is my choice whether or not to 
take part in the sub-study.  I understand that if my ability to consent or assent for myself changes, either I or my 
legal representative may be asked to re-consent prior to my continued participation in this study.
Please write your initials on the line next to the statement that reflects your choice.
_____ Yes, I agree to have my unused samples stored for future research.
_____ No, I do not agree to have my unused samples stored for future research.
Legal Name: ________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 20 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete.  The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating.
Legal Name: ________________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023


Page 21 of 21
Consent Subtitle: UMCC 2017.056
Consent Version: December2020
PERSONAL CENSUS FORM
UMCC # 2017.056
Name _______________________________________________Date ____________________
The National Cancer Institute requires that The University of Michigan Comprehensive Cancer Center report race 
and ethnicity information about people who participate in clinical research to ensure that all populations are 
offered the opportunity to participate. 
 Check here if you do not wish to provide some or all of the information below.
1.
What race do you consider yourself to be?

American Indian/Alaska Nativea
(Please select one or more)

Asianb

Black or African Americanc

Native Hawaiian or Other
Pacific Islanderd

Whitee

More than one racef
2.
Do you consider yourself to be Hispanicg?
 Yes
 No
________________________________________________________________________
a American Indian or Alaska Native- A person having origins in any of the original peoples of North, Central, or South America, 
and who maintains tribal affiliation or community attachment.
b Asian- A person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent, 
including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand and 
Vietnam.
c Black or African American- A person having origins in any of the black racial groups of Africa.  (Terms such as “Haitian” or 
“Negro” are sometimes used in addition to “Black” or “African American.”)
d Native Hawaiian or Other Pacific Islander- A person having origins in any of the original peoples of Hawaii, Guam, Samoa, or 
other Pacific Islands.
e White- A person having origins in any of the original peoples of Europe, the Middle East, or North Africa.
f More than one race- (It is preferred that this be selected in addition to the selection of the specific races listed above, but 
this may also be solely selected.)
g Hispanic or Latino- A person of Mexican, Puerto Rican, Cuban, Central or South American, or other Spanish culture or origin, 
regardless of race.  The term “Spanish origin” is sometimes used in addition to “Hispanic” or “Latino.”
Study ID: HUM00129255   IRB: IRBMED   Date Approved: 8/19/2022   Expiration Date: 8/18/2023