A Phase II Study of Anti-PD-1 Antibody (MK-3475; Pembrolizumab) for the Treatment of Minimal Residual Disease in Adults With Acute Lymphoblastic Leukemia
Phase: PHASE2
Conditions: B Acute Lymphoblastic Leukemia, Minimal Residual Disease, Recurrent Acute Lymphoblastic Leukemia, T Acute Lymphoblastic Leukemia
Sponsor: University of Washington

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ii,:;i'! i :i., i , MÅ!.{ lS 2019
TITLE: A phase II study of anti-PD-l antibody (l[idK-3475; pembrolizumab) for the treatment
of minimal residual disease in adults with acute lymphoblastic leukemia
Sponsor-Investigator:
Ryan Cassaday, MD
Assistant Professor, Department of Medicine, University of Washington School of Medicine
Assistant Member, Clinical Research Division, Fred Hutchinson Cancer Research Center
Phone: (206)606-1202
E-mail : cassaday@uw.edu
FHCRC IRB Approval
.4PR 0 4 2019
Document Released Date
IRB Approved 
Document Release Date: 04/04/2019
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TABLE OF CONTENTS
Trial Summary
Trial Design
Objectives & Hypotheses..................
Background & Rationale
Methodology ..................
Trial Flow Chart........
Trial Procedures ......
Statistical Analyses.
Labeling, Packaging, Storage and Return of Clinical Supplies
Administrative and Regulatory Details
Appendices...................
References ......
....5
....9
25
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43
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77
J
J
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Abbreviated Title
Pembrolizumab for MRD in Adults with ALL
Trial Phase
II
Clinical Indication
Acute lymphoblastic leukemia/lymphoma
Trial Type
Single-arm, non-randomized
Type ofcontrol
None
Route of administration
Intravenous
Trial Blinding
None
Treatment Groups
I
Number of trial subjects
21
Estimated enrollment period
6/U2016 - l0l1/2018
Estimated duration of trial
3 years
Duration of Participation
Up to 2 years
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1.0 TRIAL SUMMARY
2.0 TRIAL DESIGN
2.1 Trial Design
This is a single-institution, non-randomized, prospective, phase II trial of pembrolizumab (MK-
3475) in adult patients with acute lymphoblastic leukemia (ALL) with minimal residual disease
(MRD), as defined by a bone maffow examination consistent with morphologic complete
remission (i.e., less than 5%;o blasts) and no clinically-apparent extramedullary disease but
quantifiable molecular or immunophenotypic evidence of disease by either polymerase chain
reaction (PCR) or multiparameter flow cytometry (MFC), respectively.
2.2 Trial Diagram
* Subsequent cycles will be administered in the absence of morphologic relapse/progression or
development of extramedullary disease (as defined in Section 7 .I.2.6) or transition to alternative
therapy at the discretion of the patient and treating investigator.
^. Long-term follow-up will occur for up to 2 years after completion of treatment or until relapse
to determine duration of complete MRD response and overall survival.
Follow-Up^
Screening
Treatment:
Cycle I
(21 * 3 days)
Pembrolizurnab
200 rng IV x I
Treatment:
Cycle 2*
(21 + 3 days)
Pembrolizumab
200mgIVx I
Treatment
Cycle 3+*
Pembrolizumab
200 mg IV
every 2l *3
days
(up to 2 years)
 
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3.0 OBJECTIVES & HYPOTHESES
3.1 Primary Objective & Hypothesis
(1) Objective: To evaluate the efficacy of pembrolizumab in MRD-positive ALL.
Hypothesis: Pembrolizumab will yield a complete MRD response rate of > 50Yo.
3.2 Secondary Objectives & Hypotheses
(1) Objective: To describe the toxicity profile of pembrolizumab in patients with previously-
treated ALL.
Hypothesis: Pembrolizumab will be safe and well-tolerated in this patient population.
(2) Objective: To gain a preliminary assessment of how MRD response translates into relapse-
free and overall survival.
Hypothesis: Patients that experience a complete MRD response will have longer morphologic
relapse-free and overall survival than those who do not.
3.3 ExploratoryObjectives
(1) Objective: To compare disease assessments by MFC and PCR to a newly-developed and
more sensitive next generation sequencing (NGS)-based platform.
Hypothesis: NGS will be able to detect MRD in a subset of patients that appear to have
complete MRD response by MFC and/or PCR, and subsequent relapse will occur more
frequently in these patients.
(2) Objective: To correlate response to pembrolizumab to immunologic markers in peripheral
blood and bone maffow specimens.
Hypotheses: Patterns of changes in peripheral blood mononuclear cells (PBMC) and
circulating cytokines will emerge as predictors of an immunologic response and anti-
leukemia efficacy.
(3)
Objective: To evaluate if treatment with pembrolizumab has a measurable impact on
hematopoietic engraftment and graft-vs-host disease (GVHD) in patients who subsequently
undergo allogeneic hematopoietic cell transplantation (HCT).
Hypothesis: Prior treatment with pembrolizumab will not increase the risk of graft rejection
or acute GVHD (compared to historical data) in those patients that subsequently undergo
HCT.
 
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4.0 BACKGROUND & RATIONALE
4.1 Background
Refer to the Investigator's Brochure (IB)/approved labeling for detailed background information
on MK-3475.
4.1.1 Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic
transformation has been known for decades. Accumulating evidence shows a correlation between
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CDS+ effector T-cells /
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in
many solid tumors.
The PD-l receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune
control. The normal function of PD-I, expressed on the cell surface of activated T-cells under
healtþ conditions, is to down-modulate unwanted or excessive immune responses, including
autoimmune reactions. PD-l (encoded by the gene Pdcdl) 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-LI and/or PD-L2). The structure of murine PD-l has been resolved.
PD-l and family members are type I transmembrane glycoproteins containing an Ig Variable-type
(V{ype) domain responsible for ligand binding and a cltoplasmic 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-l recruits the tyrosine
phosphatases SHP-I and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the
dephosphorylation of effector molecules such as CD3(, PKC0 and ZAP70 which are involved in
the CD3 T-cell signaling cascade. The mechanism by which PD-l 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-l 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 dendritic cells. The ligands for PD-l (PD-LI andPD-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-LI serves to dampen
unwarranted T-cell function in peripheral tissues. Although healthy organs express little (if any)
PD-LI, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.
PD-l has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma
 
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(MEL). This suggests that the PD-1/PD-Ll 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
IgG4lkappa isotype designed to directly block the interaction between PD-l and its ligands, PD-
Ll and PD-L2. Ke¡rudarM (pembrolizumab) has recently been approved in the United Stated for
the treatment of patients with unresectable or metastatic melanoma and disease progression
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
4.1.2 Preclinical and Clinical Trial Data
Refer to the Investigator's Brochure for Preclinical and Clinical data.
4.2 Rationale
4.2.1 Rationale for the Trial and Selected Subject Population
ALL is among the most common forms of cancer in children, and in this circumstance it is highly
curable. However, treatment of ALL in adults is very challenging, and outcomes with standard
approaches remain unsatisfactory. Apart from the use of ABL kinase inhibitors for patients with
the Philadelphia chromosome (tl9;221, abbreviated Ph+¡, the treatment still relies primarily upon
remission induction with intensive multiagent cytotoxic chemotherapy. This is a particular
challenge in older adults diagnosed with ALL, as these regimens are (in general) prohibitively
toxic for these patients.l Therefore, improvements in the treatment of ALL in adults are critically
needed.
The importance of MRD in ALL is firmly established.2 MRD is typically assessed by two different
techniques: multiparameter flow cytometry (MFC) to detect the unique abnormal
immunophenotype of the leukemic blasts, or polymerase chain reaction (PCR) for clonal DNA
alterations (including immunoglobulin or T-cell receptor gene realrangements or oncogenic
chromosomal rearrangements like BCR-ABL). It is understood that the presence of MRD (either
as persistence during therapy or reappearance afterward) confers a poor prognosis, as it almost
ineïitably heralds frank hematologic relapse without additional intervention.3'a Our center's
experience also demonstrates the risk associated with MRD in the context of HCT. Its presence is
associated with a significantly higher risk of relapse when detected before or after myeloablative
HCT.5 Qualitatively comparable results have been observed from patients undergoing
nonmyeloablative conditioning, which may be the only option for HCT in older or medically-
infirm patients (G. Georges, personal communication). Unfortunately, for those that have MRD,
little is known about the optimal management of this high-risk scenario. However, it stands to
reason that elimination of MRD could significantly improve their outcome.
4.2.2 Rationale for Dose Selection/Regimen/lVlodification
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical
activity of single agent }y'rK-347 5 . The dose escalation portion of PN00 I evaluated three dose
levels, 1 mg/kg, 3 mglkg, 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
 
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and objective evidence of tumor size reduction at all dose levels (1 mglkg, 3 mg/kg and 10
mg/kg e2W). No MTD has been identifred to date. 10.0 mg/kg Q2V/, the highest dose tested in
pÑOOt, will be the dose and schedule utilized in Cohorts A, B, C and D of PN001 to test for
initial tumor activity. 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 suffrcient for target
engagement and clinical activity.
PK data analysis ofMK-3475 administered Q2W and Q3W showed slow systemic clearance,
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data(1f-2
release assay) suggested that peripheral target engagement is durable (>21 days). This early PK
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing
schedule.
A population pharmacokinetic analysis has been performed using serum concentration time data
from 476 patients. Within the resulting population PK model, clearance and volume parameters
of MK-3475 were found to be dependent on body weight. The relationship between clearance
and body weight, with an allometric exponent of 0.59, is within the range observed for other
antibodies and would support both body weight normalized dosing or a fixed dose across all
body weights. MK-3475 has been found to have a wide therapeutic range based on the
melânomá indication. The differences in exposure for a 200 mg fixed dose regimen relative to a
2 mglkgQ3w body weight based regimen are anticipated to remain well within the established
"*põr.ri. 
margins of 0.5 - 5.0 for MK-3475 in the melanoma indication. The exposure margins
aré based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the
proposed dose regim en of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population
ÞKìvaluation 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 explorationof 2 mg/kg and comparable doses of pembrolizumab in solid
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2mglkg
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 Q3V/ to l0 mg/kg Q3V/,
^¡) ttt" lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as
assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab
target engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on
simulations performed using the population PK model of pembrolizumab showing that the fixed
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those
obtained with the 2 mglkgdose every 3 weeks, 2) will maintain individual patient exposures in the
exposure range established in melanoma as associated with maximal efficacy response and 3) will
*uintuin individual patients exposure in the exposure range established in melanomathat are well
tolerated and safe.
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and
to reduce poteniial for dosing erîors. A fixed dosing scheme will also reduce complexity in the
logistical chain at treatment facilities and reduce wastage.
 
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4.2.3 Rationale for Endpoints
4.2.3.1 Efficacy Endpoints
Immunotherapy is a particularly attractive approach to the problem of MRD
persistence heappeararrce: the disease burden by definition is very low; and when MRD is detected
following multiple cytotoxic agents, additional cytotoxic therapy is unlikely to provide substantial
efficacy but could lead to signihcant toxicity. Proof of this principle has been demonstrated with
blinatumomab, a CD3-CD19 bispecific antibody that helps target the patient's endogenous CD3+
T cells to the CD19+ blasts in B-cell precursor ALL. Early in its development, this agent was
shown to be efficacious against chemorefractory MRD in adults with ALL, with l6 of 20 patients
remaining in hematologic remission at a median follow-up of 405 days (relapse-free survival of
78%).6 Similar results were observed in a larger study from the German Multicenter ALL Study
Group.T It is now being tested in a randomized Phase III study (ClinicalTrials.gov
#NCT02013167), and it was granted accelerated approval by the Food and Drug Administration
in December 2014. Unfortunately, blinatumomab must be administered as a 28-day continuous
intravenous (IV) infusion, making it very inconvenient for the patient and the clinical staff.
Furthermore, it is associated with significant toxicity, including serious neurologic side-effects and
cytokine release syndrome. While it can be highly efficacious in this setting, blinatumomab is not
universally effective. Further, due to its toxicity profile and need for 4-week continuous infusion
(a portiorrof which must be administered in an inpatient setting), patients may not be eligible or
willing to receive it. Immune checkpoint blockade through inhibition of the PD-I/PD-LI axis
could provide a similar benefit for a very high-risk clinical scenario with relatively low toxicity, a
significantly easier mode of administration, and inclusion of both T- and B-cell ALL.
Thus, based on the ability of immunotherapy to eliminate MRD, the belief that this endpoint will
translate into improved long-term outcomes in ALL, as well as a strong need for new treatments
for this challenging disease, we will study pembrolizumab for the treatment of MRD in adults with
ALL. This trial will offer an option to reduce the risk of frank relapse following either front-line
or salvage therapy. Should this approach prove efficacious, it could create a novel method of
treatment, in addition to providing a platform from which this agent could be tested either as a
single-agent or in combination with other treatments as consolidation for patients in complete
remission or for those with frankly relapsed/refractory ALL.
4.2.3.2 Biomarker Research
ALL is relatively unique in that frequent disease assessments are common, relatively safe and non-
invasive, and involve direct evaluation of the leukemia microenvironment (i.e., bone marrow).
This provides an attractive opportunity to explore changes in the cellular and immunologic
composition of tumor microenvironment before and after treatment with pembrolizumab. For
example, since it has been demonstrated previously that PD-l and PD-LI expression on tumor
cells and the tumor microenvironment is associated with a higher likelihood of response to
inhibition of the PD-I/PD-LI axis,8-10 we will be able to specifically evaluate the tumor
microenvironment over time via bone maffow specimens. By definition, samples from patients
on this study will have very little leukemia present, such that these analyses will be primarily
reflective of the tumor microenvironment and not the malignarrcy per se.
 
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Further, to evaluate the systemic immune response more broadly, we can study changes in
circulating PBMC and serum cytokines and inflammatory markers that occur following exposure
to pembrolizumab to draw correlations to disease response (or lack thereof). Using a flow
cytometry platform available in the UV/ Hematopathology Laboratory, relative proportions of
circulating T-cell subsets and other components of cellular immunity can be quantified and
compared pre- and post-treatment with pembrolizumab. Additionally, the Immune Monitoring
Laboratory (IML) at the Fred Hutchinson Cancer Research Center (FHCRC) can measure the
levels of approximately 40 different cytokines from samples of peripheral blood. Such analyses
may provide evidence of an on-tar get in vivo effect in responding patients. They can also advance
our understanding of why some patients respond to these agents while others seemingly do not, a
phenomenon which has been suggested previously.ll
Lastly, while MFC and PCR remain the most widely-utilized methods of MRD detection in ALL,
more sensitive methods are being developed. NGS platforms have been developed that can
amplifu and identify disease-specific index sequence from either the immunoglobulin heavy chain
(IGH) or T-cell receptor (TCR) genes that are unique to individual B-cell and T-cell ALL
irespáctively).tz,tr This technique can detect MRD with a frequency below 10-5, which is generally
> 2 orders of magnitude more sensitive than most clinically-available assays currently. Early
studies suggest thát detection even to this low level can impact outcomes in ALL.la'Is As this
clinical trial is designed specifically for patients with MRD, it will provide a unique opportunity
to further evaluate NGS as a viable method of MRD detection in ALL.
5.0 METHODOLOGY
5.1 Entry Criteria
5.1.1 Diagnosis/Condition for Entry into the Trial
All subjects must have a diagnosis of ALL of either B-cell, T-cell, or mixed (i.e., B/T) lineage.
5.1.2 Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial.
2. Be > 18 years of age on day of signing informed consent.
3. Presence of MRD (defined as < 5Yo blasts in the bone marrow by morphologic assessment
and no clinically-apparent extramedullary disease but with quantifiably-measurable
disease as assessed by either MFC or PCR) under any of the following circumstances:
a. MRD persistence > I I weeks after the start of initial therapy,
b. MRD persistence > 2 weeks after the start of salvage therapy, or
c. MRD reappearance at anY time.
 
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4. For patients with Ph+ disease, have previously received treatment with > 1 ABL kinase
inhibitor (e.g., imatinib, dasatinib, etc.) or are ineligible for such treatment.
5. Have previously received or are ineligible for treatment with blinatumomab. Ineligibility
will include (but not be limited to) CDl9-negative disease, denial of insurance coverage,
physician discretion, and/or patient refusal.
6. Be willing to provide tissue from a newly obtained bone marrow aspirate and/or biopsy.
Newly-obtained is defined as a specimen obtained up 28 days prior to initiation of
treatment on Day l. Subjects for whom newly-obtained samples cannot be provided (e.g.,
inaccessible or subject safety concern) may submit an archived specimen only upon
agreement from the PI.
7. Have a performance status of 0 to I on the ECOG Performance Scale.
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
Svstem
Laboratory Value
Hematoloeical
Ahsolute neutroohil count IANC)
>1.000 /mcl
Hemoelobin
>8 s/dl-
Platelets
>50.000 / mcl-
Renal
Serum creatinine$
Measured or calculatedu 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/l.73 m2 for subject with creatinine levels > 1.5 X
institutional ULN
Hepatic
Serum total bilirubin
< I.5 X TJLN OR
Direct bilirubin < ULN for subjects with total bilirubin levels >
I.5 ULN
AST ISGOD and ALT (SGPT)
< 2.5 X TJLN
Coasulation
International Normalized Ratio (INR) or
Prothrombin Time (PT)
Activated Partial Thromboplastin Time
(aPTT)
ll.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use
of anticoagulants
ll.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use
of anticoagulants
uCreatinine clearance or glomerular filtration rate (GFR) should be calculated per the MDRD equation
GFR fml/min/1.73 m2\: 175 x (S".)-t tsc x (Ase)-o203 x (0.742 if female) x (I.2l2if
American)
9. Female subjects of childbearing potential should have a negative urine or serum pregnancy
within 3 days 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. (For
this protocol, childbearing potential is defined in section 5.7 .2.)
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10. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course of the
study through 120 days after the last dose of study medication (Reference Section 5.7.2).
1 1. Male subjects should agree to use an adequate method of contraception (as defined in
section 5.7.2) starting with the first dose of study therapy through 120 days after the last
dose of study therapy.
5.1.3 Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of an
investigational new drug and received study therapy or used an investigational device
within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has a known history of active TB (Bacillus Tuberculosis).
4. Has a known hypersensitivity to pembrolizumab or any of its excipients.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day
I or who has not recovered (i.e., < Grade I or at baseline) from adverse events due to agents
administered more thart 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within
2 weeks prior to study Day 1 or who has not recovered (i.e., < Grade 1 or at baseline) from
adverse events due to a previously administered agent.
- Note: Subjects with < Grade 2 neuropathy or with hematologic toxicity that has
recovered to levels above that stated in Inclusion Criterion 6 are an exception to
this criterion and may qualify for the study if all other inclusion/exclusion criteria
are met.
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention (i.e., < Grade 1 or at
baseline) prior to starting therapy.
7. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin
that has undergone potentially curative therapy or in situ cervical cancer.
8. Has known active central nervous system (CNS) leukemia and/or leukemic meningitis.
Subjects with previously treated CNS leukemia may participate provided they are stable
(e.g., without evidence of active disease by imaging for at least four weeks prior to the hrst
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dose of trial treatment and any neurologic symptoms have returned to baseline) and have
no evidence of leukemic blasts on analysis of cerebrospinal fluid (CSF).
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e.
with use of disease modifuing 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.
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has previously received an allogeneic hematopoietic cell transplant, unless the following
criteria are met:
- Detection of MRD occurred > 2l days from stem cell infusion
- No active GVHD
- Receiving systemic steroid therapy of < 10 mg of prednisone daily (or equivalent)
- Has discontinued systemic immunosuppressant therapy > 7 days prior to first dose
of pembrolizumab
12. Has previously received other forms of cellular immunotherapy (e.g., chimeric antigen
receptor-modified [CAR] T cells), unless the following criteria are met:
_-Detection of MRD occurred > 2l days from cell infusion
-Any specific manifestations of cytokine release syndrome or neurologic toxicity
attributable to the cellular therapy have completely resolved (i.e., < Grade 1)
13. Has an active infection requiring systemic therapy. Antimicrobial prophylaxis will be
permitted at the discretion of the treating investigator.
14. 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.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting from the time of consent through 120 days after the
last dose of trial treatment.
17. Has received prior therapy with any immune checkpoint inhibitor.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HlV ll2 antibodies)
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19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
20. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenzavaccinesfor injection are generally inactivatedfluvaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist@) are live attenuated
vaccines, and are not allowed.
5.2 Trial Treatments
The treatment to be used in this trial is outlined below in Table 2
Table 2: Trial Treatment
Trial treatment should begin within 28 days of signed informed consent.
5.2.1 Dose Selection/lVlodification
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 DoseModification
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the
last dose of pembroliztstnab treatment and may affect more than on body system simultaneously'
Therefore, early recognition and initiation of treatment is critical to reduce complications. Based
on existing clinical study data, most irAEs were reversible and could be managed with
intemrptions of pembrolizumab, administration of corticosteroids and/or other supportive care.
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as
part of the evaluation. Based on the severity of irAEs, withhold or pennanently discontinue
pembrolizumab and administer corticosteroids. Dose modification and toxicity management
guidelines for irAEs associated with pembrolizumab are provided in Table 3.
Drug
Dose/Potency
Dose
Frequency
Route of
Administration
Regimen/Treatment
Period
Use
Pembrolizumab
200 mg
Q 21+3
days
IV infusion
Day l of each21-
day cycle
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Table 3: Dose Modifîcation Guidelines for Drug-Related Adverse Events
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade I or less and continue to taper over at least
4 weeks.
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been
reduced to Grade I or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to <1 0 mg
prednisone or equivalent per day within 12 weeks.
3. For severe and lifethreatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity grade
or conditions
(CTCAEv5.0)
Action taken to
pembrolizumab
irAE management with
corticosteroid and/or other
therapies
Monitor and follow-up
Pneumonitis
Grude2
wirhhold
a
Administer
corticosteroids (initial
dose of l-2 mglkg
prednisone or equivalent)
followed by taper
a
Monitor participants for signs and
symptoms of pneumonitis
Evaluate participants with
suspected pneumonitis with
radiographic imaging and initiate
corticosteroid treatment
Add prophylactic antibiotics for
opportunistic infections
a
Grade 3 or 4,
or recurrent
Grade2
Permanently
discontinue
Diarrhea /
Colitis
Grade 2 or 3
Withhold
Administer
corticosteroids (initial
dose of l-2 m/kg
prednisone or equivalent)
followed by taper
a
Monitor participants for signs and
symptoms of enterocolitis (ie,
diarrhea, abdominal pain, blood
or mucus in stool with or without
fever) and ofbowel perforation
(ie, peritoneal signs and ileus).
Participants with > Grade2
diarrhea suspecting colitis should
consider GI consultation and
performing endoscopy to rule out
colitis.
Participants with dianhea/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.
a
a
Grade 4
Permanently
discontinue
AST / ALT
elevation or
Increased
bilirubin
Grade 2
wirhhold
¡ Administer
corticosteroids (initial
dose of 0.5- I mdkg
prednisone or equivalent)
followed by taper
a
Monitor with liver function tests
(consider weekly or more
frequently until liver enzyme
value retumed to baseline or is
stable
Grade 3 or 4
Permanently
discontinue
r Administer
corticosteroids (initial
dose of l-2 me/ks.
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prednisone or equivalent)
followed by taper
Type I
diabetes
mellitus
(TIDM) or
Hyperglyce
mia
Newly onset
TIDM or
Grade 3 or 4
hyperglycemi
a associated
with evidence
of B-cell
failure
withhold
¡ Initiate insulin
replacement therapy for
participants with TIDM
o Administer anti-
hyperglycemic in
participants with
hyperglycemia
a
Monitor participants for
hyperglycemia or other signs and
symptoms of diabetes.
Hypophysitis
Grade2
Withhold
a
Administer
corticosteroids and
initiate hormonal
replacements as clinically
indicated.
o
Monitor for signs and symptoms
of hypophysitis (including
hypopituitarism and adrenal
insufficiency)
Grade 3 or 4
Withhold or
permanently
discontinuel
Hyperthyroid
lsm
Grade2
Continue
o Treat with non-selective
beta-blockers (eg,
propranolol) or
thionamides as
appropriate
a
Monitor for signs and symptoms
ofthyroid disorders.
Grade 3 or 4
Withhold or
permanently
discontinuel
Hypothyroidi
SM
Grade2-4
Continue
a
Initiate thyroid
replacement hormones
(eg, levothyroxine or
liothyroinine) per
standard ofcare
a
Monitor for signs and symptoms
ofthyroid disorders.
Nephritis
and Renal
dysfunction
Grade2
Withhold
a
Administer
corticosteroids
(prednisone l-2m{kgor
equivalent) followed by
taper.
a
Monitor changes of renal
function
Grade 3 or 4
Permanently
discontinue
Myocarditis
Grade I or 2
Withhold
a
Based on severity of AE
administer corticosteroids
a
Ensure adequate evaluation to
confirm etiology and/or exclude
other causes
Grade 3 or 4
Permanently
discontinue
All other
lmmune-
related AEs
Intolerable/
persistent
Grade2
Withhold
a
Based on type and
severity of AE administer
corticosteroids
a
Ensure adequate evaluation to
confirm etiology and/or exclude
other causes
Grade 3
Withhold or
discontinue
based on the
type ofevent.
Events that
require
discontinuation
include and not
limited to:
Gullain-Barre
Syndrome,
enceohalitis
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Dosing intemrptions are permitted in the case of medical lsurgical 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 Merck. The reason for intemrption
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 I of each cycle due to
administrative reasons.
All trial treatments will be administered on an outpatient basrs.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 21 + 3 days.
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/+l0 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab
infusion fluid and administration of infusion solution.
5.2.3 Trial BlindingMasking
This is an open-label trial; therefore, the study team, investigator and subject will know the
treatment administered.
5.3 Randomization or Treatment Allocation
There will not be any randomization. All subjects will receive the same treatment.
5.4 Stratification
There will not be any formal stratification.
Grade 4 or
recurrent
Grade 3
Permanently
discontinue
l. Withhold or permanently discontinue pembrolizumab is at the discretion ofthe investigator or treating physician.
NOTE
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required,
pembrolizumab may be resumed when AE resolves to < Grade 2 and is controlled with hormonal replacement
therapy or achieved metabolic control (in case of TIDM).
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5.5 ConcomitantMedications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoingtrial. If there is a clinical indication for one of these or other medications
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy 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.
5.5.1 Acceptable ConcomitantMedications
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 28 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 events of clinical interest (ECIs) as defined in Section 7.2.
5.5.2 Prohibited ConcomitantMedications
Subjects are prohibited from receiving the following therapies during the Screening and
Treatment Phase (including retreatment for post-complete response relapse) of this trial:
o Antineoplastic systemic chemotherapy or biological therapy
o Immunotherapy not specified in this protocol
o Chemotherapy not specified in this protocol
o Investigational agents other than pembrolizumab
o Radiation therapy
o 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.
o 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 may be approved after consultation with the PI.
Subjects who enroll in the context of persistent MRD following prior treatment will not be
allowed to continue this prior treatment. Subjects who, in the assessment by the investigator,
require the use of any of the aforementioned treatments for clinical management should be
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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
5.6 Rescue Medications & Supportive Care
5.6.1 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 relapsed disease or bacterial or viral infection, which might
require additional supportive care. The treatment guidelines are intended to be applied when
the investigator determines the events to be related to pembrolizumab.
Note: if after the evaluation the event is determined not to be related, the investigator is
instructed to follow the ECI reporting policies but does not need to follow the treatment
guidance . 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 than4 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 adm in istration.
o
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).
All subjects who experience diarrhea/colitis should be advised to drink liberal
quantities of clear fluids. If sufhcient 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.
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o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral
corticosteroids.
o For Grade 3 or 4 diarrhea/colitis that persists > I week, treat with intravenous
steroids followed by high dose oral steroids.
o When symptoms improve to Grade I or less, steroid taper should be started and
continued over no less than 4 weeks.
Type L diabetes mellitus (if new onset, including diabetic ketoacidosis [DKAI) or
> Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic
acidosis (DKA)
o For TIDM or Grade 3-4 Hyperglycemta
. 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 I 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 atarty 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 tþroid
disorders.
o Grade 2 hyperthyroidism events (and Grade2-4hypothyroidism):
. In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are
suggested as initial therapy.
r 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.
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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 I 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.
o For Grade 3-4 events, treat with systemic corticosteroids.
o V/hen symptoms improve to Grade 1 or less, steroid taper should be started and
continued over no less than 4 weeks.
Management of Complications Unique to HCT or Cellular Immunotherapy: A
potential risk of administering pembrolizumab to patients who have previously
received HCT or other cellular immunotherapy modalities like CAR-T cells is a
recrudescence of toxicities that are germane to these specific therapies, including
GVHD, cytokine release syndrome (CRS), and neurologic toxicity. The manifestations
of such events (e.g., diarrhea, pneumonitis, rash, hepatitis, etc.) are included in the
specific guidelines above. As needed and on a case-by-case basis, best local practices
and additional expert consultation can also be instituted as needed for management of
these toxicities, should they develop. Recording and reporting of these adverse events
will follow the same guidelines as those set out elsewhere in the protocol (Section 7.2).
o
a
o
a
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.
Minor deviations from these guidelines will be permitted, at the discretion of the
treating investigator.
Table 4 below shows treatment guidelines for subjects who experience an infusion
reaction associated with administration of pembrolizumab (MK-3475). Minor
deviations from these guidelines will be permitted, at the discretion of the treating
investigator.
Table 4 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent
dosins
Grade I
Mild reaction; infu sion interruption
not indicated; intervention not
indicated
Increase monitoring of vital signs as medically
indicated until the subject is deemed medically
stable in the opinion ofthe investigator.
Nohe
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NCI CTCAE Grade
Treatment
Premedication at subsequent
dosins
Grade 2
Requires therapy or infusion
intemrption but responds promptly to
symptomatic treatment (e.g.,
antihistamines, NSAIDS, narcotics, IV
fl uids); prophylactic medications
indicated for<:24hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
lncrease 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 infrision, the infusion may be restarted at
50% of the original infusion rate (e.9., 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
treåtment administration.
Sub-ject 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 intenuption of infusion);
recurrence of symptoms following
initial improvement; hospitalization
indicated for other clinical sequelae
(e.g., renal impairment, pulmonary
infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory
support indicated
Stop Infusion.
Additional appropriate medical therapy may
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically
indicated until the subject is deemed medically
stable in the opinion ofthe investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available and an adequately-trained medical providerþhysician readily available
during the period of drug administration.
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5.7 Diet/Activity/Other Considerations
5.7.1 Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE
such as diarrhea, nausea or vomiting.
5.7.2 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. Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or
are considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1)
surgically sterilized, or 2) postmenopausal (a woman who is >45 years of age and has not had
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually
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active for the duration of the study. The two birth control methods can be either two barrier
methods or a barrier method plus a hormonal method to prevent pregnancy. Female subjects
should start using birth control from study Visit I throughout the study period up to 120 days
after the last dose of study therapy.
The following are considered adequate barrier methods of contraception: diaphragm, condom
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal
contraceptives will include any registered and marketed contraceptive agent that contains an
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or
intramuscular agents).
Men may be enrolled if they are willing to use a condom or are considered highly unlikely to
conceive. Highly unlikely to conceive is defined as 1) surgically sterilized, 2) previously
known to have azoospeffnia, or 3) not heterosexually active for the duration of the study. Male
subjects should start using condoms from study Visit I throughout the study period up to 120
days after the last dose of study therapy.
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in
the study they must adhere to the contraception requirement (described above) for the duration
of the study and during the follow-up period dehned in section 7.2.2-Reporting of Pregnancy
and Lactation to the Sponsor-Investigator and to Merck. If there is any question that a subject
will not reliably comply with the requirements for contraception, that subject should not be
entered into the study.
5.7.3 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 PI and to Merck without
delay and within 24 hours to the PI 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-Investigator and
Merck. If a male subject impregnates his female partner the study personnel at the site must
be informed immediately and the pregnancy reported to the PI and to Merck and followed as
described above and in Section 7.2.2.
5.7.4 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.
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5.8 SubjectWithdrawaUDiscontinuation 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 treating investigator or the PI if enrollment into the trial is inappropriate, the
trial plan is violated, or for administrative andlor 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:
o
The subject or legal representative (such as a parent or legal guardian) withdraws
consent.
o Confirmedmorphologic relapse/progression
o Radiologic studies highly suspicious for extramedullary relapse (biopsy confirmation
is strongly recommended unless prohibitively risky or patient refuses)
o Unacceptable adverse experiences as described in Sectio n 5.2.1.2
o Intercurrent illness that prevents fuither administration of treatment
o Treating investigator feels that alternative treatment (e.g., allogeneic HCT) would be
more beneficial for the subject
o Investigator's decision to withdraw the subject
o The subject has a confirmed positive serum pregnancy test
o Noncompliance with trial treatment or procedure requirements
o The subject is lost to follow-up
o Completed 24 months of unintemrpted treatment with pembrolizumab or 35
administrations of study medication, whichever is later.
Note: 24 months of study medication is calculatedfrom the døte offirst dose. Subjects
who stop pembrolizumab after 24 months may be eligible for up to one year of
additional study treatment if they progress after stopping study treatment provided they
meet the requirements detailed in Section 7.1.5.5
o Administrativereasons
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
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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 medical record review and/or telephone for overall survival until death,
withdrawal of consent, or the end of the study, whichever occurs first.
5.8.1 Discontinuation of Study Therapy after Complete MRD Response
Discontinuation of treatment may be considered for subjects who have attained a confirmed
complete MRD response that have been treated for at least24 weeks with pembrolizumab and
had at least two treatments with pembrolizumab beyond the date when the initial complete
MRD response was declared. Subjects who then experience disease progression may be
eligible for up to one year of additional treatment with pembrolizumab via the Second Course
Phase at the discretion of the investigator if no cancer treatment was administered since the
last dose of pembroliz;umab, the subject meets the safety parameters listed in the
Inclusior/Exclusion criteria, and the trial is open. Subjects will resume therapy at the same
dose and schedule at the time of initial discontinuation. Additional details are provided in
Section 7.1.5.5.
5.9 Subject Replacement Strategy
Subjects will be replaced only in the rare event that they are not evaluable, which will be
dehned as alive > 3 weeks after initiation of study treatment but without sufficient response
data from bone marrow examination (refused response assessments, technical limitations
precluding ability to review bone marrow status, etc.).
5.10 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specihed below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requiremènts
3. lncidence or severity of adverse drug reaction in this or other studies indicates a potential
health haznd to subjects
4. Plans to modifr or discontinue the development of the study drug
In the event of Merck decision to no longer supply study drug, ample notification will be
provided so that appropriate adjustments to subject treatment can be made.
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6.0 TRIAL FLOW CHART
6.1 Study Flow Chart
Post-Treatment
Survival
Follow-Up
Every - 3
months
Administrative Procedures
X
X
Clinical Procedures/Assessments
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
End of
Treatment
Discontinu
ation
< 7 davs
post
discontinua
tion
X
X
X
X
X
X
Treatment Cycles"
To be repeated beyond 8
cycles
8
+3
X
X
X
X
X
X
X
7
+3
X
X
X
X
X
X
X
6
+3
X
X
X
X
X
X
X
5
ÍJ
X
X
X
X
X
X
X
4
+3
X
X
X
X
X
X
X
3
r3
X
X
X
X
X
X
X
2
+3
X
X
X
X
X
X
X
I
X
X
xd
xd
xd
Xd
Xd
Screening Phase
Screening
Visit(s)
-28 to -l
X
X
X
X
X
X
X
X
xb
xb
Xb
Trial Period:
Treatment Cycle/Title:
Scheduling Window (Days):
Informed Consent
Inclusion/Exclusion Criteria
Demographics and Medical History
Prior and Concomitant Medication Review
Pembrolizumab Administration
Post-study anticancer therapy status
Survival Status
Review Adverse Events
Full Physical Examination
Directed Physical Examination
Vital Signs and Weight
ECOG Performance Status
Pregnancy Test - Urine or Serum P-HCG
PT/INR and aPTT
CBC with Differential
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Post-Treatment
Survival
Follow-Up
Every - 3
months
Efïicacy Measurements
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
u Treatment cycles will occur every 2l + 3 days
bScreening laboratory assessments should be performed within l0 days prior to the first dose of pembrolizumab, while urine/serum pregnancy test must be
performed within 3 days of the first dose of pembrolizumab.
" Tumor imaging is only required in patients suspected of having sites of extramedullary disease.
d In the event that adequate clinical and laboratory assessments performed for screening purposes occur within 3 days ofthe start ofCycle l, they do not need to
be repeated for Cycle 1.
" Bone marrow examinations should be performed 3 + I days prior to the start of the subsequent cycle (i.e., Day 18-20) to provide adequate time for interpretation.
At a minimum, bone marrow exams will include an evaluation of morphology as well as a repeat analysis of whatever study (or studies) detected MRD at the
time of enrollment; other studies may be included as clinically indicated. An end-of-treatment bone marrow examination does not need to be repeated if
morphologic relapse/progression is identified on a scheduled surveillance examination.
r For those eligible to continue beyond Cycle 8, the timing of subsequent bone marrow exams will be left to the treating investigator, though no less often than
every 3 months while receiving study treatment will be recommended.
e Details regarding planned correlative analyses on bone maffow and blood are described in Section 7 .1.2.7 .
End of
Treatment
Discontinu
ation
< 7 days
post
discontinua
tion
X
X
X
xe
xc
xc
xc
Treatment Cycles¡
To be repeated beyond 8
cycles
8
+3
X
x",f
7
+3
X
6
+3
X
xef
5
+3
X
4
+3
X
xe
xc
xc
J
+3
X
2
+3
X
xe
xc
xc
1
x
xe
xc
Screening Phase
Screening
Visit(s)
-28 to -l
xo
Xb
Xb
X
xc
xe
xc
Trial Period:
Treatment Cycle/Title :
Scheduling Window (Days):
Comprehensive Serum Chemistry Panel
Urinalysis
T3, FT4 and TSH
Bone Marrow Examination
Tumor Imaging
Archival or Newly Obtained Tissue Collection
Correlative Studies Blood Collection
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7.0 TRIAL PROCEDURES
7.1 Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed during
each cycle. 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 PI 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.l.l.l Informed Consent
The Investigator must obtain documented consent from each potential subject prior to
participating in a clinical trial.
7.l.l.l.l General Informed Consent
Consent must be documented by the subject's dated signature or by the subject's legally
authorized representative's dated signature on a consent form along with the dated signature
ofthe person conducting the consent discussion.
A copy ofthe 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's approval/favorable
opinion in advance of use. The subject or hisiher legally authorized 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.
The informed consent will adhere to IRB requirements, applicable laws and regulations and
Sponsor-Investigator requirements.
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7.1.1.2 Inclusion/Exclusion Criteria
Prior to enrollment, all inclusion and exclusion criteria will be reviewed by the investigator or
qualified designee to ensure that the subject qualifies for the trial.
7.1.1.3 Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history
will include all active conditions, and any condition diagnosed within the prior 10 years that
are considered to be clinically significant by the Investigator. Details regarding the disease for
which the subject has enrolled in this study will be recorded separately and not listed as medical
history.
7,1.1.4 Prior 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 28 days before starting the trial. Treatment for the disease for which the subject has
enrolled in this study will be recorded separately and not listed as a prior medication.
7.1.1.4.2 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
Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.
7.1.1.6 Assignment of Enrollment Number
Once a subject has enrolled, they will be assigned a unique identifying number for the purposes
of tracking and collectingdata.
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7.1.1.7 Trial Compliance (Medication/Diet/Activity/Other)
The investigator or qualified designee will review compliance with study requirements at study
visits and as deemed necessary.
7.1.2 Clinical Procedures/Assessments
7.1.2.1 Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to the most current available version of the NCI CTCAE (see Section
12.2). Toxicities will be characterized in terms regarding seriousness, causality, toxicity
grading, and action taken with regard to trial treatment.
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 (and at time points indicated in the Trial Flow Chart). Clinically significant
abnormal findings should be recorded as medical history.
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.
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section l2.l) at screening,
prior to the administration of each dose of trial treatment and discontinuation of trial treatment
as specified in the Trial Flow Chart.
7.1.2.6 Assessment of Disease
Bone marrow examinations will be the primary modality for disease assessments on this study.
The bone maffow performed for screening/eligibility may be performed at an outside
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institution, provided an assessment of morphology was performed that confirmed morphologic
CR and MRD was detected by either MFC or PCR. If the marrow exam was performed > 28
days before the start of treatment or if either of these elements is not available, a repeat bone
maffow exam will be required prior to enrollment.
Following the initiation of treatment, bone marrow exams will be repeated after each of the
first 2 cycles of treatment. These should be performed 3 t I days prior to the start of the
subsequent cycle (i.e., Day I S-20) to provide adequate time for interpretation. At a minimum,
bone marrow exams will include an evaluation of morphology as well as a repeat analysis of
whatever study (or studies) detected MRD at the time of enrollment (e.g., if MRD was detected
by MFC and PCR at enrollment, follow-up marrow exams should include both MFC and PCR);
other studies may be included as clinically indicated.
If morphologic relapse (i.e., leukemic blasts in the peripheral blood or> 5Yo blasts in the bone
maTïow not attributable to any other cause) is detected at any time, treatment will stop and the
subject will be removed from the study. However, subjects with persistent MRD may continue,
provided other criteria to continue study treatment are met.
As our institution's standard methods for MRD detection in ALL are either MFC or PCR for
the BCR-ABZ fusion product in patients that have Ph+ disease, it is anticipated that these will
be the primary modalities by which MRD is monitored. That said, for patients from whom
adequate baseline material is available, NGS performed in the UW Hematopathology
Laboratory or at Adaptive Biotechnologies will be used as an additional method of MRD
monitoring. These results, however, will not be available in real time, and thus clinical
decision-making will rest entirely on the results of MFC and/or PCR.
For subjects who are eligible to proceed to Cycles 3 and beyond, bone marrow exams will be
repeated after every other cycle (i.e., Cycle 4,6, and 8) through Cycle 8. For those eligible to
continue beyond Cycle 8, the timing of subsequent bone marrow exams will be left to the
treating investigator, though every 3 months while receiving study treatment will be
recommended.
A bone maffow exam will also be required at the end of treatment. If the decision to
discontinue treatment coincides with the timing of one of the above follow-up assessments, a
separate end-of-treatment examination will not be required (e.g., the post-cycle 4 bone maffow
demonstrated morphologic relapse). Similarly, if morphologic relapse is detected after Cycle
1, no further bone maffow examinations will be required for this study.
For definitions of response categories, please see Section 12.3.
Imaging studies will only be performed if extramedullary disease is suspected based on the
evaluation of the treating investigator. This may occur at screening (to ensure eligibility) or at
end of treatment (to document relapse/progression). If extramedullary disease is identified,
this will constitute disease relapse: study treatment will be discontinued, and the subject will
be removed from the study.
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7.1.2.7 Tissue Collection and Correlative Studies Blood Sampling
Subjects who enroll on this study will have the option to provide tissue and blood samples for
correlative studies, as described above in Section 4.2.3.2. Subjects may enroll on this study
and opt out of these additional tests.
Bone marrow samples available from screening, post-cycle l, post-cycle 2, post-cycle 4, and
end-of-treatment will undergo DNA extraction in order to perform NGS-based MRD
assessments. As these assays require knowledge of the leukemia-specific sequence from a
sample with relatively high disease burden (e.g., initial diagnosis or morphologic relapse),
archived tissue will be requested in order to identiff this. In the event that this baseline sample
cannot be obtained, then collection of samples for these exploratory MRD assessments may be
deferred at the discretion of the PI. Lastly, DNA will be extracted from bone marrow obtained
post-cycle 4 (for those patients still enrolled at that time) to investigate for clonal changes in
the immune microenvironment.
As close as feasible to the timing of these marrow examinations at screening, post-cycle 2,
post-cycle 4, and end-of-treatment, peripheral blood will also be collected for additional
correlative studies. Flow cytometry will be performed in the UV/ Hematopathology
Laboratory to assess for changes in circulating T-cell subsets (e.g., cytotoxic T cells, regulatory
T cells) and other markers of cellular immunologic response. DNA will also be extracted to
investigate for clonal changes in the immune repertoire. Lastly, cytokine and inflammatory
marker measurements will occur in the IML at FHCRC and can include (but not necessarily
limited to) PD-LI, interleukin (lL)-z,IL-21, and tumor necrosis factor alpha.
7.1.3 Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are
provided below.
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.
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Table 5: Laboratory Tests
Other
Serum B-human chorionic gonadotropinf
G-hcG)t
Pr (rNR)
aPTT
Total thriiodothyronine (T3)
Free tyroxine (T4)
Thyroid stimulating hormone (TSH)
Blood for correlative studies
f Perform on women of childbearing potential only. If urine pregnancy results cannot be conf,rrmed as negative, a sentm pregnancy test will be required.
Urinalysis
Blood
Glucose
Protein
Specific gravity
Microscopic exam (lf abnormal,
results are noted)
Urine preg-nancy test t
Chemistry
Albumin
Alkaline phosphatase
Alanine am inotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Carbon Dioxide
(COz or biocarbonate)
Uric Acid
Calcium
Chloride
Glucose
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin
Direct Bilirubin (lf total bilirubin is
elevated above the upper limit of
normal)
Total protein
Blood Urea Nitrogen
Hematology
Hematocrit
Hemoglobin
Platelet count
WBC (total and differential)
Red Blood Cell Count
Absolute Neutrophil Count
Absolute Lymphocyte Count
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Laboratory tests for screening or entry into the Second Course Phase should be performed
within 10 days prior to the first dose of treatment. After Cycle 1, pre-dose laboratory
procedures can be conducted up to 3 days prior to dosing. Results must be reviewed by the
investigator or qualified designee and found to be acceptable prior to each dose of trial
treatment.
7.1.3.1 PharmacokineticÆharmacodynamic Evaluations
There will not be any formal pharmacokinetic/pharmacodynamic evaluations as part of this
study, apart from those described in Section 7.I.2.7.
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. Subjects who a) attain a CR or b) complete 24 months of treatment with
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet
the criteria specified in Section 7.L5.5. After discontinuing treatment following assessment
of CR, these subjects should proceed to the Follow-Up Period of the study (described in
Section 7.1.5.4).
7.1.4.2 Btinding/Unblinding
No blinding will be performed on this trial.
7.1.5 Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 -Trial Procedures.
7.1.5.1 Screening
7.1.5.1.1 Screening Period
Screening evaluations as listed in Section 6.0 - Trial Flow Chart may occur within 28 days of
initiation of treatment, with the following two exceptions: laboratory assessments (as
mentioned above) should be obtained within 10 days, and urine/serum pregnancy test must be
performed within 3 daysof the first dose of pembrolizumab.
7.1.5.2 Treatment Period
Treatment will occur every 3 weeks (21 + 3 days). Clinical and laboratory
procedures/assessments (as delineated in Section 6.0) should occur within 3 days of
administration of pembrolizumab. In the event that these assessments performed for screening
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purposes occur within 3 days of the start of Cycle 1, they do not need to be repeated for Cycle
1. Respotrse assessments by bone marrow examination will be performed as described in
Section 7.1.2.6.
7.1.5.3 Post-Treatment Visits
7.1.5.3.1 Safety Follow-Up
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 90 days of the end of treatment or before initiation of a new anti-cancer treatment
(whichever comes first) should also be followed and recorded.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will move
into the Follow-Up Phase and should be assessed approximately every 3 months for up to 2
years. These assessments may be performed by local or referring medical providers, provided
appropriate medical records can be made available to research staff. 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 7.1.5.5. Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. If this anti-neoplastic
treatment includes allogeneic HCT, occuffence of graft rejection and/or grade 3 or higher acute
GVHD according to section 12.4 will be noted.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they
experience disease progression. Details are provided in Section 6.1 - Trial Flow Chart (i.e.,
Second Course Phase will be identical to initial treatment).
7.1.5.3.3 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy,
the subject moves into the survival follow-up phase and should be contacted (via medical
record review andlor telephone) approximately every 3 months to assess for survival status
until death, withdrawal of consent, or the end of the study, whichever occurs fltrst.
7.1.5.4 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab in a complete MRD response may be eligible for up to one
year of additional pembrolizumab therapy if they experience MRD reappearance after stopping
study treatment. This retreatment is termed the Second Course Phase of this study and is only
available if the study remains open and the subject meets the following conditions:
o Stopped initial treatment with pembrolizumab after attaining an investigator-
detèrmined confirmed complete MRD response according to consensus criteria,l6 and
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o Was treated for at least 24 weeks with pembrolizumab before discontinuing
therapy
o Received at least two treatments with pembrolizumab beyond the date when the
initial complete MRD response was declared
Experienced an investigator-determined confirmed MRD reappearance after stopping
their initial treatment with pembrolizumab
Did not receive any anti-cancer treatment since the last dose of pembrolizumab
a
a
o
a
Has a performance status of 0 or I on the ECOG Performance Scale
Demonstrates adequate organ function as detailed in Section 5.1.2
Female subject of childbearing potential should have a negative serum or urine
pregnancy test within 3 days prior to receiving retreatment with study medication.
Female subject of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course of
the study through 120 days after the last dose of study medication (Reference Section
5.7.2). Subjects of child bearing potential are those who have not been surgically
sterilized or have been free from menses for > I year.
Male subject should agree to use a condom starting with the first dose of study therapy
through 120 days after the last dose of study therapy.
Does not have a history or current evidence of any condition, therapy, or laboratory
abnormality that might 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.
Subjects who restart treatment will be retreated at the same dose and dose interval as when
they last received pembrolizumab. Treatment will be administered for up to one additional
year.
Visit requirements are outlined in Section 6.1 - Trial Flow Chart.
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-
specif,red procedure. Any worsening (i.e., any clinically significant adverse change in
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a
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frequency andlor intensity) of a preexisting condition that is temporally associated with the use
of 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, menopause occulring at a physiologically
appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic
agent or protocol-specified procedure, whether investigational (including placebo or active
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed
by Merck for human use.
Adverse events may occur during the course of the use of Merck product in clinical trials or
within the follow-up period specified by the protocol, or prescribed in clinical practice, from
overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period
as a result of a protocol-specihed intervention, including washout or discontinuation of usual
therapy, diet, placebo treatment or a procedure.
Relapse/progression of ALL is not considered an adverse event unless it is considered to be
drug related by the investigator.
All ECIs (as defined in Section 7.2.3.2) and other grade 3 or higher adverse events will be
recorded from the time the consent form is signed through 30 days following cessation of
treatment and at each examination on the Adverse Event case report forms/worksheets. The
reporting timeframe for adverse events meeting any serious criteria is described in section
7.2.3.1.
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the
Sponsor-Investigator and to Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000
mg or greater (ì5 times the indicated dose). No specific information is available on the
treatment of overdose ofpembrolizumab. 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 (ooresults from") the overdose of a Merck product, the
adverse event(s) is reported as a serious adverse event, even ifno 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 'oaccidental or intentional
overdose without adverse effect."
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All reports of overdose with and without an adverse event must be reported within 24 hours to
the Sponsor-Investigator and within 2 working days hours to Merck Global Safety. (Attn:
Worldwide Product Safety; FAX 215-661-6229)
7.2.2 Reporting of Pregnancy and Lactation to the PI and to Merck
Although pregnancy and infant exposure during breast feeding are not considered adverse
events, it is the responsibility of investigators or their designees to report any pregnancy or
lactation in a participant (spontaneously reported to them) that occurs during the study.
Pregnancies and infant exposures during breastfeeding that occur after the consent form is
signed but before treatment allocation/randomization must be reported by the investigator if
they cause the participant 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 infant exposures during breastfeeding that occur from the time of treatment
allocatiorVrandomizatíon through 120 days following cessation of Sponsor's product, or 30
days following cessation of treatment if the participant 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: V/orldwide Product Safety; FAX 215-66L'6229)
7.2.3 Immediate Reporting of Adverse Events to the PI 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
pembrolizumab that:
o Results in death;
o Is life threatening;
o Results in persistent or significant disability'incapacity;
o Results in or prolongs an existing inpatient hospitalization;
o Is a congenital anomaly/birth defect;
o Is a new cancer (that is not a condition of the study);
o Is associated with an overdose;
o Is another important medical event
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment
allocation/randomization, any serious adverse event, or follow up to a serious adverse event,
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including death due to any cause that occurs to any participant must be reported within 24
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the
participant 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 participant initiates
new anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a
serious adverse event, including death due to any cause 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 Merck Global Safety.
All participants 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: +l-215-661-6229
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 215-661-6229) 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 2 working days to Merck Global Safety. (Attn: Worldwide
Product Safety; FAX 2 1 5-6 6I -6229).
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 participant must
be reported within 2 working days to Merck Global Safety if it causes the participant to be
excluded from the trial, or is the result of a protocol-specihed 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 participant 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 2 working days to Merck Global Safety.
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l. 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-Investigator, that is not associated
with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2Xthe
upper limit of normal, as determined by way of protocol-specified laboratory testing or
unscheduled laboratory testing. *
*Note: These criteria are based upon available regulatory guidance documents. The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require
an additional evaluation for an underlying etiology. The trial site guidance for assessment
and follow up of these criteria can be found in the Investigator Trial File Binder (or
equivalent).
7.2.4 Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the
most current available version of NCI Common Terminology for Adverse Events (CTCAE).
Any adverse event which changes CTCAE grade over the course of a given episode will have
each change of grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 6: Evaluating Adverse Events
An investigator, who is a qualified physician, will evaluate all adverse events as to:
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Moderate: minimal. loc¡l or noninvasive intervention indicated¡ limitine ¿se-aDpropriate instrumental ADL.
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated;
disabline; limitins self-care ADL.
Life
Death related to AE
A serious adverse event is
adverse event
at
use of Merck
that:
Results in
or
tls life threatening; or places the subject, in the view ofthe investigator, at immediate risk ofdeath from the event as it occurred (Note: This does not include an
adverse event
had it occurred in a more severe
caused
or
lna
or
disa
of one's
to conduct normal life
or
tResults in or prolongs an existing inpatient hospitalization (hospitalization is defined as
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization
an inpatient admission, regardless oflength ofstay, even ifthe
[including hospitalization for an elective procedure] for apreexisting
does not constitute a serious adverse event.
or
defect
of
the
to
Is a new
is not a condition ofthe
or
Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not
associated with an adverse event is considered a
event of clinical interest and must be
within 24 hours.
Other important medical events that may not result in death, not be life threatening, or
based upon appropriate medical judgment, the event may jeopardize the subject and may
not require hospitalization may be considered a serious adverse event when,
require medical or surgical intervention to prevent one of the outcomes
listed previously (desimated above by a T).
Record the start and stoo dates ofthe adverse event. Ifless than I dav. indicate the appropriate length oftime and units
Did the adverse event cause the Merck product to be discontinued?
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product
investigator who is a qualified physician. The investigator's signed/dated initials on the source document or
caused the adverse event will be provided by an
worksheet that supports the causality noted on the AE
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event
based upon the available information.
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and
their
number and/or
the more
the Merck
event
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable
count. diarv. etc.). exoected pharmacolosic effect, or measurement of drug/metabolite in bodily specimen?
compliance assessment (pill
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?
Is the time of onset of the AE comoatible with a drue-induced effect (applies to trials with investigational medicinal product)?
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or
factors
environmental
Grade I
Grade 2
Grade 3
Grade 4
Grade 5
Exposure
Time Course
Likely Cause
CTCAE
Gradins
Seriousness
Duration
Action taken
Relationship to
test drug
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The following components are to be used to assess the relationship between the test drug and the AE: (continued)
Was the Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
Ifyes, this is a positive dechallenge. Ifno, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation
of the Merck product; or (3) the trial is a sinele-dose drus trial): or (4) Merck oroductls) is/are onlv used one time.)
Was the subject re-exposed to the Merck product in this study?
Ifyes, did the AE recur or worsen?
lfyes, this is a positive rechallenge. Ifno, this is a negative rechallenge.
(Note: This criterion is not applicable if: (l) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or
(3) Merck product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SEzuOUS AND WHICH MAY HAVE BEEN
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology
or toxicology?
consideration of the above elements.
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship).
There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to the administration of the Merck product
is reasonable. The AE is more likely explained by the Merck product than by another cause.
Subject did not receive the Merck product OR temporal sequence ofthe AE onset relative to administration ofthe Merck product is not reasonable
OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.)
Dechallenge
Rechallenge
Consistency
with Trial
Treatment
Profile
Record one of the following
Yes, there is a reasonable
possibility of Merck product
relationship.
No, there is not a reasonable
possibility Merck product
relationship
Relationship
to Merck
product
(continued)
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8.0 DATA AND SAFETY MONITORING PLAN
Institutional support of trial monitoring will be in accordance with the Fred Hutch /University of
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of
this plan, Fred Hutch Clinical Research Support coordinates data and compliance monitoring conducted
by consultants, contract research organizations, or Fred Hutch employees unaffiliated with the conduct
of the study. Independent monitoring visits occur at specified intervals determined by the assessed risk
level of the study and the findings of previous visits per the institutional DSMP.
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety
Monitoring Committee (DSMC), Fred Hutch Scientific Review Committee (SRC) and the Fred Hutch
/University of Washington Cancer Consortium Institutional Review Board (IRB). The review
committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and
safety monitoring plan for studies actively enrolling or treating patients. The IRB reviews the study
progress and safety information to assess continued acceptability of the risk-benefit ratio for human
subjects. Approval of committees as applicable is necessary to continue the study.
The trial will comply with the standard guidelines set forth by these regulatory committees and other
institutional, state and federal guidelines.
9.0 STATISTICAL ANALYSIS PLAN
9.1 Statistical Analysis Plan Summary
The primary objective of this study is to evaluate the efficacy of pembrolizumab in MRD-positive ALL.
To address this, a Simon two-stage minimax design will be used.
9.2 Statistical Analysis Plan
The primary endpoint of this phase II study will be the rate of complete MRD response, defined as the
percentage of evaluable subjects who achieve a complete MRD response, as defined in Section 1 1.3. The
study of blinatumomab for chemorefractory MRD cited previously assumed an historical rate of complete
MRD response to standard chemotherapy of 5o10.6 Considering the fact that the current study will enroll
patients that have previously received or are ineligible for treatment with blinatumomab, we feel it is
reasonable to assume a similar historical rate of complete MRD response for subjects in this trial. The
design will be based on Simon's two-stage minimax design with an historical response rate of 5Yo and an
assumed-true response rate of 20%o for patients receiving treatment on this protocol. The design also
assumed a l\Yo type-I error rate and a 20Yo type-Il error rate. Under these assumptions and parameters,
the first stage will enroll 12 evaluable patients. If 0 responses are seen among these 12,the study will be
paused for futility to consider altemative strategies to improve efficacy versus consideration of study
closure (the probability of 0 responses among 12 under the alternative hypothesis of 20Yo response is
0.07). On the other hand, if at least 1 response is seen among the first 12 patients, an additional 9 will be
enrolled for a total of 21. If at least 3 responses occur among the 2l (143% or more), this will be
considered as sufficient evidence to conclude that the observed response rate is statistically better than
the fixed historical rate of 5%. This yields a type-I error rate of .08 and power of 80% along with an
expected sample size of 16.1.
Additionally, the study will be stopped early if there is a signal of unacceptably-high early morphologic
relapse. For this stopping rule, the rate of morphologic relapse within the first 2 cycles of treatment will
be assessed in cohorts of 5 for the first 15 patients enrolled. If the lower bound of the 80olo confidence
 
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interval of the morphologic relapse rate exceeds 50Yo at these assessments (i.e., > 4 out of 5, I 7 out of
10, and > l0 out of l5), the study will close early.
Reporting of secondary endpoints, including toxicity profiles, OS, and impact of biomarkers, will be
primarily descriptive.
1O.O LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
10.1 Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and
ensure appiopriate 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 TableT.
Table 7: Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mgl 4mL
Solution for Injection
10.2 Packaging and Labeling Information
Clinical supplies will be affrxed with a clinical label in accordance with regulatory requirements.
10.3 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.
10.4 Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified
on the label.
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
10.5 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
*ill b" desiroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for
 
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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 ofdisposal are kept.
11.0 ADMINISTRATIVE AND REGULATORY DETAILS
11.1 Confidentiality
The investigator will assure that subjects' anonymity will be strictly maintained and that their identities
are protected from unauthorized parties. Only subject initials, date of birth and a study identification code
will be recorded on any form or biological sample submitted to Merck or applicable outside
institutions/laboratories. Laboratory specimens will be labeled in such a way as to protect subject identity
while allowing the results to be recorded to the proper subject. The investigator will keep a screening log
showing study identification codes, names, date of birth and last known address for all subjects screened
and for all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable
regulations.
ll.2 Compliance with Financial Disclosure Requirements
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54,1998, providing
documentation of their financial interest or arrangements with Merck, or proprietary interests in the
investigational drug under study. This documentation will be provided prior to the investigator's (and any
subinvestigator's) participation in the study. The investigator and subinvestigator will notifr applicable
parties of any change in reportable interests during the study.
11.3 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modemization 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.
11.4 Retention of Records and Study Files
The investigator will maintain adequate and accurate records to enable the conduct ofthe study to be fully
documented and the study data to be subsequently verified. All clinical study documentation will be
retained by the investigator according to local laws and regulatory requirements.
11.5 Data Management
Under the supervision of the investigators, research staff will maintain case report forms and secured
databases on the relevant clinical and laboratory data. Records maintained in investigators' offices will
be secured with access limited to study personnel. Authorization for access to medical records will be
obtained from all patients in accordance with provisions of the Health Insurance Portability and
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12.0 ORIGINAL SIGNED INFORMED CONSENT FORMS WILL BE KEPT WITHIN THE
SECURED STUDY TEAM OFFICE, ACCESS IS LIMITED TO STUDY PERSONNEL. A
COPY OF THE SIGNED INFORMED CONSENT FORM IS GIVEN TO THE
PARTICIPANT. DATA WILL BE COLLECTED ON PATIENT CHARACTERISTICS,
DISEASE CHARACTERISTICS, PROTOCOL THERAPY, RESPONSE TO
TREATMENT, ADVERSE EVENTS AND FOLLOW.UP FOR RELAPSE AND
SURVIVAL. COPIES OF THE PATIENT'S MEDICAL RECORD INCLUDING HISTORY
AND PHYSICAL EXAMS, DOCUMENTATION OF PROTOCOL THERAPY, LABSO
SCANS, X.RAYS, HOSPITALIZATIONS, OPERATIVE REPORTS, PATHOLOGY
REPORTS ETC. ARE REQUIRED.
l2.l ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to caffy 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 <50yo of the time. Ambulatory and capable of all self-care, but
unable to carry out any work activities. Up and about more than 50olo
of wakine hours.
aJ
In bed >50%o of the time. Capable of only limited self-care, conf,rned
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, 7.8.,
McFadden, 8.7., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperatìve Oncologt
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis
M.D.. Group Chair.
12.2 Common Terminology Criteria for Adverse Events (CTCAE)
The descriptions and grading scales found in the most current available version of NCI Common
Terminology Criteria for Adverse Events (CTCAE) will be utilized for adverse event reporting.
(http:llctep.cancer.gov/reporting/ctc.html)
12.3 Response Evaluation Criteria
Consensus guidelines regarding definitions of MRD were developed following the Second International
Symposium on MRD Assessment.l6 To summarize, quantifiable MRD is required for eligibility for this
study. Complete MRD response is defined as having achieved MRD negativity or no longer detectable.
MRD persistence is defined as continuously quantifiable MRD positivity measurable at> 2 time points
with > 1 relevant treatment element (e.g., a cycle of study treatment) in between. MRD reappearance is
 
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conversion from MRD negativity to quantifiable MRD positivþ. Low-level, non-quantiflrable MRD
positivity does not fit into any of these categories.
For the purposes of determining morphologic relapse/progression, this will be defined as the appearance
of leukerniõ bhsts in the peripheral blood or> 5Yo blasts in the bone marrow not attributable to any other
cause.lT
When considering subject eligibility or signs of treatment failure, extramedullary disease will be
suspected in the presence of lymph nodes > 1.5 cm in longest diameter, extranodal sites > 1.0 cm in
longest diameter, or splenomegaly with an increase in length of > 50Vo. These definitions are adapted
from international *oiking group criteria for the evaluation of lymphoma (the Lugano classification).I8
For the pu{poses of this study, these parameters will not define the presence of extramedullary disease,
but instêad will be used as a guide to consider its presence; when feasible and if the results of imaging
studies are equivocal, biopsy will be preferred to confirm or refute this suspicion.
12.4 Grading of Acute Graft-Versus-Host Disease"
Severity of Individual Organ Involvement
Skín
+1
a maculopapular eruption involving less than 25%
ofthe body surface
+2
a maculopapular eruption involving 25-50% of the
body surface
+3
generalized erythroderma involving >50yo of the
body surface
+4
generalized erythroderma with bullous formation
and often with desquamation
Liver
+1
bilirubin (2.0-2.9 mg/ I 00ml)
+2
bilirubin (3-5.9 mg/l 00ml)
+3
bilirubin (6-14.9 mg/l 00ml)
+4
bilirubin > 15mg/100m1
Gut
Diarrhea is graded +l to +4 in severity. Nausea and vomiting
and/or anorexia caused by GVHD is assigned as *l in
severity. The severity of gut involvement is assigned to the
most severe involvement noted. Patients with visible bloody
diarrhea are atleast stage +2 gut and grade +3 overall
Dìarrhea
+1
< 1000 ml of liquid stool/day*
+2
>1,000 ml of stool/day*
 
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+3
>1,500 ml of stool/day*
+4
2,000 ml of stoollday*
*In the absence of infectious/medical cause
Severity of GVHD
Grøde I
+l fo +2 skin rash
No gut or liver involvement
Grøde II
+1 to +3 skin rash and/or
+1 gastrointestinal involvement and/or +1
liver involvement
Grade III
+4 skin involvement and/or
+2 to +4 gastrointestinal involvement andior
+2to +4liver involvement with or without a
rash
Grade IV
Pattern and severity of GVHD similar to
grade 3 with extreme constitutional
symptoms or death
a. From "Graft-vs-host disease" Sullivan, Keith M. Hematopoietic Cell Transplantation Ed: D. Thomas,
K. Blume, S. Forman, Blackwell Sciences; 1999, pages 518-519.
 
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13.0 REFERENCES
1. 
Gokbuget N. How I treat older patients with ALL. Blood 2013;122:1366-75.
2. 
Bruggemann M, Raff T, Kneba M. Has MRD monitoring superseded other prognostic factors
in adult ALL? Blood 2012;120:4470-81.
3. 
Bruggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease
quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 2006;107:ll16-
23.
4. 
Raff T, Gokbuget N, Luschen S, et al. Molecular relapse in adult standard-risk ALL patients
detected by prospective MRD monitoring during and after maintenance treatment; data from the
GMALL 06199 and 07103 trials. Blood 2007;109:910-5.
5. 
Bar M, Wood BL, Radich JP, et al. Impact of minimal residual disease, detected by flow
cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic
leukemia. Leuk Res Treatment. E-pub: 23 };4arch2014. 10.1155/20141421723.
6. 
Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cell-engaging antibody
blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic
leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol
20ll;29:2493-8.
7. 
Gökbuget N, Dombret H, Bonifacio M, et al. Long-Term Outcomes after Blinatumomab
Treatment: Follow-up of a Phase 2 Study in Patients (Pts) with Minimal Residual Disease (MRD)
Positive B-Cell Precursor Acute Lymphoblastic Leukemia (ALL). ASH Annual Meeting 2015;126:
Abstract 680.
8. 
Herbst RS, Soria JC, Kowanetz}y'r, et al. Predictive correlates of response to the anti-PD-Ll
antibody MPDL3280A in cancer patients. Nature 2014;515:563-7.
9. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1
antibody in cancer. N Engl J Med 2012;366:2443-54.
10. 
Tumeh PC, Harview CL, Yearley JH, et al. PD-l blockade induces responses by inhibiting
adaptive immune resistance. Nature 20 I 4;5 I 5 :5 68-7 | .
I 1. 
Armand P, Nagler A, Weller EA, et al. Disabling immune tolerance by programmed death-l
blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-
cell lymphoma: results of an international phase II trial. J Clin Oncol 2013;31:4199-206.
12. 
Wu D, Emerson RO, Sherwood A, et al. Detection of minimal residual disease in B
lymphoblastic leukemia by high-throughput sequencing of IGH. Clin Cancer Res 2014;20:4540-8.
13. 
Wu D, Sherwood A, Fromm JR, et al. High-throughput sequencing detects minimal residual
disease in acute T lymphoblastic leukemia. Sci Transl Med20l2;4:134ra63-
14. 
Sala Torra O, Othus M, Williamson DW, et al. Minimal Residual Disease Detection By Next
Generation Sequencing in Adult B-Cell Acute Lymphoblastic Leukemia (ALL) Patients Treated on
SWOG Trial 50333. ASH Annual Meeting 2014;,124: Abstract2399.
1 5. 
Logan AC, Vashi N, Faham M, et al. Immunoglobulin and T cell receptor gene high-throughput
sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-
transplantation relapse and survival. Biol Blood Marrow Transplant 2014;20:1307-13.
16. 
Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification in European
ALL trials: proceedings ofthe Second International Symposium on MRD assessment in Kiel, Germany,
I 8-20 September 2008. Leukemia 20 I 0 ;24:521 -3 5 .
17. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International
Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and
 
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Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003;21:4642-
9.
18. 
Cheson BD, Fisher R[, Bamington SF, et al. Recommendations for initial evaluation, staging,
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin
Oncol 201 4;32:3 059 -68.
 
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