A Phase 1 Study of Ipilimumab in Combination With Decitabine in Relapsed or Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Previously Treated Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Myelodysplasia-Related, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Myelodysplastic Syndrome, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndrome
Sponsor: National Cancer Institute (NCI)

1 
 
 
To:  
Cancer Therapeutic Evaluation Program  
From:       Jacqueline S. Garcia, MD 
Date:  
June 30, 2020 
Re: 
Response to Request for Amendment for Protocol #10026: “A Phase 1 Study of 
Ipilimumab in Combination with Decitabine in Relapsed or Refractory 
Myelodysplastic Syndrome/Acute Myeloid Leukemia” 
 
I. 
Request for Amendment 
 
# 
Section 
Comments 
1. 
Participating 
Organizations 
Changes to Participating LAOs:  
 
Deleted: GA031 Northside Hospital  
LAO-OH007 / Ohio State University Comprehensive Cancer Center 
LAO 
RESTRICTED TO: OH029 Case Western Reserve University  
PI Response:  We have made the requested changes. 
 
 

1 
 
NCI Protocol #: 
10026 
 
Local Protocol #: 
17-718 
 
ClinicalTrials.gov Identifier:  NCT02890329 
 
TITLE:  A Phase 1 Study of Ipilimumab in Combination with Decitabine in Relapsed or 
Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia   
  
Corresponding Organization: LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
Principal Investigator: 
Jacqueline S. Garcia, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215-5450 
Telephone: 617-632-6349 
Fax: 617-582-9806 
Email: jacqueline_garcia@dfci.harvard.edu 
 
Participating Organizations  
LAO-CA043  
City of Hope Comprehensive Cancer Center LAO 
                                        RESTRICTED TO: 
CA043 
City of Hope Comprehensive Cancer Center 
LAO-CT018  
 Yale University Cancer Center LAO 
                                        RESTRICTED TO:  
CA249 
University of California San Diego Moores Cancer Center 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
                                        RESTRICTED TO: 
VA009 
University of Virginia Cancer Center 
         *Disclaimer: Sites require approval from overall PI before opening the study.  
 
 
 
 
 
 

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Statisticians: 
Donna S. Neuberg, ScD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02115 
Phone: 617-632-2448 
Fax: 617-632-2444 
Email (preferred mode of contact): neuberg@jimmy.harvard.edu    
 
Yael Flamand, MS 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02115 
Phone: 617-632-2511  
Fax: 617-632-2444 
Email (preferred mode of contact): yael@jimmy.harvard.edu 
 
Responsible Study Coordinators: 
Jeremy Stewart  
Dana-Farber Cancer Institute 
Longwood Galleria, 350 Longwood Ave. 
Boston, MA 02115 
Phone: 617-582-8063 
Fax: 617-632-4752 
Email: jeremyM_stewart@dfci.harvard.edu  
 
Alexandra Savell 
Dana-Farber Cancer Institute 
10 Brookline Place BP 1150 
Boston, MA 02115 
Phone: 617-632-3539 
Fax: 617-632-5152 
Email: asavell@partners.org  
 
Responsible Research Nurse: 
Ilene Galinsky, N.P.   
Dana-Farber Cancer Institute 
450 Brookline Avenue, Dana 2057 
Boston, MA 02215 
Phone: 617-632-3902 
Fax: 617-632-5168 
Email: Ilene_Galinsky@dfci.harvard.edu 
 
Responsible Data Managers: 
Jeremy Stewart 

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Dana-Farber Cancer Institute 
Longwood Galleria, 350 Longwood Ave. 
Boston, MA 02115 
Phone: 617-632-8063 
Fax: 617-632-4752 
Email: jeremym_stewart@dfci.harvard.edu  
 
Alexandra Savell 
Dana-Farber Cancer Institute 
10 Brookline Place BP 1150 
Boston, MA 02115 
Phone: 617-632-3539 
Fax: 617-632-5152 
Email: asavell@partners.org 
 
 
NCI-Supplied Agent:  Ipilimumab  (NSC 732442) 
Other Agent:  Decitabine (NSC 127716)  - Commercial  
  
 
IND #:   
IND Sponsor:  DCTD, NCI 
 
  
Protocol Type / Version # / Version Date: 
Original/ Version #21 / 6/30/2020 
 
 
 
 

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SCHEMA 
 
 
 
 
 
Dose Escalation Schedule 
Dose Level 
Dose 
Ipilimumab 
(mg/kg)  
Decitabine 
(mg/m2) 
Level -1 
1 
20 
Level 0 
(starting dose) 
3 
20 
Level 1 
5 
20 
Level 2 
10 
20 
 
 

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TABLE OF CONTENTS 
 
SCHEMA .............................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Relapsed/Refractory MDS/AML .............................................................................9 
2.2 
CTEP IND Agent: Ipilimumab ..............................................................................11 
2.3 
Decitabine ..............................................................................................................28 
2.4 
Rationale ................................................................................................................30 
2.5 
Correlative Studies Background ............................................................................33 
3. 
PATIENT SELECTION ....................................................................................................36 
3.1 
Eligibility Criteria ..................................................................................................36 
3.2 
Exclusion Criteria ..................................................................................................38 
3.3 
Pregnancy ...............................................................................................................40 
3.4 
Inclusion of Women and Minorities ......................................................................41 
4. 
REGISTRATION PROCEDURES ...................................................................................41 
4.1 
Investigator and Research Associate Registration with CTEP ..............................41 
4.2 
Site Registration .....................................................................................................43 
4.3 
Patient Registration ................................................................................................45 
4.4 
General Guidelines .................................................................................................46 
5. 
TREATMENT PLAN ........................................................................................................46 
5.1 
Agent Administration .............................................................................................47 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................52 
5.3 
Dose Expansion Cohorts ........................................................................................53 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................54 
5.5 
Duration of Therapy ...............................................................................................54 
5.6 
Duration of Follow Up ...........................................................................................55 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................56 
6.1 
Dose Delay Recommendations for Patients with Suspected Decitabine 
Related Toxicity .....................................................................................................56 
6.2 
Dose Delay Recommendations for Patients with Suspected Ipilimumab 
Toxicity or Combination Therapy .........................................................................57 
6.3 
Other Guidance for the Treatment of Ipilimumab Associated Reactions ..............62 
6.4 
Monitoring and Management of Immune-mediated Adverse Reactions ...............63 
6.5 
Prohibited and Restricted Therapies ......................................................................68 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................70 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................70 

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7.2 
Adverse Event Characteristics ...............................................................................80 
7.3 
Expedited Adverse Event Reporting ......................................................................81 
7.4 
Routine Adverse Event Reporting .........................................................................83 
7.5 
Secondary Malignancy ...........................................................................................84 
7.6 
Second Malignancy ................................................................................................84 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................84 
8.1 
CTEP IND Agent: Ipilimumab ..............................................................................84 
8.2 
Commercial Agent: Decitabine..............................................................................88 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................89 
9.1 
Pharmacodynamic Study .......................................................................................95 
9.2 
Exploratory/Ancillary Correlative Studies ............................................................95 
10. 
STUDY CALENDAR .....................................................................................................100 
10.1 
Study Schedule.....................................................................................................101 
10.2 
Correlative Sample Schedule ...............................................................................105 
11. 
MEASUREMENT OF EFFECT......................................................................................107 
11.1 
Antitumor Effect – Hematologic Tumors ............................................................107 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................108 
12.1 
Study Oversight ...................................................................................................109 
12.2 
Data Reporting .....................................................................................................109 
12.3 
CTEP Multicenter Guidelines ..............................................................................111 
12.4 
Collaborative Agreements Language ...................................................................111 
12.5 
Genomic Data Sharing Plan .................................................................................113 
13. 
STATISTICAL CONSIDERATIONS.............................................................................113 
13.1 
Study Design/Endpoints.......................................................................................113 
13.2 
Sample Size/Accrual Rate ....................................................................................115 
13.3 
Stratification Factors ............................................................................................115 
13.4 
Analysis of Primary Endpoints ............................................................................116 
13.5 
Analysis of Secondary Endpoints ........................................................................116 
REFERENCES ............................................................................................................................117 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................124 
APPENDIX B 
SUGGESTED GRAFT VERSUS HOST DISEASE WORKSHEET .....125 
APPENDIX C 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS, 
DIARRHEA, HEPATOTOXICITY, ENDOCRINOPATHY, SKIN AND 
NEUROPATHY * ...........................................................................................................131 
APPENDIX D    
ACUTE MYELOID LEUKEMIA RESPONSE CRITERIA ..................138 

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APPENDIX E  MDS RESPONSE CRITERIA ...........................................................................140 
APPENDIX F ADVERSE EVENT GUIDANCEAND PRE TREATMENT CRITERIA 
CHECKLIST....................................................................................................................141 
APPENDIX G PATIENT SAFETY WALLET MEDICATION CARD  ...................................142 
APPENDIX H EUROPEAN LEUKEMIA NET CRITERIA .....................................................145 
 
 
 

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1. OBJECTIVES 
 
A recognized feature of cancer is escape from immune surveillance. Therefore augmenting 
tumor immunity is a promising treatment approach. Immune checkpoint blockade with drugs 
such as ipilimumab (anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapy) [1] and 
nivolumab [2] or pembrolizumab (anti-PD-1 therapies) [3] have been successful in providing 
marked prolonged survival benefits among patients with metastatic melanoma. The role of 
CTLA-4 blockade has been preliminarily explored in hematologic malignancies in the post-
transplant setting with demonstration of safety and activity primarily in patients with acute 
myeloid leukemia (AML) with low disease burden [4, 5].  
 
The primary objective of this phase 1 study is to identify an MTD for ipilimumab in combination 
with standard dose decitabine therapy in patients with relapsed or refractory myelodysplastic 
syndrome (MDS)/AML. If there is demonstration of safety, tolerability and preliminary efficacy, 
further testing of ipilimumab in combination with decitabine will be explored in a future phase 2 
trial. 
 
This is an open-label phase 1 study using a 3+3 design with planned dose escalation of 
ipilimumab in combination with standard dose decitabine in patients with relapsed or refractory 
MDS/AML. The study will include three treatment phases, including epigenetic priming (lead in) 
with decitabine monotherapy x 1 cycle), induction (cycles 1-4 with combination decitabine and 
ipilimumab), and maintenance (cycles 5-12 with combination decitabine and ipilimumab).    
 
1.1 
Primary Objectives 
 
1.1.1 To determine the maximum tolerated dose (MTD) or recommended phase 2 dose 
(RP2D) of combination decitabine and ipilimumab for relapsed or refractory MDS 
or relapsed or refractory AML in patients who are post allogeneic hematopoietic 
stem cell transplant (allo-HCT).  
1.1.2 To determine the MTD or RP2D of combination decitabine and ipilimumab for 
relapsed or refractory MDS or relapsed or refractory AML in patients who are 
transplant naive.  
 
1.2 
Secondary Objectives 
 
1.2.1 To observe and record anti-tumor activity.  Although the clinical benefit of this 
novel combination has not yet been established, the intent of offering this 
treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor response and symptom relief in addition to safety 
and tolerability. 
 

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1.2.2 To determine the overall response rate (ORR) including complete remission (CR) 
and complete remission with incomplete count recovery (CRi) for AML following 
2003 IWG response criteria [6].  
1.2.3 To determine the ORR including CR, partial remission, marrow CR, hematologic 
improvement for MDS using 2006 IWG criteria [7]. 
1.2.4 To determine the overall survival and progression free survival at 1 year.  
1.2.5 To determine the duration of remission. 
1.2.6 To capture the incidence and severity of acute graft-versus-host disease (GVHD) 
in the post allo-HCT cohort. 
1.2.7 To capture the incidence and severity of chronic graft-versus-host disease (GVHD) 
in the post allo-HCT Cohort 
 
 
1.3 
 Exploratory Objectives 
1.3.1 To measure the absolute lymphocyte count (ALC) prior to treatment and during 
treatment. We will compare changes in ALC between responders and non-
responders given evidence that ALC after two cycles may be a predictor of clinical 
response in solid tumors.  
1.3.2 To evaluate the genome for evidence of clonal evolution among longitudinal 
samples (prior to treatment, during treatment, and at relapse if relevant) from 
individual patients. We will compare leukemic genotypic patterns among 
responders and non-responders. 
1.3.3 To evaluate the histopathologic findings of immune response using 
immunohistochemistry.  
1.3.4 To determine the immune response in the AML tumor microenvironment by using 
flow cytometry and single cell mass cytometry to evaluate T cell subsets. We will 
evaluate cytokine and chemokine panels. We will further evaluate the gene 
expression patterns of immune infiltrates.  We will evaluate for alterations in 
antigen presenting cells in response to decitabine and combination therapy.  We 
will evaluate for resistance to immune response due to STAT3 activation. 
 
2. BACKGROUND 
 
2.1 
Relapsed/Refractory MDS/AML 
 
High-risk MDS and outcomes 
MDS is predominantly a disease of the elderly. The International Prognostic Scoring System is a 
tool used to predict the likely survival of MDS patients at the time of diagnosis [8, 9].  Patients 
with higher-risk MDS account for 29% of the patient population, including 22% with 
intermediate-2 MDS and 7% with high-risk MDS [9].  In fact, for patients with intermediate-2 
and high-risk MDS, the median survival without therapy was predicted to be 1.1 years and 0.4 
years, respectively. Thus, for higher-risk MDS patients, the primary goals for treatment focus on 
extending overall survival and altering the natural course of disease by delaying time to leukemic 
transformation.  First line agents to treat MDS include hypomethylating agents such as 
azacitidine and decitabine.  These DNA methyltransferase inhibitors promote the synthesis of 
DNA that otherwise were silenced by methylation marks.  Results from a multi-center study 

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demonstrated that treatment with 5 consecutive days of decitabine at 20 mg/m2 intravenously 
(IV) among 99 patients resulted in an improvement in approximately half the patients on study, 
including 17 patients with complete remission (CR), 15 patients with marrow CR, and 18 patient 
with hematologic improvement [10]. Among patients who benefited from treatment, responses 
were as early as the end of cycle 2.  
 
AML and outcomes 
AML is a disease of the elderly with a median age of diagnosis of 67 years (SEER 2008-2012).  
Chemotherapy resistance and disease relapse are the primary challenges affecting the majority of 
patients in the treatment of acute leukemia. For patients less than 60 years of age, traditional 
induction chemotherapy with combination anthracycline and cytarabine results in CR rates of 50-
70% [11]. Despite achieving remission, a significant number of younger patients with AML with 
poor risk features at diagnosis will be refractory to induction therapy or ultimately relapse after 
initial response to induction chemotherapy.  Poor risk features include antecedent hematological 
disorder, adverse cytogenetic features, and adverse molecular mutations [12]. Disease relapse 
remains the primary cause of treatment failure.  Elderly patients with AML have a poor 
prognosis due to increased disease resistance to standard intensive chemotherapy regimens and 
relatively decreased tolerance to these agents [13].  There is no identified optimal treatment 
strategy for elderly patients who are not candidates for allo-HCT, which remains the only 
curative option in this setting but is actually applied to only a small number of patients.  Less 
intensive and therefore better-tolerated regimens include low-dose cytarabine and 
hypomethylating agents.  Azacitidine is approved for the treatment of MDS and for patients with 
AML with low blast count (20-30% bone marrow blasts).  Although approved in the United 
States for the treatment of MDS including patients with 20-30% bone marrow blasts and in 
Europe for the treatment of AML, decitabine continues to be used off-label given its anti-
leukemic activity and tolerability.  In a multicenter phase 2 study, elderly patients with untreated 
AML received decitabine 20 mg/m2 intravenously for 5 consecutive days every 28 days [14].  
Results from this study showed a CR rate of 24%, a median OS of 7.7 months and a 30-day 
mortality rate of 7% [14].  A large, randomized phase III study for patients 65 years and older 
with untreated AML comparing decitabine to supportive care and cytarabine demonstrated a CR 
plus CRp rate of 17.8% versus 7.8%, respectively [15].  Hence, hypomethylating agents such as 
decitabine are a reasonable anti-leukemic agent given its tolerability but its anti-leukemic activity 
and survival benefits are limited as a single agent.  The development of novel and effective non-
intensive therapeutic strategies for elderly AML patients remain an unmet need.   
 
Relapsed MDS/AML after transplant  
Patients with relapsed or refractory AML have a dismal prognosis.  Allo-HCT is an established 
and potentially curative treatment option for patients with AML and high-risk MDS.  Transplant 
or treatment related mortality has decreased significantly with the implementation of reduced-
intensity conditioning regimens, enabling allo-HCT to become an option for patients with older 
age and with co-morbidities [16].  Despite these recent improvements in conditioning regimens 
and in supportive care, 30-40% of patients with AML [17] and 15-35% of patients MDS [18, 19] 
still relapse after allo-HCT.  Disease recurrence after allo-HCT is a devastating event with a 
median time to relapse of approximately 4 months. These patients have a 5-year OS of about 5%.  
Available treatment options with variable outcomes include clinical trials with novel therapies, 
withdrawal of immunosuppressive therapy, donor lymphocyte infusion (DLI), chemotherapy, 

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hypomethylating agents, and a second allo-HCT.   
 
Role of immunotherapies in MDS/AML 
The role of immunotherapy, specifically checkpoint blockade, requires further exploration in 
AML. The graft versus tumor (or graft versus leukemia) effect observed in patients who undergo  
allo-HCT [20, 21] is evidence that modulation of the immune system can have an anti-leukemic 
effect. Tumors can avoid immune surveillance by stimulating immune inhibitory receptors that 
negatively regulate T-cell activation.  CTLA-4 is expressed on both activated T cells and 
regulatory T cells and binds to ligands B7.1 (CD80) and B7.2 (CD86) on antigen presenting cells 
(APC) [22]. It functions as a negative regulator of T cell activation by triggering intracellular 
pathways that suppress proliferative and anti-apoptotic signals on effector T cells, enhancing 
activity of CD4+ regulatory T cells, and down-regulating T-helper cell activity [22].  Blockade 
of this immune inhibitory checkpoint provides a potential method to boost anti-leukemic 
immunity. 
 
2.2 
CTEP IND Agent: Ipilimumab 
 
2.2.1 Ipilimumab 
 
For complete information, please refer to the most recent Investigator’s Brochure. 
 
Ipilimumab (MDX-010, MDX-CTLA4, BMS-734016) is being developed by CTEP as an 
anticancer agent in collaboration with Bristol-Myers-Squibb (BMS).  On March 25, 2011, the 
FDA approved ipilimumab injection (YERVOY, BMS) for the treatment of unresectable or 
metastatic melanoma.  Ipilimumab is a human IgG1κ monoclonal antibody (mAb); it is specific 
for human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152) expressed on 
activated T cells.  Ipilimumab is now produced and formulated from transfected Chinese hamster 
ovary (CHO) cells.   
 
CTLA-4 is a negative regulator of T-cell responses following T-cell stimulation [23, 24].  
CTLA-4 knockout mice suffer from a fatal lymphoproliferative disorder, supporting the idea that 
CTLA-4 functions as a negative regulator of T-cell responses in vivo [25-27].  Disrupting CTLA-
4 interaction with its ligands B7-1 (CD80) and B7-2 (CD86), which are expressed on antigen-
presenting cells (APCs), with ipilimumab, augments immune responses (Investigator Brochure, 
2011).  In vivo blockade of CTLA-4, utilizing anti-CTLA-4 mAb, induced regression of 
established tumors and enhanced antitumor immune responses in several murine tumor models.  
Blockade of CTLA-4-mediated signals is effective in inducing rejection of immunogenic cancers 
in mice.  Moreover, when anti-CTLA-4 mAb is used in conjunction with granulocyte 
macrophage-colony stimulating factor (GM-CSF)-secreting tumor vaccines, poorly 
immunogenic cancers in mice are rejected.  These findings suggest that CTLA-4 blockade, alone 
or in combination with antigenic stimulation and other immune modulating agents can induce a 
potent antitumor response.   
 
Pharmacology of Ipilimumab 
In vitro studies were performed with ipilimumab to demonstrate that it is specific for CTLA-4, 
actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity 

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with human B7.1 or B7.2 negative cell lines, and stains the appropriate cells without non-specific 
cross-reactivity in normal human tissues.  Ipilimumab does cross-react with CTLA-4 in non-
human primates including cynomolgus monkeys.  Blockade of CTLA-4/B7 interactions 
enhanced T-cell responses to CD3 / CD28, peptide antigens, or superantigens in mice [28-30].  
CTLA-4 knockout mice appear to have spontaneously activated T cells evident at approximately 
1 week after birth, followed by rampant lymphoproliferation and lymphadenopathy.  These mice 
die at approximately 3 weeks of age, either as a result of polyclonal T-cell expansion and tissue 
destruction or as a result of toxic shock resulting from lymphokine production.  Genetically 
engineered mice heterozygous for CTLA-4 (CTLA-4+/-), appeared healthy and gave birth to 
healthy CTLA-4+/- heterozygous offspring.  Mated CTLA-4+/- heterozygous mice also 
produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-).  Since thymocyte 
differentiation and selection proceed normally in CTLA-4-deficient mice, the rampant T-cell 
expansion that occurs in the mice indicates that CTLA-4 plays a critical role in down-regulating 
post- thymic T-cell responses in the periphery following stimulation of naïve, memory, and 
effector T cells [30].   
 
Pharmacodynamic Effects 
In clinical studies, ipilimumab increased absolute lymphocytes counts (ALC) in peripheral blood 
(Investigator Brochure, 2011).  However, CD4+/CD8+ ratio did not appear to be affected. 
Across three phase 2 studies in 463 subjects with advanced melanoma, ipilimumab increased 
ALC in a dose-dependent manner, with the largest increase observed at 10 mg/kg dose. ALC 
continued to increase over time during the induction treatment at least until week 12 at the 3 
mg/kg and 10 mg/kg dose, but not at the 0.3 mg/kg dose. The slope of ALC increase also 
suggested the 10 mg/kg dose is more biologically active than the 3.0 mg/kg or 0.3 mg/kg dose 
 
Mechanism of Action 
The proposed mechanism of action for ipilimumab is T-cell potentiating through interference of 
the interaction of CTLA-4 with B7 (CD80 or CD86) molecules on APCs, with subsequent 
blockade of the inhibitory function of CTLA-4 (Investigator Brochure, 2011). Ipilimumab 
impacts tumor cells indirectly, and measurable clinical effects emerge after the immunological 
effects. Tumor infiltration with lymphocytes and the associated inflammation is likely the 
cornerstone of the effect of ipilimumab and can manifest in various patterns of clinical activity 
leading to tumor control. These immunologic responses may take time to develop and so tumor 
responses may be delayed and tumor progression may occur during the initial period followed by 
responses. In some cases, tumor response based on tumor infiltration with immune cells may be 
preceded by an apparent increase in initial tumor volume and/or the appearance of new lesions, 
which may be taken for tumor progression on radiological evaluations. Delayed responses 
following increasing tumor size or appearance of new lesions have been seen in approximately 
10-20% of patients with metastatic melanoma. For patients who are not experiencing rapid 
clinical deterioration, allowing sufficient time to observe responses including disease 
stabilization or confirmation of progression is recommended; as discussed in the section “Overall 
Risk/Benefit Assessment” may allow better assessment of clinical activity and avoid 
unnecessarily initiating additional therapies in subjects who might be benefitting from treatment. 
Immune-related (ir) response criteria were developed based on these observations in patients 
with melanoma to systematically categorize novel patterns of clinical activity and are currently 
being prospectively evaluated in clinical studies. 

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Pharmacokinetics  
The pharmacokinetics of ipilimumab was studied in 785 patients with advanced melanoma who 
received induction doses ranging from 0.3 to 10 mg/kg administered once every 3 weeks for 4 
doses. Cmax, Cmin and AUC of ipilimumab were found to be dose proportional within the dose 
range examined. Upon repeated dosing of ipilimumab administered every 3 weeks, clearance 
was found to be time-invariant, and minimal systemic accumulation was observed as evident by 
an accumulation index 1.5 fold or less. Ipilimumab steady-state was reached by the third dose. 
Based on population pharmacokinetic analysis, the following mean (percent coefficient of 
variation) parameters of ipilimumab were obtained: terminal half-life of 15.4 days (34.4%); 
systemic clearance of 16.8 ml/h (38.1%); and volume of distribution at steady-state of 7.47 l 
(10.1%). The mean (percent coefficient of variation) ipilimumab Cmin achieved at steady-state 
with a 3 mg/kg induction regimen was 19.4 μg/ml (74.6%). Ipilimumab clearance increased with 
increasing body weight and with increasing LDH at baseline; however, no dose adjustment is 
required for elevated LDH or body weight after administration on a mg/kg basis. Clearance was 
not affected by age (range 23-88 years), gender, concomitant use of budesonide or dacarbazine, 
performance status, HLA-A2*0201 status, mild hepatic impairment, renal impairment, 
immunogenicity, and previous anticancer therapy. The effect of race was not examined as there 
was insufficient data in non-Caucasian ethnic groups. No controlled studies have been conducted 
to evaluate the pharmacokinetics of ipilimumab in the paediatric population or in patients with 
hepatic or renal impairment. Based on an exposure-response analysis in 497 patients with 
advanced melanoma, OS was independent of prior systemic anti-cancer therapy and increased 
with higher ipilimumab Cminss plasma concentrations.  
 
Renal impairment 
In the population pharmacokinetic analysis of data from clinical studies in patients with 
metastatic melanoma, pre-existing mild and moderate renal impairment did not influence the 
clearance of ipilimumab. Clinical and pharmacokinetic data with pre-existing severe renal 
impairment are limited; the potential need for dose adjustment cannot be determined 
 
Hepatic impairment 
In the population pharmacokinetic analysis of data from clinical studies in patients with 
metastatic melanoma, pre-existing mild hepatic impairment did not influence the clearance of 
ipilimumab. Clinical and pharmacokinetic data with pre-existing moderate hepatic impairment 
are limited; the potential need for dose adjustment cannot be determined. No patients with pre-
existing severe hepatic impairment were identified in clinical studies. 
 
Clinical Pharmacokinetics of Ipilimumab Monotherapy 
The PK of ipilimumab has been extensively studied in subjects with melanoma, at the 3 and 10-
mg/kg doses administered as a 1.5-hour IV infusion. The PK of ipilimumab was characterized by 
population PK (PPK) analysis and determined to be linear and time invariant in the dose range of 
0.3 to 10 mg/kg.  The mean CL (+/-SD) value after IV administration of 10 mg/kg was 18.3 ± 
5.88 mL/h, and the mean steady-state volume of distribution (Vss) [+/-SSD] value was 5.75 +/-
S1.69 L. The CL and Vss from Studies CA184007 and CA184008 were similar to those reported 
from Study MDX010-15. 
 

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Population Pharmacokinetics 
The PPK of ipilimumab was studied in 785 subjects (3200 serum concentrations) with advanced 
melanoma in 4 Phase 2 studies (CA184004, CA184007, CA184008, and CA184022), 1 Phase 3 
study (CA184024), and 1 Phase 1 study (CA184078). The PPK analysis demonstrated that the 
PK of ipilimumab is linear, the exposures are dose proportional across the tested dose range of 
0.3 to 10 mg/kg, and the model parameters are time-invariant, similar to that determined by 
noncompartmental analyses. Upon repeated dosing of ipilimumab, administered q3w, minimal 
systemic accumulation was observed by an accumulation index of 1.5-fold or less, and 
ipilimumab steady-state concentrations were achieved by the third dose. The ipilimumab CL of 
16.8 mL/h from PPK analysis is consistent with that determined by noncompartmental PK 
analysis. The terminal T-HALF and Vss of ipilimumab calculated from the model were 15.4 
days and 7.47 L, respectively, which are consistent with that determined by noncompartmental 
analysis. Volume of central compartment (Vc) and peripheral compartment were found to be 
4.35 and 3.28 L, respectively, suggesting that ipilimumab first distributes into plasma volume 
and, subsequently, into extracellular fluid space. CL of ipilimumab and Vc were found to 
increase with increase in BW. However, there was no significant increase in exposure with 
increase in BW when dosed on a milligram/kilogram basis, supporting dosing of ipilimumab 
based on a weight normalized regimen. The PK of ipilimumab is not affected by age, gender, 
race, and immunogenicity (anti-drug antibody [ADA] status); concomitant use of chemotherapy; 
prior therapy; BW; performance status; or tumor type. Other covariates had effects that were 
either not statistically significant or were of minimal clinical relevance. 
 
Nonclinical Toxicology  
 
Please note relevant toxicity for single agent ipilimumab has been almost completely 
derived from clinical studies.  
 
In a study using cynomolgus macaques, anti-melanocyte responses were observed in animals 
given up to four doses of 10 mg/kg ipilimumab after receiving a melanoma cell vaccine [31].  
Depigmentation has been observed in other nonclinical immunotherapy studies that involve 
treatment with melanoma peptides [32-37].  The symptoms in animals appear to resemble 
vitiligo observed in clinical immunotherapy trials of melanoma patients and may be an 
unavoidable consequence of treatment [38]. 
 
Additional repeat-dose toxicity studies conducted using cynomolgus macaques demonstrated that 
the IV administration of ≤30 mg/kg every 3 days for three doses, 10 mg/kg weekly for 1 month, 
1 mg/kg weekly for 10 weeks, or 10 mg/kg monthly for 6 months was generally well tolerated, 
without significant clinical, immunotoxicological, or histopathological findings (Investigator 
Brochure, 2011).  However, when ipilimumab was administered in combination with another 
immunomodulatory antibody (BMS-663513, a fully human anti-CD137 mAb) and simian 
immunodeficiency virus (SIV) DNA, two immune-related adverse events (irAEs) were observed:  
severe colitis requiring euthanasia in one monkey and reversible dermatitis/rash in the inguinal 
area and peripheral lymphadenopathy in another monkey. 
 

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Complete information on the pre-clinical toxicology studies can be found in the Ipilimumab 
Investigator Brochure (IB).  Non-clinical toxicity assessments included in vitro cynomolgus 
monkeys alone and in the presence of vaccines.  Low to moderate ADCC activity was noted at 
concentrations up to 50 mcg/mL.  These data are consistent with the requirement of high levels 
of antigen expression on the surface of target cells for efficient ADCC or CDCC.  No mortality 
or signs of toxicity were observed in three independent 14-day intravenous (IV) toxicology 
studies in cynomolgus monkeys at multiple doses up to 30 mg/kg/dose.  Furthermore, 
ipilimumab was evaluated in sub-chronic and chronic toxicology studies in cynomolgus 
monkeys with and without Hepatitis B (HepB) Vaccine and Melanoma Vaccine.  Ipilimumab 
was well tolerated alone or in combination in all studies.  There were no significant changes in 
clinical signs, body weight values, clinical pathology values or T-cell activation markers. In 
addition, there were no significant histopathology changes in the stomach or colon. 
 
Clinical Development of Ipilimumab   
 
Company-Sponsored Studies 
BMS and Medarex (acquired by BMS in Sep-2009) have co-sponsored an extensive clinical 
development program for ipilimumab, encompassing more than 19,500 subjects (total number of 
subjects enrolled in ipilimumab studies) in several cancer types in completed and ongoing 
studies, including a compassionate use. The focus of the clinical program is in melanoma, 
prostate cancer, and lung cancer, with advanced melanoma being the most comprehensively 
studied indication. Ipilimumab is being investigated both as monotherapy and in combination 
with other modalities such as chemotherapy, radiation therapy, and other immunotherapies. 
Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 2 
completed Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically 
meaningful and statistically significant survival benefit in pretreated advanced melanoma and 
previously untreated advanced melanoma with a manageable safety profile, respectively. An 
ongoing Phase 3 study (CA184029) in melanoma is investigating ipilimumab as adjuvant 
monotherapy for high-risk Stage III melanoma. In addition, a Phase 3 study (CA184169) 
comparing the safety and efficacy of 3 versus 10 mg/kg ipilimumab monotherapy in pretreated or 
treatment-naïve subjects with unresectable or metastatic melanoma is ongoing 
 
BMS and Medarex (acquired by BMS in Sep-2009) have co-sponsored an extensive clinical 
development program for ipilimumab, encompassing more than 19,500 subjects (total number of 
subjects enrolled in ipilimumab studies) in several cancer types in completed and ongoing 
studies, including a compassionate use. The focus of the clinical program is in melanoma, 
prostate cancer, and lung cancer, with advanced melanoma being the most comprehensively 
studied indication. Ipilimumab is being investigated both as monotherapy and in combination 
with other modalities such as chemotherapy, radiation therapy, and other immunotherapies. 
Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 2 
completed Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically 
meaningful and statistically significant survival benefit in pretreated advanced melanoma and 
previously untreated advanced melanoma with a manageable safety profile, respectively. An 
ongoing Phase 3 study (CA184029) in melanoma is investigating ipilimumab as adjuvant 
monotherapy for high-risk Stage III melanoma. In addition, a Phase 3 study (CA184169) 
comparing the safety and efficacy of 3 versus 10 mg/kg ipilimumab monotherapy in pretreated or 

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treatment-naïve subjects with unresectable or metastatic melanoma is ongoing 
 
The completed Phase 3 study (CA184043) evaluated ipilimumab in subjects with mCRPC who 
had progressed during or following treatment with docetaxel. Eligible subjects were randomized 
to a single dose of bone-directed RT, followed by either ipilimumab 10 mg/kg or placebo (799 
randomized: 399 ipilimumab and 400 placebo). This study did not meet its primary endpoint of 
OS. The HR of 0.85 (95% CI: 0.72, 1.00) for survival favored ipilimumab but did not reach 
statistical significance with a P value of 0.053. Planned sensitivity analyses favored ipilimumab, 
where the greatest benefit appeared to be in subgroups defined by good prognostic features and 
low burden of disease. Additional evidence of ipilimumab activity observed in the study included 
a reduced risk of disease progression relative to placebo (HR = 0.70), superior clinical outcomes 
compared to placebo in tumor regression, and declines in PSA. The safety profile in this study 
was consistent with the previously defined AE profile at the same dose. 
 
A second Phase 3 study (CA184095) evaluated ipilimumab 10 mg/kg versus placebo in subjects 
with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC with no visceral 
metastases.  
 
Activity was also observed in a large Phase 2 study in lung cancer (NSCLC and SCLC; 
CA184041) in combination with chemotherapy. Two ongoing Phase 3 studies are evaluating 
ipilimumab in combination with chemotherapy in squamous NSCLC (CA184104) and SCLC 
(CA184156). In Study CA184104, the last patient, last visit was achieved in June-2015, and 
database lock occurred on 01-Sep-2015. No final data are currently available, but preliminary 
data indicate that no new safety concerns were identified in the course of standard clinical safety 
monitoring of the study. In Study CA184156, preliminary data indicate the primary endpoint of 
prolonging survival was not achieved, but no new safety signals were identified. 
 
While the types of safety events observed in subjects receiving ipilimumab do not appear to 
change, even in combination with other anti-cancer agents, the proportion of subjects 
experiencing 1 type or another irAE may be impacted by the choice of combination partner. Skin 
and GI irAEs predominate in monotherapy studies. In combination with DTIC (melanoma), the 
incidence of skin and GI irAEs was lower than expected, and the incidence of hepatic irAEs was 
higher. In combination with paclitaxel and carboplatin (NSCLC), the incidence of all types of 
irAEs appeared to be numerically lower compared to the incidence observed for ipilimumab 
monotherapy in the Phase 2 program. In a Phase 1 study (CA184161), the concomitant 
administration of vemurafenib and ipilimumab in subjects with BRAF-mutated metastatic 
melanoma resulted in asymptomatic and reversible increases in aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT), exceeding the incidence to be expected when either agent is 
administered as a single agent therapy, leading to discontinuation of this treatment. In a Phase 2 
study (CA184240), sequential treatment with vemurafenib followed by 10 mg/kg ipilimumab in 
subjects with BRAF-mutated metastatic melanoma was tolerable with a manageable safety 
profile. No significant signals of hepatobiliary toxicity were reported. The benefit/risk of this 
sequence needs to be evaluated further based on individual subject characteristics and new 
treatment options.  
 

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Ipilimumab is also being evaluated in clinical studies conducted independently by the Cancer 
Therapy Evaluation Program of the US NCI, as well as in several additional externally-
sponsored studies. 
 
Other Clinical Studies with Ipilimumab 
 
Renal cell carcinoma (RCC) 
Yang and colleagues presented data on a phase 2 study of ipilimumab conducted in patients with 
metastatic RCC [39].   Sequential cohorts received either 3 mg/kg followed by 1 mg/kg or all 
doses at 3 mg/kg q3w.  One of 21 patients receiving the lower dose had a PR.  Five of 40 patients 
at the higher dose had PRs (95% CI, cohort response rate 4 to 27%) and responses were seen in 
patients who had previously not responded to IL-2.  Thirty-three percent of patients experienced 
grade 3 or 4 irAEs.  There was a highly significant association between autoimmune events and 
tumor regression (response rate = 30% with AE, 0% without AE).  The authors concluded that 
CTLA-4 blockade with ipilimumab induced cancer regression in some patients with metastatic 
clear cell renal cancer, even if they had not responded to other immunotherapies.   
 
Melanoma (ipilimumab plus bevacizumab) 
At the 2011 ASCO meeting Hodi and colleagues presented results on 21 evaluable patients (22 
patients enrolled) with unresectable stage III or stage IV melanoma treated with the combination 
of 10 mg/kg ipilimumab and 7.5 mg/kg bevacizumab on a phase 1 study [40].  AEs included 
giant cell arteritis (1), hypophysitis (3), thyroiditis (4), grade 3-4 hepatitis (2), bilateral uveitis 
(2), and grade 2 colitis (2); 5 patients required systemic steroids and stopped treatment.  All 
toxicities were resolved.  Eight PRs and 6 SDs were observed.  All responses were durable (>6 
months).  Post-treatment biopsies in 12 patients revealed activated vessel endothelium with 
extensive T-cell trafficking non-productive central angiogenesis, and peripheral blood 
monitoring revealed a marked increase in CD4/CCR7/CD45RO central memory cells in the 
majority of patients,  not seen with ipilimumab alone.  The authors concluded that the 
combination of ipilimumab with bevacizumab can be safely administered with clinical activity 
and correlatives suggesting synergistic effects.  
 
Bladder cancer 
Carthon and colleaugues reported immunodulatory effects following a brief exposure of anti-
CTLA-4 in patients with urothelial carcinoma of the bladder requiring surgery (BMS study 
CA184027) [41].  12 patients were enrolled (6 patients received 3 mg/kg/dose of ipilimumab and 
another 6 patients received 10 mg/kg/dose for two doses prior to surgery).  The treatment was 
found to be tolerable in the cohort of patients with 11 of 12 patients receiving both doses of 
antibody.  Grade 1-2 diarrhea and rash were the most common drug-related AEs.  The only noted 
grade 3 irAEs were ischemic papillopathy and diarrhea, which were both responsive to treatment 
with steroids.   
 
Liakou and colleagues found that CD4 T cells from peripheral blood and tumor tissues of all 
bladder cancer patients treated with anti-CTLA-4 antibody had markedly increased expression of 
inducible costimulator (ICOS) [42].  These CD4+ICOShi T cells produced interferon-gamma 
(IFN-γ) and could recognize the tumor antigen NY-ESO-1.  Increase in CD4+ICOShi cells led to 
an increase in the ratio of effector to regulatory T cells.  The authors indicated that these 

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immunologic changes were reported in both tumor tissues and peripheral blood as a result of 
treatment with anti-CTLA-4 antibody, and they may be used to guide dosing and scheduling of 
this agent to improve clinical responses.  A sustained increased frequency of CD4+ICOShi T cells 
may serve as a biomarker of anti-CTLA-4 activity and/or of clinical benefit for patients who are 
being treated with this novel agent [41].   
 
Pancreatic cancer 
Royal and colleagues presented the results on 27 patients (metastatic disease: 20 and locally 
advanced: 7) [43].  Three subjects experienced ≥ grade 3 irAEs (colitis:1, encephalitis:1, 
hypophysitis:1).  One subject experienced a delayed response after initial progressive disease.  In 
this subject, new metastases after 2 doses of ipilimumab established progressive disease.  
However, continued administration of the agent per protocol resulted in significant delayed 
regression of the primary lesion and 20 hepatic metastases with normalization of tumor markers 
and clinically significant improvement of performance status.  The investigators concluded that 
single agent ipilimumab at 3.0 mg/kg/dose was ineffective for the treatment of advanced 
pancreatic cancer.  However, a significant delayed response in one subject of this trial suggests 
that immunotherapeutic approaches to pancreatic cancer deserve further exploration. 
 
Lung Cancer 
Study CA184041 was a double-blind, randomized, parallel-group, 3-arm, multicenter, Phase 2 
study in previously untreated subjects with NSCLC and SCLC that evaluated the efficacy and 
safety of 2 schedules of ipilimumab (10 mg/kg) in combination with paclitaxel (175 mg/m2) 
and carboplatin (AUC = 6) compared to subjects receiving paclitaxel/carboplatin alone at the 
same doses. 
Control arm: patients received up to 6 cycles of paclitaxel and carboplatin. 
Concurrent schedule: ipilimumab induction doses were given with the first 4 chemotherapy 
doses (Cycles 1 to 4). 
Phased schedule: ipilimumab induction doses were given with the last 4 chemotherapy doses 
(Cycles 3 to 6). Patients in all 3 arms received maintenance with ipilimumab 10 mg/kg or 
placebo q12w after completion of induction therapy.The primary endpoint of the study was 
irPFS in the NSCLC cohort. Immune-related response criteria were developed to better capture 
novel response patterns observed with immunotherapy in melanoma (Wolchok J.D., Clin 
Cancer Res, 2009). Secondary endpoints included PFS by WHO criteria, BORR, and OS in the 
NSCLC and SCLC cohorts. 
 
CTEP-Sponsored Studies 
The DCTD, NCI, has sponsored nine studies with ipilimumab including one pilot study (NCI 
#5744, lymphoma), three phase 1 studies (5708 [ovarian], 6082 [solid tumors], and 7458 [solid 
tumors]), one phase 1/2 study (6359 [non-Hodgkin’s lymphoma]) with single agent ipilimumab, 
two phase 1 combination studies in prostate cancer with GM-CSF (6032) and with prostate-
specific antigen (PSA)-TRICOM vaccine (7207), one phase 2 combination study of ipilimumab 
with GM-CSF (E1608, melanoma) and one phase 3 study (E1609) of adjuvant ipilimumab 
therapy versus high-dose interferon alpha-2b in patients with resected high-risk melanoma.   
 
Results from 11 patients (colon, n=3; non-Hodgkin’s lymphoma, n=4; prostate, n=4) who 

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received ipilimumab on study 5744 included tumor regression in 2 patients with lymphoma; 1 of 
whom (follicular lymphoma patient) had a partial response (PR) of 14-month duration [44].  
Ipilimumab was well tolerated with predominantly grade 1/2 toxicities.  One drug-related grade 3 
AE was observed.  Tregs, as detected by expression of CD4+CD25+CD62L+, declined at early 
time points but rebounded to levels at or above baseline values at the time of the next infusion.  
The investigators concluded that ipilimumab treatment depressed Treg numbers at early time 
points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ 
T-cell responses in these patients previously treated with a variety of investigational anticancer 
vaccines.   
 
Hodi and colleagues reported preliminary results on 20 patients (11 metastatic melanoma 
patients and 9 metastatic ovarian carcinoma patients) on study 5708 [45].  None of the 11 
patients from the metastatic melanoma cohort manifested grade 3 or 4 inflammatory toxicities; 
however, all subjects revealed mild inflammatory pathologies associated with low-level 
constitutional symptoms.  The most common toxicity (10/11 subjects) was a grade 1-2 reticular 
and erythematous rash on the trunk and/or extremities that arose between 3 days and 3 weeks 
after antibody administration and then gradually resolved without specific intervention.  Biopsies 
of involved skin revealed low-grade interface dermatitis, minor to moderate mononuclear 
infiltrates surrounding the superficial dermal vasculature, and increased mucin deposition in the 
papillary and reticular dermis.  These pathologic features resembled those observed in mild 
cutaneous forms of systemic lupus erythematosis.  Three PRs (range, 21-34+ months) and five 
events of stable disease (SD) (range, 4-25 months) were observed.  One PR and three SDs (2, 4, 
and 6+ months) were observed in the ovarian carcinoma group.  The investigators concluded that 
selective targeting of antitumor regulatory T cells (Treg) may constitute a complementary 
strategy for combination of ipilimumab and GM-CSF-based antigen tumor cell vaccine therapy.  
 
Results from 29 patients with malignancies that were recurrent or progressive after allogeneic 
hematopoietic cell transplantation (allo-HCT) demonstrated that drug was well tolerated at single 
doses up to 3 mg/kg [5].  Four patients experienced organ-specific irAEs of reversible grade 3 
arthritis, grade 2 hyperthyroidism, dyspnea, and grade 4 pneumonitis.  Three patients had 
objective responses: one PR lasting for 2 months, and two durable complete responses (CRs).  
Two additional patients with Hodgkin’s disease who had evidence of rapid disease progression 
prior to ipilimumab treatment achieved SD for 3 and 6 months, following infusion at the 3 mg/kg 
dose level.  Median OS was 24.7 months.  At a 3.0 mg/kg dose, active serum concentrations of 
ipilimumab were maintained for !30 days following a single infusion.  Zhou and colleagues 
reported immunophenotypes of peripheral blood T cells, including T-cell reconstitution, 
activation, and Treg expression, in 29 patients before and after a single-dose infusion of 
ipilimumab [46].  CTLA-4 blockade by a single infusion of ipilimumab increased CD4 and 
CD4HLA-DR T lymphocyte counts and intracellular CTLA-4 expression at the highest dose 
level (3.0 mg/kg).  There was no significant change in Treg cell numbers after ipilimumab 
infusion.  These data demonstrate that significant changes in T-cell populations occur on 
exposure to a single dose of ipilimumab.   
 
Harzstark and colleagues reported results on 36 patients with hormone refractory metastatic 
prostate cancer [47].  Of six patients treated with ipilimumab at a dose of 3 mg/kg, three patients 
had confirmed PSA declines of ≥50%, with a time to progression (TTP) of 22, 26, and 103 

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weeks.  One of these patients had a PR in hepatic metastases.  Grade 3 IrAEs consisted of rash in 
five patients, panhypopituitarism in one patient, temporal arteritis in one patient, and diarrhea in 
three patients.  Non-irAEs included grade 3 and 4 cerebrovascular events (one patient each), 
grade 3 angina (one patient), grade 3 atrial fibrillation (one patient), grade 3 fatigue (four 
patients), and grade 5 pulmonary embolism (one patient).  One patient treated at 10 mg/kg had a 
PSA decline of ≥50% with a TTP of 39 weeks.  Higher doses of treatment with MDX-010 + 
GM-CSF induced the expansion of activated circulating CD25+, CD69+, and CD8+ T cells more 
frequently than was seen in patients who received the same doses of either MDX-010 or GM-
CSF alone [48].  The sera screening with protein arrays showed that the treatment can induce 
antibody responses to the testicular antigen NY-ESO-1.   
 
Patients with metastatic prostate cancer were treated with ProstVac vaccine and ipilimumab 
before chemotherapy.  The median OS for all patients on study was 31.8 months with a 74% 
survival probability at 24 months [49].  The median Halabi predicted OS for all patients was 18.5 
months.  There was no significant difference in OS at different dose levels of antibody (range 1-
10 mg).  A unique effect of the vaccines on the rate of tumor growth may be a novel method to 
evaluate the anti-tumor effects of the vaccine [50].  The authors suggested that the addition of 
immune checkpoint inhibition may augment the clinical benefit of vaccines.  
 
Ansell and colleagues reported data on 18 treated patients with NHL [51].  Two clinical 
responses were observed:  one patient with diffuse large B-cell lymphoma (BCL) had an ongoing 
CR (>31 months), and one with follicular lymphoma had a PR lasting 19 months.  In 5 of 16 
cases tested, T-cell proliferation to recall antigens was >2 fold increased after ipilimumab 
therapy.  The investigators have found that blockade of CTLA-4 signaling with the use of 
ipilimumab is well tolerated at the doses used.  Ipilimumab has antitumor activity in patients 
with BCL, resulting in durable responses in a minority of patients.  Ipilimumab at 3 mg/kg 
monthly for 4 months can be given safely and is the dose that recommended for future 
combination studies.   
 
Clinical Safety   
 
Safety Experience  
The most common treatment-related AEs (those considered possibly, probably, or definitely 
related to study drug by the investigator) associated with the use of ipilimumab were immune 
related irAEs (Investigator Brochure, 2011).  The irAEs primarily involved the gastrointestinal 
(GI) tract (e.g., diarrhea and colitis) and skin (e.g., pruritus and rash), and less frequently, the 
liver, endocrine glands (including the thyroid, pituitary, and adrenal glands) and nervous system.  
IrAEs were generally managed with either symptomatic therapy (grade 1-2 events), systemic 
corticosteroids (grade 3-4 events), or other immunosuppressants (e.g., infliximab, mycophenolate 
mofetil) for steroid-unresponsive GI or hepatic irAEs, as appropriate.  Management of irAEs was 
usually paired with omission of dosing for mild or moderate events and permanent 
discontinuation for severe irAEs.  Ipilimumab can result in severe and fatal immune-mediated 
reactions due to T-cell activation and proliferation.  Fatalities due to GI perforation, hepatic 
failure, toxic epidermal necrolysis, and Guillain-Barré syndrome have been reported in clinical 
trials of ipilimumab.   
 

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Clinical trials are conducted under widely varying conditions so that extrapolation to novel 
settings and combinations regarding rates and severity of events may be unreliable.  Given the 
expected rate of toxicity which may require stopping study drug but may also be related to a 
therapeutic immunologic response alternative DLT criteria are discussed in section 6.  
 
Min and colleagues reported three patients who received ipilimumab alone or combined with 
bevacizumab therapy and developed thyroiditis, and the first report of euthyroid Graves’ 
ophthalmopathy [52].  They recommend that all patients on ipilimumab alone or combined with 
bevacizumab therapy have baseline thyroid function tests and careful monitoring for new onset 
of thyroid disease, particularly during the first 3 months of treatment. See specific events in 
section 5.  
 
Safety Profile of Ipilimumab at a Dose of 10 mg/kg (Phase 2 data) 
The safety profile of ipilimumab as monotherapy over multiple doses at a dose of 10 mg/kg in 
325 subjects was determined from 4 completed melanoma studies.  Overall, the incidence of 
grade 3/4 AEs attributable to study drug was 31%.  The target organ system, the incidence, and 
the severity of the most commonly observed irAEs vary among studies and with drug 
combinations.  Typically, the severity but not necessarily the overall incidence increases with 
dose.  Additional information on specific events is provided in section 7.1 and the IB:   
 
Summary of irAE Safety Data for 10 mg/kg in Melanoma 
 
Total 
Low-grade 
(Grade 1 - 2) (%) 
High-grade 
(Grade 3 - 4) (%) 
Median Time to 
Resolution of 
Grade 2 - 4 irAEs 
(weeks) 
All irAEs 
72.3 
46.2 
25.2 
- 
Skin (e.g., rash, pruritus) 
52.0 
49.2 
2.8 
6.14 
GI (e.g., colitis, diarrhea) 
37.2 
24.9 
12.3 
2.29 
Liver (e.g., LFT elevations) 
8.0 
0.9 
6.8 
4.0 
Endocrine (e.g., hypophysitis, 
hypothyroid) 
6.2 
3.7 
2.5 
20.1 
 
Pregnancy 
Preliminary results are available in cynomolgus monkeys.  Pregnant monkeys received 
ipilimumab every 21 days from the onset of organogenesis in the first trimester through delivery, 
at dose levels either 2.6 or 7.2 times higher than the clinical dose of 3 mg/kg of ipilimumab (by 
AUC).  No treatment-related adverse effects on reproduction were detected during the first two 
trimesters of pregnancy.  Beginning in the third trimester, the ipilimumab groups experienced 
higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth 
weight), and higher incidences of infant mortality in a dose-related manner compared to controls.  
Based on animal data, ipilimumab may cause fetal harm.  The use of ipilimumab during human 
pregnancy has not been formally studied in clinical trials.  There have been 7 known pregnancies 
during ipilimumab treatment: in 3 female subjects and in the partners of 4 male study subjects.  
Two (2) of the 3 female pregnancies ended with elected terminations.  The third female subject 
had a history of seizures and delivered the baby at 36 weeks gestation.  The baby had respiratory 

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complications that resolved by birth week 16.  Three (3) of the 4 partners of male study subjects 
had full term, normal babies.  The fourth baby had small ureters, which are expected to grow as 
the baby matures.  Although these outcomes do not indicate that stillbirths or other severe 
abnormalities will occur, pregnancy should be avoided during treatment with ipilimumab.  
 
Immunogenicity 
In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against 
ipilimumab in an electrochemiluminescent (ECL) based assay.  This assay has substantial 
limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-
related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not 
reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.  
Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was 
performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable 
patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against 
ipilimumab.  These results are highly dependent on methodology, and comparison of incidence 
of antibodies to ipilimumab with the incidences of antibodies to other products may be 
misleading. 
 
Study Results and Clinical Efficacy  
The clinical efficacy of ipilimumab as a single agent at a dose of 3 mg/kg administered q3w for 4 
doses has been established in MDX010-20 (a randomized, controlled study in second line, 
locally advanced/metastatic melanoma), which led to approval of ipilimumab by the FDA.  In 
study CA184024, the addition of 10 mg/kg ipilimumab to dacarbazine led to a prolongation of 
overall survival in patients with previously untreated melanoma.  
 
In melanoma studies, disease stabilization in subjects receiving ipilimumab is characteristic of 
anti-tumor activity.  Stable disease, sometimes of long duration, or slow steady decline of tumor 
lesion size over long periods of time, has been observed.  Some subjects demonstrate initial 
tumor volume increase before response, possibly due to T-cell infiltration as shown by biopsies 
or to the time required for immunologic activation.  Consequently, an initial determination of 
progressive disease and consequently PFS may not capture all patterns response and may 
underestimate the clinical activity of ipilimumab.  Please see section “Considerations for Using 
Immune-Related Tumor Assessment Criteria (irRC).”  
 
MDX010-20 (Phase 3, 3 mg/kg, previously treated melanoma) 
A Phase 3, double-blind study enrolled patients with advanced (unresectable or metastatic) 
melanoma who had previously been treated with regimens containing one or more of the 
following: IL-2, dacarbazine, temozolomide, fotemustine, or carboplatin. Patients were 
randomized in a 3:1:1 ratio to receive ipilimumab 3 mg/kg + an investigational gp100 peptide 
vaccine (gp100), ipilimumab 3 mg/kg monotherapy, or gp100 alone. All patients were HLA-
A2*0201 type; this HLA type supports the immune presentation of gp100. Patients were enrolled 
regardless of their baseline BRAF mutation status. Patients received ipilimumab every 3 weeks 
for 4 doses as tolerated (induction therapy). Patients with apparent tumour burden increase 
before completion of the induction period were continued on induction therapy as tolerated if 
they had adequate performance status. Assessment of tumour response to ipilimumab was 
conducted at approximately Week 12, after completion of induction therapy. Additional 

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treatment with ipilimumab (re-treatment) was offered to those who developed PD after initial 
clinical response (PR or CR) or after SD (per the modified WHO criteria) > 3 months from the 
first tumour assessment. The primary endpoint was OS in the ipilimumab+ gp100 group vs. the 
gp100 group. Key secondary endpoints were OS in the ipilimumab+ gp100 group vs. the 
ipilimumab monotherapy group and in the ipilimumab monotherapy group vs. the gp100 group. 
A total of 676 patients were randomized: 137 to the ipilimumab monotherapy group, 403 to the 
ipilimumab + gp100 group, and 136 to the gp100 alone group. The majority had received all 4 
doses during induction. Thirty-two patients received re-treatment: 8 in the ipilimumab 
monotherapy group, 23 in the ipilimumab + gp100 group, and 1 in the gp100 group. Duration of 
follow-up ranged up to 55 months. Baseline characteristics were well balanced across groups. 
The median age was 57 years. The majority (71-73%) of patients had M1c stage disease and 37-
40% of patients had an elevated lactate dehydrogenase (LDH) at baseline. A total of 77 patients 
had a history of previously treated brain metastases. The ipilimumab-containing regimens 
demonstrated a statistically significant advantage over the gp100 control group in OS. The 
hazard ratio (HR) for comparison of OS between ipilimumab monotherapy and gp100 was 0.66 
(95% CI: 0.51, 0.87; p = 0.0026). 
 
By subgroup analysis, the observed OS benefit was consistent within most of the subgroups of 
patients (M [metastases]-stage, prior interleukin-2, baseline LDH, age, sex, and the type and 
number of prior therapy). However, for women above 50 years of age, the data supporting an OS 
benefit of ipilimumab treatment were limited. The efficacy of ipilimumab for women above 50 
years of age is therefore uncertain. As the subgroups analysis includes only small numbers of 
patients, no definitive conclusions can be drawn from these data 
 
In the ipilimumab 3 mg/kg monotherapy group, median OS was 22 months and 8 months for 
patients with SD and those with PD, respectively. At the time of this analysis, medians were not 
reached for patients with CR or PR. 
 
For patients who required re-treatment, the BORR was 38% (3/8 patients) in the ipilimumab 
monotherapy group, and 0% in the gp100 group. The disease control rate (DCR) (defined as 
CR+PR+SD) was 75% (6/8 patients) and 0%, respectively. Because of the limited number of 
patients in these analyses, no definitive conclusion regarding the efficacy of ipilimumab re-
treatment can be drawn. The development or maintenance of clinical activity following 
ipilimumab treatment was similar with or without the use of systemic corticosteroids 
 
CA184024 (Phase 3, previously untreated melanoma, 10 mg/kg) 
The primary objective of this study was the comparison of OS in subjects administered 
ipilimumab (10 mg/kg) + DTIC versus DTIC monotherapy in previously untreated patients. The 
HR for comparison of OS between the groups was 0.72 (95% CI: 0.59, 0.87; P = 0.0009) at the 
time of the primary analysis.66 The improvement in OS for ipilimumab + DTIC versus placebo 
+ DTIC is evident in the clear separation of treatment groups in the Kaplan-Meier plot and in an 
increased median OS (95% CI) of 11.17 (9.40, 13.60) months and 9.07 (7.75, 10.51) months, 
respectively. The Kaplan-Meier survival curve for the ipilimumab plus DTIC group revealed that 
a plateau begins at approximately Year 3, which extends to Year 5 and beyond (although heavy 
subject censoring may limit interpretation of survival data beyond 5 years). One of the hallmarks 
of ipilimumab efficacy is long-term survival. Survival updates from subjects enrolled in clinical 

NCI Protocol #: 10026 
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trials continue to show a durable long-term benefit with ipilimumab. Five-year survival rates 
from Study CA184024 (DTIC with or without ipilimumab) continue to support a long-term 
benefit of ipilimumab in treatment-naïve subjects with advanced melanoma. The 5-year OS rates 
in the current analyses were 18.2% for ipilimumab + DTIC and 8.8% for placebo + DTIC. The 
rates are similar to the previously reported 3- and 4-year OS rates and suggest that OS plateaus at 
the 3-year mark. 
 
Overall Adverse Events (CA184024) 
The most common treatment-related AEs in the ipilimumab + DTIC group were skin and GI 
irAEs. The most common (≥20%) treatment-related AEs of any grade in the ipilimumab plus 
DTIC group were nausea (40.1%), fatigue (33.6%), diarrhea (32.8%), pyrexia (31.2%), ALT 
increased (29.1%), AST increased (26.7%), pruritus (26.7%), vomiting (26.3%), and rash 
(22.3%). The most common events in the DTIC group were nausea (42.6%), fatigue (27.1%), 
and vomiting (20.7%). The most common  
 
10 mg/kg Dosing with Ipilimumab 
Several additional trials studied the efficacy and safety of 10 mg/kg dosing, and additional 
information gained from these trials is listed below: 
 
A dose of 10 mg/kg may be necessary to ensure blockade of the CTLA-4 pathway; in vitro, a 
concentration of 20 mcg/mL of ipilimumab was the minimal concentration able to fully abrogate 
the binding of CTLA-4 to B7.1 and B7.2.  With a dose of 3 mg/kg q3w, 30% achieved a trough 
concentration of ipilimumab greater than 20 Pg/mL, compared to 95% of subjects treated at 10 
mg/kg q3w. 
 
In addition, in all ipilimumab trials examined to date, mean Absolute Lymphocyte Count (ALC) 
increased after ipilimumab treatment throughout the 12-week induction-dosing period, in a dose-
dependent manner.  In an analysis of ipilimumab at 0.3, 3, or 10 mg/kg in melanoma studies 
CA184007, CA184008, and CA184022 combined, the rate of change in ALC after ipilimumab 
treatment was significantly associated with dose (p = 0.0003), with the largest rate at 10 mg/kg 
ipilimumab.  Moreover, the rate of change in ALC over the first half of the induction-dosing 
period was significantly associated with clinical activity in these studies (p = 0.009), where 
clinical activity was defined as CR, PR, or prolonged SD (i.e., SD lasting at least 6 months from 
first dose). Although these analyses alone could not determine whether the rate of change in 
ALC was specifically associated with clinical activity in response to ipilimumab treatment, as 
opposed to being generally prognostic, these results do suggest a potential benefit to higher rates 
of ALC increase after ipilimumab treatment.  Among the 3 doses evaluated, 10 mg/kg 
ipilimumab led to the greatest such rates. 
 
In the 3 primary studies conducted in advanced melanoma (CA184007, CA184008, and 
CA184022), subjects treated with 10 mg/kg single agent ipilimumab had the highest response, 
disease control rates, median OS as well as 1-year and 2-year survival rates compared to lower  
doses. The CA184022 data are summarized in the table below. 
 

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Summary of Phase 2 Response Data in Melanoma (CA184022 see IB ) 
 
10 mg/kg 
(n = 72) 
3 mg/kg 
(n = 72) 
0.3 mg/kg 
(n = 73) 
BORR (mWHO) – % 
(95% CI) 
11.1 
(4.9 - 20.7) 
4.2 
(0.9 - 11.7) 
0 
(0.0 - 4.9) 
DCR (mWHO) – % 
(95% CI) 
29.2 
(19.0 - 41.1) 
26.4 
(16.7 - 38.1) 
13.7 
(6.8 - 23.8) 
Survival rate at 1 year - % 
%, 95% CI 
48.64 
(36.84, 60.36) 
39.32 
(27.97, 50.87) 
39.58 
(28.20, 51.19) 
Survival rate at 2 year - % 
%, 95% CI 
29.81 
(19.13, 41.14) 
24.20 
(14.42, 34.75) 
18.43 
(9.62, 28.22) 
Overall median survival 
95%CI (months) 
11.43 
(6.90, 16.10) 
8.74 
(6.87, 12.12) 
8.57 
(7.69, 12.71) 
 
Dose, Schedule, and Regimen 

While optimal doses and schedules for ipilimumab have not yet been determined, in proposed 
proof of principle studies demonstration of efficacy at 10 mg/kg would allow future studies to 
explore biologic and clinical efficacy at lower doses with reduced toxicity. For most studies in 
new combinations or settings, a short phase 1 component at 3 mg would be appropriate with a 5 
or 6 mg/kg dose added as an additional cohort if needed.    
 
A recommended dose of 10 mg/kg is proposed by the manufacturer for most studies of 
ipilimumab.  In melanoma, a similar survival benefit was demonstrated in phase 3 trials at the 3 
mg/kg and at 10 mg/kg with DTIC.  However, the incidence of grade >3 toxicity was 15 and 
25% respectively.   
 
Based on Phase 2 studies, response rates of ipilimumab appear to be dose dependent up to 10 
mg/kg.  Exposure-response analyses [Cminss Analysis of PK data from patients treated with 
ipilimumab at 0.3 mg/kg (N=47), 3 mg/kg (N=60) and 10 mg/kg (N=311)], showed that the 
target Cminss target threshold of 20 mcg/ml was exceeded in 0%, 30% and 95% subjects 
respectively.  The slope of change in absolute lymphocyte count (ALC) correlated with clinical 
benefit and T-cell activation markers such as HLA-class II expression may also be dose 
dependent.  Responses have not been compared systematically in randomized phase 2 or phase 3 
studies in patients with tumor types other than melanoma.  
 
Regarding schedule, the typical schedule for advanced melanoma at present is once q3w for four 
doses followed by a maintenance phase of four doses every 12 weeks.  Of interest, ipilimumab 
was evaluated in NSCLC and SCLC using a dose of 10 mg/kg given concomitantly or following 
initial paclitaxel/cisplatin.  When used in the phased schedule, 10 mg significantly improved 
irPFS and mWHO defined responses but not PFS determined by Response Evaluation Criteria in 
Solid Tumors (RECIST).  There also was a trend for an improvement in OS in both indications.  
Doses less than 10 mg/kg have not been evaluated in either NSCLC or SCLC.  

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Studies comparing doses in non-melanoma and combinations have not been widely done.  There 
are also no clear data that peak levels, Cmin, AUC, exposure and number of doses given, or the 
occurrence of autoimmune events, predict responses in individual patients.  We note that the 
incidence of specific events such as hypophysitis may vary from study to study and with 
different combinations of agents.  The severity and possibly time to onset but not necessarily the 
frequency of events increases with dose.  In addition, there are rare but serious events such as 
toxic epidermal necrolysis (TEN) for which a dose relationship has not been established. Case 
report forms should include data on the prior treatment, timing, number of doses, duration of 
event, response to treatment, and complications to allow comparisons among studies.   
 
Prescribing Information 
Ipilimumab is indicated for the treatment of (1) unresectable or metastatic melanoma and (2) 
adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional 
lymph nodes of more than 1 mm who have undergone complete resection, including total 
lymphadenectomy. For (1) unresectable or metastatic melanoma, ipilimumab is dosed at 3 mg/kg 
intravenously over 90 minutes every 3 weeks for a total of 4 doses. For (2) adjuvant melanoma 
treatment, ipilimumab is dosed at 10 mg/kg intravenously over 90 minutes every 3 weeks for 4 
doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease 
recurrence or unacceptable toxicity.  
 
 
 
Considerations in Using Immune-Related Tumor Assessment Criteria (irRC) 
New end point definitions for trials of immunologic agents have been proposed based on novel 
patterns of clinical activity in malignant melanoma [53, 54].  These alternative definitions allow 
time for  immunologically mediated effectors to develop that may result in late tumor responses 
even after initial progression by RECIST.  Also, in some patients, tumors necrosis and 
inflammation may increase tumor size radiographically prior to response.  Changing the 
definitions of OR and PD may alter (increase) the number patients achieving responses and the 
duration of PFS.  
 
On a protocol by protocol basis, we would consider allowing study treatment to continue during 
initial progression up to the 12-16 week assessment to allow time for responses to be observed, if 
the patient is clinically stable, there is no deterioration in PS, and there is no need for immediate 
additional treatment.  While maintaining standard definitions of progression and response, we 
would allow new lesions and some progression beyond 20% increases in tumor measurements 
during the initial treatment period to allow time for responses to develop (these delayed tumor 
responses may be seen in 10-20% of melanoma patients who initially progress during the initial 
treatment cycles and evaluation).  We do not have experience with response patterns with 
combination therapy nor in diseases other than melanoma.  Please use standard response 
definitions as the primary end point in these studies.   
 
Note that the proposed irRC may be incorporated as secondary end points to compare to standard 
criteria and evaluate alternative patterns of response in various disease setting and treatment 
regimens.   
 

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Patients who demonstrate mixed responses, stable disease, or objective responses by standard 
RECIST following initial progression may be identified separately as “delayed SD, PR, or CR”.   
 
Overall Risk/Benefit Assessment 
The unique immune-based mechanism of action is reflected in the clinical patterns of anti-cancer 
activity in some patients.  Ipilimumab affects tumor cells indirectly, and measurable clinical 
effects emerge after the immunological effects.  Tumor infiltration with lymphocytes and the 
associated inflammation (documented by biopsy in some subjects) is likely the cornerstone of the 
effect of ipilimumab and can manifest in various patterns of clinical activity leading to tumor 
control.  In some cases, response may be preceded by an apparent increase in initial tumor 
volume and/or the appearance of new lesions, which may be mistaken for tumor progression on 
radiological evaluations.  Therefore, in subjects who are not experiencing rapid clinical 
deterioration, confirmation of progression is recommended, at the investigator’s discretion, to 
better understand the prognosis as well as to avoid unnecessarily initiating potentially toxic 
alternative therapies in subjects who might be benefitting from treatment.  Immune-related (ir) 
response criteria were developed based on these observations to systematically categorize novel 
patterns of clinical activity and are currently being prospectively evaluated in clinical studies. 
 
In metastatic diseases, stabilization is more common than response, and in some instances is 
associated with slow, steady decline in tumor burden over many months, sometimes improving 
to partial and/or complete responses.  Thus, the immune-based mechanism of action of 
ipilimumab results in durable disease control, sometimes with novel patterns of response, which 
contribute to its improvement in OS. 
 
The immune-based mechanism of action is also reflected in the safety profile.  The most 
common drug-related AEs are immune-mediated, consistent with the mechanism of action of the 
drug and generally medically manageable with topical and/or systemic immunosuppressants.  As 
previously discussed, the immune-mediated adverse reactions primarily involve the GI tract, 
skin, liver, endocrine glands, and nervous system. 
 
The early diagnosis of immune-mediated adverse reactions is important to initiate therapy and 
minimize complications.  Immune-mediated adverse reactions are generally manageable using 
symptomatic or immunosuppressive therapy as recommended through detailed diagnosis and 
management guidelines, as described fully in the current IB.  The management guidelines for 
general immune-mediated adverse reactions and ipilimumab-related GI toxicities, hepatotoxicity, 
endocrinopathy, and neuropathy are provided in the appendices of the current IB.  
 
For this clinical trial (CTEP 10026), ipilimumab has already demonstrated a signal of clinical 
efficacy in patients with relapsed/refractory MDS/AML [4]. There is no accepted standard of 
care for patients with relapsed/refractory MDS/AML including for those that relapse post-HCT. 
Thus treatment for this population remains an unmet need. There has been significant clinical 
data demonstrating safety with hypomethylating agents in relapse both in the post-transplant 
setting and in the transplant naive.  The combination of checkpoint blockade with 
hypomethylating agent is still investigational.   
 
Rationale for Ipilimumab in this Study 

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There is no clear standard of care for patients with hematologic malignances who relapse after 
allo-HCT.  Ipilimumab has been evaluated in two separate studies for patients with relapsed 
hematologic malignancies after allo-HCT with evidence of safety at low doses and preliminary 
efficacy when tested at doses currently approved in advanced melanoma [4, 5]. These two 
clinical studies suggest that the role for checkpoint blockade requires further exploration in the 
relapsed setting.  
 
2.3 
Decitabine 
 
Decitabine (Dacogen) is an FDA-approved drug for the treatment of MDS. The information 
below is gathered from the FDA package label. Please see package insert for more details.   
Dacogen is indicated for treatment of patients with myelodysplastic syndromes (MDS) including 
previously treated and untreated, de novo and secondary MDS of all French-American-British 
subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with 
excess blasts, refractory anemia with excess blasts in transformation, and chronic 
myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International 
Prognostic Scoring System groups. 
 
Mechanism of Action 
Decitabine is believed to exert its antineoplastic effects after phosphorylation and direct 
incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of 
DNA and cellular differentiation or apoptosis. Decitabine inhibits DNA methylation in 
vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. 
Decitabine-induced hypomethylation in neoplastic cells may restore normal function to genes 
that are critical for the control of cellular differentiation and proliferation. In rapidly dividing 
cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts 
between DNA methyltransferase and decitabine incorporated into DNA. Nonproliferating cells 
are relatively insensitive to decitabine. 
 
Pharmacokinetics 
Pharmacokinetic parameters were evaluated in patients. Eleven patients received 20 mg/m2 
infused over 1 hour intravenously (treatment Option 2), fourteen patients received 15 mg/m2 
infused over 3 hours (treatment Option 1). Plasma concentration-time profiles after 
discontinuation of infusion showed a biexponential decline. The CL of decitabine was higher 
following treatment Option 2. Upon repeat doses there was no systemic accumulation of 
decitabine or any changes in PK parameters. Population PK analysis (N=35) showed that the 
cumulative AUC per cycle for treatment Option 2 was 2.3-fold lower than the cumulative AUC 
per cycle following treatment Option 1. 
 
Pharmacodynamics 
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. However, there 
have been no studies of decitabine induced hypomethylation and pharmacokinetic parameters. 
 
Major route of elimination 

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The exact route of elimination and metabolic fate of decitabine is not known in humans. One of 
the pathways of elimination of decitabine appears to be deamination by cytidine deaminase 
found principally in the liver but also in granulocytes, intestinal epithelium and whole blood. 
 
Metabolism  
Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver 
microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In 
vitro metabolism studies have suggested that decitabine is not a substrate for human liver 
cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), 
interactions due to displacement of more highly protein bound drugs from plasma proteins are 
not expected. 
 
NONCLINICAL TOXICOLOGY 
Carcinogenesis, Mutagenesis and Impairment of Fertility 
Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of 
decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation 
frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia 
coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal 
rearrangements in larvae of fruit flies. The effect of decitabine on postnatal development and 
reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection 
(approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights 
of males and females exposed in utero to decitabine were significantly reduced relative to 
controls at all postnatal time points. No consistent effect on fertility was seen when female mice 
exposed in utero were mated to untreated males. Untreated females mated to males exposed in 
utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, 
respectively). In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine 
(approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, 
decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and 
WBC counts). Testes weights were reduced, abnormal histology was observed and significant 
decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed 
with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and pre-implantation loss was 
significantly increased. 
 
Clinical activity in AML 
Decitabine is a well-tolerated DNA-hypomethylating agent that induces differentiation and 
cytotoxicity of leukemic cells.  CR rates from phase 2 and 3 AML clinical trials with front-line 
decitabine range from 18-25% [15]. 
 
Rationale for the Proposed Starting Dose and Dose Escalation Scheme in this Trial 
The optimal dosing schedule for ipilimumab in hematologic malignancies is not entirely clear. 
Studies thus far have mimicked scheduled based on solid tumors (primarily melanoma studies). 
Ipilimumab is currently approved in unresectable or metastatic melanoma on a 3 week schedule 
for a total of 4 doses and in the adjuvant melanoma setting on a 3 week schedule for 4 doses (for 
induction phase) followed by an every 12 week schedule for up to 3 years (for maintenance 
phase) until disease recurrence or unacceptable toxicity. Ipilimumab has a prolonged half life of 
~ 15 days. Dosing during the induction phase on a four week schedule has been previously 

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evaluated in melanoma in combination with dacarbazine [55] and in B-cell non-Hodgkin 
lymphoma as monotherapy with evidence of safety and anti-tumor activity [51].  In the 
Checkmate-012 lung cancer study, multiple schedules of combined nivolumab and ipilimumab 
were evaluated with similar safety profiles when ipilimumab was dosed on a 3 week versus 6 
week versus 12 week schedule. Ipilimumab has been further evaluated in combination with 
peptide vaccination with a 6 to 8 week schedule with a similar safety profile [56]. Given the 
highly proliferative nature of AML and the known activity with single agent decitabine (median 
time to best response 2-4 cycles and median duration of response from 9-14 months) [14, 15], we 
will shorten the interval between doses in the maintenance phase for ipilimumab from 12 weeks 
to 8 weeks.  
 
This study will have two arms (cohorts) to the study separated by transplant status.  Arm A will 
include patients who are post allo-HCT. These include patients who are previously had an allo-
HCT of any donor source at any time.  Arm B will include patients who are transplant naïve. 
Both arms A and B will be evaluated at the same three dose escalation levels (and same starting 
dose level) but as the MTD/RP2D may differ based on transplant status, these two patient 
cohorts will be evaluated separately for safety and toxicity.  There will be three intended phases 
of this clinical trial (for both Arms A and B): priming, induction phase, and maintenance phase.   
x Priming Phase (Lead- In): The priming phase includes decitabine alone at 20 mg/m2 
given daily for 5 consecutive doses starting on days 1-5 on a 28 day cycle to provide 
priming and disease control.  Hypomethylating agents, such as decitabine have been 
tested in the post allo-HCT setting with evidence of safety and tolerability [57-59] 
including at the same dose proposed in this study. 
x Induction Phase (cycles 1-4): Cycles 1 through 4 will include treatment with decitabine 
20 mg/m2 daily for five consecutive doses on days 1-5 plus ipilimumab (given per dose 
level) on day 1 on a 28 day cycle.  There will be three dose escalation levels tested: 3.0 
mg/kg (starting dose), 5.0 mg/kg, and 10.0 mg/kg. There will be a dose de-escalation 
level provided (1.0 mg/kg). Pharmacokinetic data generated from the initial pilot study 
demonstrated that higher doses of ipilimumab correlated with increased ipilimumab 
exposure and that those doses may be sufficient to saturate CTLA-4 binding sites [5]. The 
starting dose level of 3.0 mg/kg was tested in the phase 1b study for relapsed hematologic 
malignancies after allo-HCT with demonstration of safety and tolerability [4]. There was 
evidence of preliminary clinical activity (discussed in Section 2.4 in detail) in this study 
at 10 mg/kg but with evidence of immune related adverse events and GVHD in some 
cases. Thus we will also test the dose of 5.0 mg/kg. 
x Maintenance Phase (cycles 5-12): Cycles 5 through 12 will include treatment with 
decitabine 20 mg/m2 daily for five consecutive doses on days 1-5 on a 28 day cycle. 
Ipilimumab will continue on day 1 every 8 weeks for a total of 4 doses.  
 
2.4 
Rationale 
 
Disease relapse remains the predominant problem for patients with AML/MDS.  Data from solid 
tumor studies suggest that treatment including CTLA-4 blockade may provide durable 
remissions.  In pooled analysis across advanced melanoma studies, treatment with ipilimumab 
regardless of dose resulted in survival curves that clearly plateau around year 3 (with an OS rate 
of ~20%) [60].  Responses in metastatic melanoma have been associated with tumor reactive T 

NCI Protocol #: 10026 
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cells expanding from a tumor site.  In vitro evaluation with CTLA-4 blockade has shown 
induction of a proliferative signature predominantly in a subset of transitional memory T cells 
[61]. PD-1 blockade, alternatively, showed changes in genes involved in cytolysis and NK cell 
function.  CTLA-4, thus, is a reasonable target for therapy. 
 
Clinical activity with CTLA-4 blockade in relapsed hematologic malignancies in the post-
transplant setting 
Evidence for anti-leukemic activity in the absence of graft versus host reactivity with CTLA-4 
blockade was previously studied in a mouse model of minor histocompatibility-mismatched bone 
marrow transplantation [62].  In a mouse model of minor histocompatibility mismatched bone 
marrow transplantation, delayed CTLA-4 blockade induced anti-leukemic activity in the absence 
of graft versus host reactivity [62]. A pilot study next demonstrated safety with low-dose 
ipilimumab in the treatment of patients with relapsed hematologic malignancies post alloHCT 
[5].  Results from this study suggested that titration of ipilimumab might be possible in order to 
generate a graft-versus-tumor response. Pharmacokinetic data generated from this pilot study 
demonstrated that higher doses of ipilimumab correlated with increased ipilimumab exposure 
and that those doses may be sufficient to saturate CTLA-4 binding sites [5]. A Dana-Farber 
Cancer Institute led Phase I/Ib multi-center study (NCT01822509) of dose-escalated ipilimumab 
in the post-transplant setting for relapsed hematologic malignancies demonstrated substantial 
anti-tumor activity [4, 63].  There was no formal clinical response for patients treated in the 3 
mg/kg cohort.  Out of 6 evaluable patients in the 3 mg/kg cohort, one patient had chronic GVHD 
of the liver, which was the only DLT in the cohort. There was evidence of immune-related 
adverse events in two patients (1 patient with grade 2 pneumonitis and 1 patient with grade 2 
diarrhea), which rapidly reversed with glucocorticoids and did not prevent further administration 
of ipilimumab.  Twenty-two patients including an expansion cohort went on to receive 10 mg/kg 
dosing of ipilimumab.  The overall response rate (ORR) in the 10 mg/kg dose cohort was 32% 
(7/22) although 59% (13/22) had disease reduction. Responders included 5 with AML, 1 partial 
response (PR) with classical Hodgkin’s, and 1 PR with multiple myeloma with highly refractory 
lung plasmacytoma.  Of the AML patients treated on study, 42% (5 of 12) achieved complete 
remission (CR), including 3 with extramedullary AML, 1 with myeloid sarcoma and 1 with 
smoldering MDS/AML with marrow involvement (low blast burden).  Importantly, responses 
have been durable in three of the AML responders, ranging from 12-16 months.  The median 
duration of response has not yet been reached. The 1 year OS was 49% at 15 months [4]. 
Exploratory correlative studies revealed a decrease in the ratio of Treg/Tconv ratio, suggesting 
possible augmentation of the graft versus tumor effect. Results from this phase I/Ib study suggest 
that ipilimumab is feasible for relapsed disease after allo-HCT although at the dose of 10 mg/kg 
there was evidence of both immune related adverse events and GVHD, which were distinguished 
by biopsy. In the 10 mg/kg cohort, there was evidence of dose-limiting toxic effects including 2 
patients with chronic GVHD of the liver and 1 patient with grade II acute GVHD of the gut. 
These GVHD cases resolved with steroids but precluded further administration of ipilimumab.  
Immune-related adverse events were observed in 3 patients (1 patient with grade 2 immune 
thrombocytopenia; 1 patient with grade 3 colitis; 1 patient with grade 2 pneumonitis and 1 
patient with grade 4 pneumonitis).  With steroid treatment, ipilimumab was resumed ~ 3 weeks 
in 2 patients.  One of these patients died 42 days after receiving initial ipilimumab (grade 3 
colitis and grade 4 pneumonitis).  Notably, no infectious complications were seen that were 
grade 3 or higher. Consequently, the trial is now investigating the safety and preliminary efficacy 

NCI Protocol #: 10026 
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at an intermediate dose arm of 5 mg/kg.   
 
Epigenetic priming prior to checkpoint blockade 
Epigenetic silencing of immune-protective signature genes may affect clinical responses to 
immunotherapy.  Preclinical data support the combination of epigenetic therapy with checkpoint 
blockade to induce the expression of immune regulatory genes in cancer. Treatment with 
epigenetic therapies in epithelial cancer models led to (1) the induction of regulators of interferon 
signaling through the hypomethylation of endogenous retroviral sequences [64] and (2) the 
removal of repression of Th1 type-chemokine expression (ie CXCL9 and CXCL10) which 
correlated with anti-tumor activity [65]. In AML, treatment with decitabine in cultured cells and 
in an established mouse EL4 tumor model resulted in upregulated expression of the CTLA-4 
ligand CD80 [66]. Further, in leukemic blasts isolated from AML patients treated with 
hypomethylating agents (HMA), there was evidence for CTLA-4 expression upregulation [67].  
We hypothesize that decitabine priming prior to ipilimumab treatment may lead to further 
activation of the immune system to stimulate anti-leukemic activity.  HMA use post-HCT has 
been studied as maintenance [58] or in the setting of relapse with DLI [68].  HMA, such as 
azacitidine, has been shown to increase the number of regulatory T cells (which inhibit the 
development of graft-versus-host disease) and cytotoxic CD8+ T cells (which may enhance the 
graft-versus-leukemia effect) in the post-HCT setting [69].  HMA therapy has been shown to be 
safely administered to heavily pretreated post-HCT patients with evidence of prolonged event 
free survival and overall survival (OS) [58, 59].  Decitabine is more potent inhibitor of DNMT-1 
than azacitidine. The Washington University group has demonstrated that decitabine enhances 
FOXP3 expression and converts CD4+CD25-FOXP3- T cells into CD4+CD25+FOXP3+ T 
regulatory cells, the latter are cells critical to modulating GVHD without compromising the GVL 
effect [70].  For this study, thus, decitabine is an attractive agent, given its mild toxicity and 
proven anti-leukemic activity, for combination therapy.   
 
Preclinical data support the combination of epigenetic therapy with immunotherapy.  Studies 
from AML cell lines and murine models demonstrate up-regulation of CD80 expression with 
decitabine treatment [66]. In primary AML samples, CTLA-4 up-regulation was also detected 
among patients who were treated with hypomethylating agents [71]. Recently, an Italian group 
demonstrated enhanced anti-tumor activity with CTLA-4 blockade in a syngenic mouse model 
bearing palpable tumor grafts of murine mammary carcinoma cells following epigenetic priming 
with the second generation investigational SGI-110, a dinucleotide of decitabine [72]. In this 
study, mice were treated with a CTLA-4 monoclonal antibody either concurrent (on days 2, 5, 
and 8) with or subsequent (on days 8, 11, and 14) to SGI-110 therapy. Tumor growth inhibition 
of 84% was appreciated when treatment was scheduled sequentially. Epigenetic silencing of 
immune-protective signature genes may affect clinical responses to immunotherapy. Peng D et 
al., found that 5-aza-2’-deoxycytidine reprogrammed epigenetic pathways by removing 
repression of T helper 1 (TH1) type-chemokine expression, including that of CXCL9 and 
CXCL10, and increased effector T-cell tumor infiltration leading to slowed tumor growth and 
improved therapeutic efficacy of checkpoint blockade in tumor-bearing mice [65]. Therefore, we 
hypothesize that sequential decitabine and ipilimumab treatments may lead to further activation 
of the immune system to stimulate anti-leukemic activity. 
 
Hypothesis 

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Given the evidence of single-agent ipilimumab activity among AML patients with low-disease 
burden from the on-going Phase 1/1b study [4], we aim to improve the overall response by 
combining ipilimumab with a therapy that not only cytoreduces, but has the potential to alter the 
expression of immune regulatory genes to render leukemic cells more sensitive to checkpoint 
blockade. We hypothesize that epigenetic modifying agents may enhance the immune response 
by improving the recognition and destruction of leukemia cells by cytotoxic T lymphocytes in 
combination with anti-CTLA-4 therapy. We thus propose a phase 1 clinical study of sequential 
decitabine and ipilimumab to evaluate for safety and toxicity in patients with relapsed/refractory 
MDS and AML. We hypothesize that patients that relapse post-HCT may be at risk for GVHD at 
higher doses of ipilimumab compared to patients that have no prior transplant history. If this 
occurs, patients post-transplant may have a different maximum tolerated dose (MTD) or 
recommended phase 2 dose (RP2D) compared to the non-transplant population.   
 
We have thus designed a dose-escalation study separating the patient cohorts by transplantation 
status. Biologically, it is also unknown whether alloreactivity in the post-HCT setting is required 
for clinical activity.  This clinical study will evaluate the role of CTLA-4 blockade in AML and 
hopefully will add to the limited armamentarium available for the relapsed and refractory AML 
population.  Current therapies available for elderly and relapsed AML are not curative without 
allo-HCT. Immunotherapy, alternatively, may generate long-lasting durable responses through 
the generation of cancer specific central memory T cells. If there is demonstration of preliminary 
efficacy and safety with sequential epigenetic and ipilimumab therapy, then this combination can 
serve as a new therapeutic strategy for AML and may potentially enhance graft-versus-leukemia 
effects for those who relapse post-transplant. Positive findings from this study would support 
further exploration of the role of checkpoint blockade to modulate anti-leukemic immune 
responses.   
 
2.5 
Correlative Studies Background 
 
The goal of this study is to evaluate if decitabine (priming) sensitizes patients with 
MDS/AML to checkpoint blockade in the transplant naïve and post allo-HCT setting. We 
seek to evaluate if epigenetic therapy combined with blockade of immune checkpoints might 
augment response in leukemia by shifting the balance between immune activation and immune 
inhibition.  This trial will be biopsy driven and offer the opportunity to examine whether 
decitabine, a nucleotide analog DNA demethylating agent will sensitize malignant cells to anti-
leukemic immune responses. We predict that targeting of DNA methyltransferases with 
decitabine may “reprogram” tumor cells (as seen in solid tumor in vitro studies [73, 74]) by up-
regulating the tumor immune stimulating profile.  Additional work is still needed to understand 
how these mechanisms may differ between CTLA-4 blockade in the transplant naive and post-
HCT setting and what effect epigenetic priming may have on the mechanism of checkpoint 
blockade.  We will collaborate with several investigators, including Drs. Jerry Ritz, Catherine 
Wu, Scott Rodig, and Stephen Hodi (Center for Immuno-Oncology) to perform the immunologic 
correlative studies proposed in this clinical study.  The correlative studies proposed in this 
clinical study will evaluate the role of epigenetic priming prior to CTLA-4 blockade in the 
transplant naive and post-HCT setting. We have designed a comprehensive set of phenotypic and 
genotypic assays to interrogate the immune and leukemic population dynamics both to identify 
novel predictors of response to checkpoint blockade as well as illuminate the mechanism of 

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action of CTLA-4 blockade in myeloid leukemias in the pre- and post allo-HCT setting.    
 
Pharmacodynamic study: Measuring absolute lymphocyte count as a potential biomarker 
for response to ipilimumab 
We will capture absolute lymphocyte counts (ALC) at baseline and on treatment with each cycle. 
It has been previously demonstrated that a rise in ALC during ipilimumab treatment may be 
associated with clinical response and OS in patients with cutaneous and uveal melanoma [75, 
76].  We will compare measured levels at baseline (defined as prior to dosing on cycle 1 day 1) 
and at pre-determined time points (end of cycles 1, 2, and 4) and we will also compare changes 
in ALC from baseline (defined as prior to dosing on cycle 1 day 1) to the pre-determined time 
point (end of cycle 2) for survival differences given the evidence that ALC after two cycles may 
be a predictor of clinical response.  As decitabine may cause myelosuppression, ALC elevation 
may not be reliable.  
  
Correlative study: Clonal evaluation of patients on treatment 
AML is commonly characterized by genetic alterations including gene mutations, copy number 
alterations and translocations.  Genomic analysis of AML samples has expanded the number of 
known molecular mutations present in this disease [77]. Clonal evolution is a feature of the 
natural history of the disease that may also be influenced by the selective pressure of 
chemotherapy [78]. MDS is also a recognized clonal disorder with evidence of evolution or 
dynamic shaping of complex oligoclonal architectures upon some treatments [79].  
Understanding the dynamic shaping of the clonal architectures including the outgrowths of 
founder-, sub- or even fully independent clones will provide insight on the dynamic rate of clonal 
turnover and potential guide clinical treatment decisions. In addition to their prognostic value, 
mutations present at diagnosis may also affect the response to initial treatment. To understand 
the genotypic alterations that may be associated with response, we will perform evaluations at 
baseline, after four cycles, and at time of relapse if relevant.  Specifically, we will compare 
changes in variant allele fraction of pathogenic lesions found at baseline to response.  Following 
clonal patterns may provide an alternative measurement of antitumor activity and help to identify 
the persistence of emergence of resistant clones during treatment, which mediate disease relapse 
[80].   
 
Correlative study: Determining histopathologic patterns of response 
We hypothesize that infiltrating T cells at the site of tumor microenvironment is critical to tumor 
control.  Samples to be tested include marrow and extramedullary site (if amenable to biopsy) 
including skin in leukemia cutis. Using immunohistochemistry, we will evaluate for activated T-
cells with CD8 and,granzyme B double IHC at baseline and post-treatment. We will also 
evaluate CD4, PD-1, and PD-L1. We will collaborate with Dr. Scott Rodig and his core 
laboratory at the Brigham and Women’s Hospital to perform these evaluations. We will evaluate 
samples from time of screening and at the end of 2 cycles of treatment with the combination.  As 
biopsies will otherwise be required per protocol at additional time points, we will capture IHC 
responses at later time points if we see evidence for delayed biological activity.   
 
Correlative study: Evaluation of the immune phenotypic response to combination therapy   
CTLA-4 expression is induced upon T cell activation. We hypothesize that epigenetic therapy 
may modulate T cell activation and that the addition of immunotherapy will give rise to an 

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increased number of CD4 and CD8 T cells infiltrating the tumor sites. Further, there is limited 
data available on the immune response to epigenetic therapy.  Based on the observations in the 
single-agent ipilimumab post allo-HCT study [4] , we hypothesize that checkpoint blockade 
increases the number of effector memory T cells (TEM), which likely helps to augment GVT in 
responders. From whole blood, we will perform serial immunophenotypic analysis of immune 
cells utilizing flow cytometry to evaluate lymphocyte subsets and ELISA to assess 
chemokine/cytokine profiles (CXCL2, CXCL5, MICA, and others) to assess whether we observe 
similar results in patients treated with combination ipilimumab/ decitabine. Lymphocytes have 
an expansive repertoire and heterogeneity that is difficult to fully capture by conventional flow 
cytometry techniques.  If we detect T cell activation using conventional flow cytometry, we then 
propose to further interrogate the lymphocyte repertoire using mass cytometry.  Fluorescent dye-
based flow cytometry can analyze up to 8-10 parameters of a single cell, but due to overlapping 
excitation and emission spectra of the different fluorescent dyes, the parameters cannot be 
expanded.  We will use single cell mass cytometry (cytometry by time-of-flight, CyTOF), which 
enables analysis to 34 or more simultaneous parameters, to do a detailed analysis of both 
phenotypic and functional markers of all peripheral blood lymphocytes for patients on trial. We 
will use a panel of surface membrane and intracellular markers to assess the number and 
activation status of Treg, TEM, TCM, Tnaive, and NK cells, including but not limited to CTLA-4, 
ICOS, PDL-1, TIM-3. We will collaborate with Dr. Jerome Ritz and Dr. Jacalyn Rosenblatt at 
the Dana-Farber Cancer Institute and Center for Immuno-Oncology.  We will evaluate samples 
collected at baseline (prior to dosing on study), after the lead in period (epigenetic priming), and 
on treatment (at the end of cycles 2 and 4).  
 
Correlative study: Evaluation of the transcriptional response to therapy  
We will evaluate the gene expression pattern of immune infiltrates to understand differences in 
the tumor microenvironment in situ. We will utilize whole exome sequencing or bulk versus 
single cell transcriptomics to elucidate the heterogeneity of immune and cancer cell populations 
before and after therapy to understand how leukemic and immune populations co-evolve during 
response or resistance.  Immune cell gene expression patterns and networks that correlate with 
clinical outcome will be inferred computationally and confirmed by multiplexed 
immunofluorescence for associated protein markers.  Leukemic neoantigens that attract and drive 
anti-tumor immune responses will be identified and evaluated for correlation with clinical 
outcome.  We will collaborate with Drs. Pavan Bachireddy/Catherine Wu at the Dana-Farber 
Cancer Institute. We use samples collected at baseline (i.e. aspirate if marrow disease, at time of 
screening), end of the lead in period (end of epigenetic priming), and end of cycle 2.  
 
Potential Future Correlative study: Evaluation for resistance to immune response  
Inadequate co-stimulation of T cells may be one mechanism underlying failure of adoptive 
immunity after alloHCT.  T cell immune responses result from a balance between stimulatory 
and inhibitory signals.  STAT3/5 activation can increase the expression of immunosuppressive 
proteins and decrease expression of co-stimulatory proteins. STAT3 is an oncogenic 
transcription factor that modulates immune checkpoint activity in cancer cells and its activation 
has been detected in leukemic blasts and is associated with chemoresistance [81].  Chemical 
inhibition of STAT3 activity using atovaquone and pyrimethamine in cultured AML cell lines up 
regulates the expression of immune co-stimulatory molecules and down regulates the expression 
of potential immunosuppressive proteins (unpublished data, see Figure 1 below, laboratory of 

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Dr. David Frank at the Dana-Farber Cancer Institute).   
 
 
 
 
Figure 1. STAT3 inhibition with atovaquone 
or pyrimethamine (a) up regulates co-
stimulatory molecules and (b) down regulates 
expression of immunosuppressive cytokines 
and molecules 
 
 
 
 
 
 
 
 
We hypothesize that non-responders may show evidence of STAT3/5 activation in the tumor 
microenvironment, which may dampen the immunogenicity of AML cells.  To evaluate the role 
of STAT3/5 activation as a mechanism of resistance, STAT3, STAT5, p-STAT3 and p-STAT5 
will be captured by CyTOF among T cell subsets.  If there is evidence of STAT3 activation 
among non-responders to treatment, we will further explore whether or not STAT3 target genes 
may be associated with treatment response [82].   
 
Future studies: As more data becomes available during the study and as we analyze the 
transcriptome data, we may find candidate genes of interest to pursue further (i.e. are they 
subject to methylation) from the tumor microenvironment.  In anticipation of this, we will save 
an aliquot of the samples to evaluate the methylome (one potential strategy is to perform whole-
genome bisulfite sequencing to assess intra-tumor DNA methylation heterogeneity before and 
after epigenetic priming and after combination therapy).  We will also consider TCR repertoire 
sequencing studies comparing peripheral blood and bone marrow samples.  This technique will 
identify expanded T cell clones that likely mediate any clinical response.  Samples from baseline 
(aspirate at screening), at the end of cycle 1, and on treatment will be saved for future 
exploration.   
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Age 18 and older.       
 
3.1.2 Subjects with evidence of AML or MDS that meet at least one of the following 
criteria:  
o Relapsed AML: evidence of ≥ 5% blasts in the bone marrow; or 
reappearance of blasts in the peripheral blood; or development of 

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extramedullary disease (according to 2003 IWG criteria [6]) who relapse 
after: 
 Allogeneic hematopoietic stem cell transplant, or 
 After one cycle of standard cytotoxic chemotherapy or two cycles 
of any hypomethylating agent-based therapy 
o Refractory AML: ≤ 2 prior induction regimens (example: patients who 
receive 7+3 followed by 5+2 would count as one induction regimen) or a 
minimum of two cycles of any hypomethylating agent-based therapy. 
o Treatment-naive AML: must be 75 years and older with de novo or 
secondary AML to be considered eligible 
o Relapsed MDS: disease recurrence after CR, PR or hematologic 
improvement with bone marrow blasts ≥ 5% who relapse after: 
 Allogeneic hematopoietic stem cell transplant, or 
 After four cycles of any hypomethylating agent-based therapy 
o Refractory MDS: disease progression at any time after initiation of 
hypomethylating agent treatment or persistent bone marrow blasts ≥ 5% 
despite a minimum of four cycles of hypomethylating agent therapy. 
o Untreated or previously treated therapy- related or secondary MDS  
 
3.1.3 Allowed prior allogeneic hematopoietic stem cell transplantation (allo-HCT) 
regardless of stem cell source. Patients must be at least 3 months post allo-HCT (at 
time of treatment start).  Mismatched transplantations would be allowed. 
 
3.1.4 Patients must be off systemic immunosuppressive medications >2 weeks prior to 
treatment start. If patients are in systemic corticosteroids and must be on a dose of 
prednisone 5 mg/day or less (or equivalent), then patients must be on this reduced 
dose for >1 week prior to treatment start. Topical steroids are allowed  
 
3.1.5 If post allo-HCT, then patient must have baseline donor T cell chimerism of ≥ 20% 
(from peripheral blood).  Evaluation can be made within 4 weeks of treatment 
start.  
 
3.1.6 No limitations on prior therapies.    
 
3.1.7 ECOG performance status ≤ 2 (see Appendix A)  
 
3.1.8 Participants must have normal organ as defined below: 
x Total bilirubin ≤ 1.5 × local institutional upper limit of normal (ULN)  
o If elevated total bilirubin is due Gilbert’s disease or disease-related 
hemolysis then total bilirubin ≤ 3.0 x local institutional ULN  
x Aspartate aminotransferase (AST) or SGOT ≤ 3.0 × local institutional ULN 
x Alanine aminotransferase (ALT) or SGPT ≤ 3.0 × local institutional ULN 
x Serum creatinine ≤ 2.0 x local institutional ULN  
 

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3.1.9  Negative serum pregnancy test for women who are of child bearing potential (test 
must be repeated if performed> 72 hours from treatment start). The effects of 
ipilimumab on the developing human fetus are unknown.  For this reason and 
because immunotherapy agents as well as decitabine are known to be teratogenic, 
women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to 
study entry and for the duration of study participation.  Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this 
study, she should inform her treating physician immediately.  Men treated or 
enrolled on this protocol must also agree to use adequate contraception prior to the 
study, for the duration of study participation, and 4 months after study drug 
administration. 
 
3.1.10 Patients with known active HIV infection. Patients with chronic HIV with a CD4 > 
250, undetectable viral load by PCR, without opportunistic infection, and on a 
stable regimen of HAART therapy would be eligible 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Participants who have had chemotherapy or radiotherapy within 2 weeks prior to 
treatment start or those who have not recovered from adverse events due to agents 
administered more than 2 weeks prior to treatment start.   
x Hydroxyurea is allowed  for symptomatic leukocytosis if clinically 
necessary. A total white blood cell (WBC) count < 25 x 109/L prior to first 
dose of decitabine on trial is required. Prior leukopheresis and/or prior or 
concurrent treatment with hydroxyurea to achieve this level are allowed. 
x Ongoing concurrent hormonal therapy is allowed 
 
3.2.2 Participants with known CNS involvement with leukemia or who are receiving 
intrathecal chemotherapy for active CNS leukemia 
x Those with a history of CNS involvement that has been completely treated 
and those who require intrathecal chemotherapy prophylaxis are eligible in 
the expansion cohorts 
 
 
3.2.3 Prior HMA therapy is allowed, however this study excludes patients with 
progression or relapse that occur while receiving HMA-based therapy within 12 
weeks prior to treatment start on study. 
 
Disease progression is defined as either: (1) patients with prior MDS who progress 
to AML (defined by the presence of ≥ 20% blasts in peripheral blood or bone 
marrow) on HMA-based therapy; OR (2) patients with AML with evidence of 
progressive disease according to ELN 2017 criteria (Appendix H for details) (e.g. 

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>50% increase in marrow blasts over baseline or >50% increase in peripheral 
blasts to > 25 x109/L (>25,000/uL) (in absence of differentiation syndrome)).  
 
(Note: Patients who relapse post-transplant who received HMA treatment prior to 
transplant are eligible for study.) 
 
3.2.4 Donor lymphocyte infusion within 8 weeks prior to treatment start if post-
transplant. 
  
3.2.5 For patients that are post-transplant, ineligible patients include those with a history 
of overall grade III or IV (severe) acute GVHD at any time even if resolved. 
 
3.2.6 Patients with a history of prior treatment with anti-CTLA-4 antibody, anti-PD 1 
antibody, or anti- PDL1 antibody.  
 
3.2.7 Participants who are receiving any other investigational agents. 
 
3.2.8 Participants with known CNS involvement with leukemia or who are receiving 
intrathecal chemotherapy that is either prophylactic or therapeutic.  History of 
CNS involvement that has been completely treated (no longer receiving intrathecal 
chemotherapy) will be allowed.   
 
3.2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. Any other prior or ongoing condition, in the opinion of 
the investigator, that could adversely affect the safety of the patient or impair the 
assessment of study results. As patients with AML and MDS are prone to 
infections, if patients are actively being treated with appropriate antibiotics or 
antifungal therapy with clinical evidence of infection control, then they will be 
considered eligible for study.  
 
3.2.10 Autoimmune disease: Patients who are not eligible include those with a history of 
inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, are 
excluded from this study, as are patients with a history of symptomatic disease 
(e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic 
lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); 
CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre 
Syndrome and Myasthenia Gravis, multiple sclerosis).Patients with a history of 
autoimmune disease (specifically including: diabetes mellitus, vitiligo, 
hashimoto’s thyroiditis) who are asymptomatic, do not require immune 
suppression or steroids, and do not have threatened vital organ function from these 
conditions may be considered after discussion with the PI 
 

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3.2.11 No concurrent active malignancies are allowed on study for ≥ 2 years prior to 
treatment start with the exception of currently treated basal cell or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the cervix or breast. 
 
3.2.12 Patients with known active hepatitis B virus (HBV) infection should be excluded 
because of potential effects on immune function and/or drug interactions. 
However, if a patient has HBV history with an undetectable HBV load by 
polymerase chain reaction (PCR), no liver-related complications, and is on 
definitive HBV therapy, then he/she would be eligible for study. 
 
3.2.13 Patients with known active hepatitis C virus (HCV) infection. Patients with a 
history of HCV infection who received definitive therapy and has an undetectable 
viral load by PCR would be eligible. 
 
3.2.14 Pregnant women are excluded from this study because ipilimumab has the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with ipilimumab, breastfeeding should be discontinued if the mother is 
treated with ipilimumab.  These potential risks may also apply to decitabine. 
 
3.3 
Pregnancy 
 
The effects of ipilimumab on the developing human fetus are unknown.  For this reason and 
because immunotherapy agents as well as decitabine are known to be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior to the 
study, for the duration of study participation, and 4 months after study drug administration.  
 
Sexually active women of child-bearing potential (WOCBP) must use an effective method of 
birth control during the course of the study, in a manner such that risk of failure is minimized. 
Before enrolling WOCBP in this clinical study, the investigator must review the guideline about 
study participation for WOCBP which can be found in the GCP Manual for Investigators. The 
topics include the following: 
x General Information 
x Informed Consent Form 
x Pregnancy Prevention Information Sheet 
x Drug Interactions with Hormonal Contraceptives 
x Contraceptives in Current Use 
x Guidelines for the Follow-up of a Reported Pregnancy. 
 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during study participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form documenting this discussion. 

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All WOCBP MUST have a negative serum quantitative pregnancy test within 72 hours of 
receiving treatment on study. The minimum sensitivity of the pregnancy test must be 25 IU/L 
or equivalent units of HCG. If the pregnancy test is positive, the subject must not receive 
ipilimumab and must not be enrolled in the study. 
 
In addition, all WOCBP should be instructed to contact the investigator immediately if 
they suspect they might be pregnant (e.g., missed or late menstrual period) at any time 
during study participation. 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
subject safety). Pregnancies should be reported directly to CTEP through the Adverse Event 
Reporting System ( AERS) and must also be accompanied by the Pregnancy Information Form  
 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g., X-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. In addition, the investigator must report 
and follow-up on information regarding the course of the pregnancy, including perinatal and 
neonatal outcome. Infants should be followed for a minimum of 8 weeks. 
 
3.4 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH-
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research.  Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification.  Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources.  Women of 
childbearing potential should not be routinely excluded from participation in clinical research.  
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
Both men and women of all races and ethnic groups are eligible for this trial. Please see table in 
section 13.2 on planned distribution of subjects by sex/gender, race, and ethnicity. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 

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(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
D 
D 
D 
 
HSP/GCP training 
D 
D 
D 
 
Agent Shipment Form (if applicable) 
D 
 
 
 
CV (optional) 
D 
D 
D 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
x Added to a site roster 
x Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x Act as the site-protocol PI on the IRB approval 
x Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 

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Additional information can be found on the CTEP website at  
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please 
contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
 
4.2 
Site Registration 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following:  
 
x An active Federal Wide Assurance (FWA) number 
x An active roster affiliation with the Lead Network or a participating organization 
x A valid IRB approval 
x Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
x Active registration status 
x The IRB number of the site IRB of record listed on their Form FDA 1572 
x An active status on a participating roster at the registering site 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not 
required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using 
the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an 
automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-
approved institutions aligned with the Signatory Institution are participating in the study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 10026 protocol page located on the 
CTSU Web site.  Permission to view and download this protocol is restricted and is based 
on person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol 
organization in the RSS.  
 
x Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
x Click on the Protocols tab in the upper left of your screen.  
x Either enter the protocol # in the search field at the top of the protocol tree, or 

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x Click on the By Lead Organization folder to expand, then select LAO-MA036 
and protocol #10026. 
x Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above) 
 
4.2.2 Requirements for 10026 Site Registration 
 
x A screening request form must be completed by the site and sent to the lead site 
for approval and acknowledgement prior to consenting a patient. 
x IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 
x Site Initiation Visit (SIV Report) must be uploaded to the CTSU Regulatory 
Office prior to enrolling patients 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) Æ 
Regulatory Tab ÆRegulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support. 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU 
website.   
x Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 

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username and password
x Click on the Regulatory tab at the top of your screen
x Click on the Site Registration tab
x Enter your 5-character CTEP Institution Code and click on Go
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does 
not reflect compliance with protocol requirements for individuals participating on the 
protocol or the enrolling investigator’s status with the NCI or their affiliated networks.
4.3
Patient Registration
4.3.1
Obtaining Lead Site/Coordinating Center Approval Prior to Registration
To obtain approval to enroll a participant, the following documents should be completed by the
external site research nurse or data manager and e-mailed to the Research Project 
Manager of the lead site ( Dana Farber Cancer Institute) 
Copy of labs and clinical information that satisfy inclusion criteria
Signed participant consent form
HIPAA authorization form (if applicable)
Registration Form
Completed eligibility checklist
To complete the registration process, the Research Project Manager at the lead site will 
follow DF/HCC Standard Operating Procedure for Human Subject Research titled
Subject Protocol Registration (SOP# REGIST-101) and send an email to the external site 
confirming  that the patient is cleared to be enrolled into OPEN/IWRS for formal 
registration.
4.3.2

OPEN / IWRS
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis. It
is integrated with the CTSU Enterprise System for regulatory and roster data interchange
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave.
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 

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initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. Registrars must 
hold a minimum of an AP registration type 
x To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
x Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes.   
x If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:   
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11 
This link to the Theradex website is also on the CTSU website OPEN tab. For questions 
about the use of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-
7802 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment as soon as possible (within 5 
days of enrollment).  Issues that would cause treatment delays should be discussed with the 
Principal Investigator.  If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible. 
 
5. TREATMENT PLAN 
  

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5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy, except for hydroxyurea. 
Prophylactic intrathecal chemotherapy is allowed if determined to be clinically necessary. Please 
see section 6.5 for details on IT chemotherapy prophylaxis.  
 
This is a standard 3+3 dose escalation study with two patient cohorts, separated by transplant 
status (Arm A = post allo-HSCT; Arm B = transplant naive).  Given the concern for potential 
toxicity in the post allo-HSCT arm (Arm A), we will first demonstrate safety at the first dose 
level (e.g. Dose Level 0; starting dose, see table in Section 5.1 below) with patients on Arm B 
(transplant naive cohort) prior to Arm A enrollment.  If there is no DLT in the first 3 patients, 
then we will proceed to enrollment on Arm A at the first dose level. However, if there is a DLT 
event in the first 3 patients assessed in Arm B, then following 3+3 rules, an additional 3 patients 
(a total of 6) will be tested at the same dose level.  If there are no additional DLTs within those 6 
patients, then we will allow enrollment on Arm A.   
 
After the first dose level is assessed for safety in Arm B, then subjects can be simultaneously 
enrolled to the appropriate arm with no further observation period or delay between the start of 
therapy for each enrolled patient in either arm. Overall, patients in Arm A and Arm B will be 
tested at the same three dose levels, as described in the table below (section 5.1).   
 
In the event that 0 of 3 patients in a dose level experience a DLT, the dose level may still be 
expanded to 6 evaluable patients based on observed toxicity at the current dose level at the 
discretion of the overall PI to capture patient safety prior to expanding.   
 
Dose Escalation Schedule for both Arm A and Arm B 
Dose Level 
Dose 
Ipilimumab  
(mg/kg) 
on day 1 
Decitabine* 
(mg/m2) 
on days 1-5 
Level -1 
(dose de-escalation) 
1 
20 
Level 0 
(starting dose) 
3 
20 
Level 1 
5 
20 
Level 2 
10 
20 
*Decitabine is NOT dose-escalated and will be given at standard dosing of 20 mg/m2 IV daily x 
5 consecutive doses on days 1-5 of a 28-day cycle 
 
Treatment Overview 
x Each cycle is 28 days in length  

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x There will be three phases: priming, induction and maintenance 
x Hydroxyurea may be used to control leukocytosis  
 
x Lead In: Priming phase with decitabine alone 
o Treatment:  Decitabine 20 mg/m2 IV daily over 60 minutes (+/- 15 minutes) x 5 
consecutive doses on days 1-5 given per institutional guidelines  
 Pre-medication prior to chemotherapy: per institutional standards   
 Supportive medication such as allopurinol or equivalent should be 
considered in patients with white blood cell counts > 10 x 109 /L to reduce 
risk of tumor lysis syndrome. 
o Clinic visits on day 1 and day 15 (+/- 3 days)  
o Labs on day 1 and day 15 (+/- 3 days) 
o Research blood and aspirate collection at the end of the lead in period on a day 
between days 24-28 (see correlatives calendar in section 10.2). 
o Adverse event evaluation: 
 Intolerability during priming phase: If a patient experiences unexpected 
intolerability to decitabine during the lead in that cannot be ameliorated by 
supportive care measures, then that patient will not continue on trial and 
will be replaced.   
 Graft versus host disease (GVHD): If there is evidence of acute GVHD 
that requires the use of systemic corticosteroids agents during the lead in, 
then the patient will be taken off study due to concern for safety with 
checkpoint blockade and replaced.  
x Cycles 1-4: Induction phase with combination decitabine and ipilimumab 
o Pre-Treatment Requirements 
 Hematologic criteria to start cycle 1: None required 
 Hematologic criteria to start cycle 2:   
x If there is persistent disease (e.g. peripheral blasts, any marrow 
disease, persistent leukemia cutis or other form of extramedullary 
disease) at the time of disease response evaluation at the end of 
cycle 1, then there are no hematologic requirements to start cycle.  
x In the absence of disease, patients must have an absolute 
neutrophil count ≥ 500 x 109/L or platelet count to ≥ 25,000 x 
109/L to proceed; otherwise administration of treatment will be 
delayed.  
 Hematologic criteria to start cycle 3:   
x If there is persistent disease (e.g. peripheral blasts, any marrow 
disease, persistent leukemia cutis or other form of extramedullary 
disease) at the time of disease response evaluation at the end of 
cycle 2, then there are no hematologic requirements to start cycle.  
x In the absence of disease, patients must have an absolute 
neutrophil count ≥ 500 x 109/L or platelet count to ≥ 25,000 x 
109/L to proceed. 
 Hematologic criteria to start cycle 4:   
x If there is persistent disease (e.g. peripheral blasts, any marrow 
disease, persistent leukemia cutis or other form of extramedullary 

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disease), then there are no hematologic requirements to start cycle .  
x In the absence of disease, patients must have an absolute 
neutrophil count ≥ 500 x 109/L or platelet count to ≥ 25,000 x 
109/L to proceed; otherwise administration of treatment will be 
delayed.  
o Treatment 
 Decitabine 20 mg/m2 IV daily over 60 minutes (+/- 15 minutes) x 5 
consecutive doses on days 1-5 every 4 weeks given per institutional 
guidelines  
x Pre-medication prior to chemotherapy: per institutional 
standards   
 Ipilimumab IV (per dose level as in table above) on day 1 over 90 minutes 
(+/- 15 minutes) every 4 weeks for a total of 4 doses during induction 
x Dose escalation levels: 3 mg/kg (starting dose, dose level 0), 5 
mg/kg (dose level 1), and 10 mg/kg (dose level 2) 
x Dose de-escalation level: 1 mg/kg  
 Decitabine will be dosed prior to ipilimumab on day 1 
 Vitals signs will be repeated hourly from time of ipilimumab infusion for 
up to two hours after infusion ends (+/- 30 minutes) on day 1 after first 
dose and up to one hour after infusion ends (+/- 30 minutes) on day 1 for 
subsequent doses. 
o Clinic visits (including physical exam, medication review, ECOG and AE review) 
 Cycle 1: on day 1 and day 15 (+/- 3 days)  
 Cycles 2-4: on day 1 (+/- 3 days). 
o Procedures:  
 Labs  
x Cycle 1: on day 1, day 15 (+/- 3 days).   
x Cycles 2-4: on day 1 (+/- 3 days).   
x End of cycles 1, 2 and 4 on day of bone marrow biopsy (on a day 
between days 24-28). 
 Bone marrow biopsy (including aspirate (if aspirable), core, flow 
cytometry, cytogenetics) will be at the end of cycles 1, 2 and 4 (on a day 
between days 24-28) for response assessment.   
 If sole extramedullary disease (unless leukemia cutis), routine evaluation 
may include PET imaging (if FDG avid at time of diagnosis) at the end of 
cycles 2 and 4 (on a day between days 24-28) for response assessment. 
o Correlative studies: peripheral blood and aspirate collection at the end of cycles  
1, 2 and 4 on a day between days 24-28 (see correlatives calendar in section 10.2). 
o The DLT window will be the first 8 weeks of combination treatment with 
decitabine and ipilimumab (starting day 1 of cycle 1). 
o At the time of response assessments, patients with evidence of disease progression 
will come off study unless they have evidence of treatment tolerability and 
clinical benefit (i.e. improvement in transfusion frequency or peripheral blast 
reduction or symptom improvement). Patients with evidence of disease 
progression may be allowed to stay on study if deriving clinical benefit with 
approval from the overall PI as there may be a delayed response with 

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immunotherapy.  
o Patients with stable disease or better at the end of cycle 4 will move forward with 
treatment in the maintenance phase.  
 
x Cycles 5-12: Maintenance phase with combination decitabine and ipilimumab 
o Pre-treatment Criteria 
 In the absence of disease, patients should have an absolute neutrophil 
count ≥ 500 x 109/L or platelet count to ≥ 25,000 x 109/L to proceed with 
each cycle.  Dose delay recommendations are provided in section 6.   
 If there is still disease ( partial or stable) then no hematologic requirements 
are required to start cycle 
o Treatment 
 Decitabine 20 mg/m2 IV daily over 60 minutes (+/- 15 minutes) x 5 
consecutive doses on days 1-5 every 4 weeks given per institutional 
guidelines  
x Pre-medication prior to chemotherapy: per institutional 
standards   
 Ipilimumab IV (per dose level as in table above) on day 1 over 90 minutes 
(+/- 15 minutes) every 8 weeks for a total of 4 doses during maintenance 
 Decitabine will be dosed prior to ipilimumab on day 1 
 Vitals signs will be repeated hourly from time of ipilimumab infusion for 
up to one hour after infusion ends (+/- 30 minutes) on day 1. 
 
o Clinic visits (including physical exam, medication review, ECOG and AE review) 
 Cycles 5-12: on day 1 (+/- 3 days). 
o Procedures:  
 Labs  
x Cycles 5-12: on day 1 (+/- 3 days).   
x At the end of cycles 7 and 10 on a day between days 24-28 and at 
end of study on a day between days 24-28. 
 Bone marrow biopsy (including aspirate (if aspirable), core, flow 
cytometry, cytogenetics) will be at the end of cycles 7, 10 and at end of 
study (on a day between days 24-28) for response assessment.   
o Correlative studies: peripheral blood and aspirate collection at the end of cycles 
7 and 10 on a day between days 24-28 and at the end of study (see correlatives 
calendar in section 10.2). 
o At the time of response assessments, patients with evidence of disease progression 
will come off study unless they have evidence of clinical benefit (i.e. 
improvement in transfusion frequency or peripheral blast reduction). Patients with 
evidence of disease progression may be allowed to stay on study if deriving 
clinical benefit with approval from the overall PI as there may be a delayed 
response with immunotherapy.  
o Additional maintenance dosing (following the same schedule of ipilimumab 
dosed on day 1 every other cycle with monthly decitabine) for patients with 
clinical benefit at completion of maintenance therapy will be considered with 
Overall PI until progression or unacceptable toxicity.   

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Regimen Description 
Agent 
Premedications; Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Decitabine 
Anti-emetic agent per 
institutional guidelines (i.e. 
compazine 10 mg injection or 
equivalent as slow push at a rate 
not to exceed 5 mg/min per 
institutional standards given 30 
minutes [+/- 15 minutes] prior to 
chemotherapy) 
20 mg/m2  
 
(reconstituted 
and mixed per 
institutional 
guidelines)  
Recommend 
giving decitabine 
first prior to 
ipilimumab.   
 
IV over 60 minutes 
[+/- 15 minutes]. 
Days 1-5 every 
4 weeks 
28 days 
(4 
weeks) 
Ipilimumab None unless history of prior 
reaction  
 
Please see section 6.3 for 
recommendations for 
hypersensitivity precautions 
 
1, 3 (starting 
dose level), 5, or 
10 mg/kg 
IV over 90 minutes 
(not bolus or IV 
push) [+/- 15 
minutes].  
 
Administer after 
decitabine infusion 
is completed (any 
time within four 
hours after 
infusion 
completion). 
Day 1* every 4 
weeks during 
induction and 
every 8 weeks 
during 
maintenance 
*Ipilimumab does not start until cycle 1 
 
Please also refer to section 6 for dose delay guidelines.  
 
5.1.1 CTEP IND Agent: Ipilimumab 
 
Unit: Ipilimumab 5 mg/mL, in 40-mL vials 
 
Route: Intravenous infusion 
 
Dosing: Treatment doses of both decitabine and ipilimumab will be based on the participant’s 
weight obtained on day 1 of each cycle. Dose levels include: 1 mg/kg (dose level -1, dose de-
escalation), 3 mg/kg (dose level 0, starting dose, FDA-approved dose), 5 mg/kg (dose level 1), 
and 10 mg/kg (dose level 2, FDA-approved dose). 
 
Appearance: Clear, colorless solution 
 
5.1.2 Decitabine 
 
Administration:Per institutional guidelines.. Patients will be dosed for 5 consecutive days 
unless there is a clinical reason to hold the drug as described in section 6 of the protocol   
 
Dosing: On days when both drugs are required, decitabine should be administered prior to 
ipilimumab. Treatment doses of both decitabine and ipilimumab will be based on the 
participant’s weight obtained on day 1 of each cycle.   

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
Prophylaxis: No prophylaxis is required however anti-viral therapy (i.e. acyclovir 400 mg po 
three times a day or equivalent) is common practice.  
 
Supportive care regimens: Prior to administration of chemotherapy (decitabine) recommend an 
anti-emetic agent to be given 30 minutes (+/- 15 minutes) prior to chemotherapy to increase 
tolerability. Anti-emetic agent should be per institutional guidelines. 
 
5.2 
Definition of Dose-Limiting Toxicity 
DLT for dose-escalation purposes will be determined during the first 8 weeks of combination 
therapy (56 days from start of combination, starting cycle 1 day 1 of ipilimumab and decitabine) 
during the induction phase only. A DLT will be defined as any of the following toxicities that are 
determined to be at least possibly related to treatment with combination ipilimumab and 
decitabine and not related to underlying disease or intercurrent illness or to decitabine alone. 
Adverse events that occur after the first 8 weeks will also be evaluated by the investigator and 
may be considered dose limiting depending on the clinical scenario. Events will be graded by 
CTCAE v5.0 criteria. 
DLTs include: 
x Any study treatment related death (not due to disease or intercurrent illness). 
x Acute GVHD that is an overall grade III or higher (see Appendix B) 
o Exception: For skin GVHD alone, must be an overall grade II with at least stage 3 
involvement or higher to be considered a DLT (skin GVHD that is stage 1-2 will 
not be considered a DLT). 
x Grade 3 or higher non-hematologic toxicity 
o Exceptions:  
 Fatigue, nausea, weight loss, electrolyte abnormalities managed by 
replacement or correction, endocrine abnormalities managed by 
replacement therapy, skin rash, and those attributable to GVHD (as above) 
 Infections will be considered a DLT if grade 4 or higher or grade 3 that 
does not recover to grade 1 within 4 weeks 
x Admission and IV antibiotics for neutropenic fever without sepsis or severe complication 
will not be considered a DLT (this is a frequent complication of underlying disease and 
of decitabine therapy) 
x Grade 3 immune-related adverse events (e.g. diarrhea, pruritus, rash, endocrinopathies) 
that respond to corticosteroids and improve to grade 1 or less within 4 weeks will NOT 
count as DLTs. Optional biopsy of affected organs will be encouraged to help determine 
whether the immune-related condition is due to direct effects of ipilimumab versus 
GVHD. 
x Grade 3 ipilimumab infusion reactions; a second consecutive occurrence or grade 4 or 
high infusion reaction will be considered a DLT. 
x Grade 4 or higher hematologic toxicity will be considered a DLT if patients do not 
recover their absolute neutrophil count to ≥ 500 x 109/L or platelet count to ≥ 25,000 x 
109/L, at the end of the DLT window, with a hypocellular marrow and absence of 

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underlying disease. 
 
Management and dose delays associated with the above adverse events are outlined inSection 6.  
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
For patients who are removed from treatment because of a > 4 week delay in receiving the next 
dose of ipilimumab: this will be classified as a DLT only if AE resulting in the treatment delay 
qualifies as a DLT. 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
x If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
x If 1 or more of this group experience DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
Delayed toxicities (toxicities after 8 weeks of combination therapy):  As delayed toxicity may 
occur (immune related AE) at any point after checkpoint blockade therapy, we recommend that 
any event beyond the first 8 weeks of combination therapy that is considered to be an immune 
related AE or concerning for GVHD be reported to the Overall PI. These events will be captured 
and reported, but will not determine dose-escalation.  These patients would also be removed 
from study if they have a toxicity event described in section 5.2.  
 
5.3 
Dose Expansion Cohorts 
 
Once the RP2D is reached, an additional 6-12 patients will be treated at this dose per arm. For a 
given arm, if all 3 dose cohorts are filled to 6 patients, then a 6 patient expansion will be added. 
If 2 or fewer dose cohorts are filled to 6 patients, then a 12 patient expansion will be added so 
that no more than 24 patients (dose escalation + expansion) will be treated on a given arm. 

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For the expansion cohort, patients will continue to be monitored for occurrence of DLT.  If ≥2 of 
6 patients experience DLT, the Principal Investigator will discuss with all study investigators and 
with CTEP whether further addition of patients is needed to re-assess the RP2D.  Monitoring of 
all safety and toxicity data is done by the Principal Investigator and the Corresponding 
Organization on a real-time basis as data are entered into Medidata Rave using the Web 
Reporting Module.  All participating sites are expected to notify the Principal Investigator when 
a DLT has occurred. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Growth factor support is not routinely recommended for low blood counts unless there is a 
concern for severe sepsis, septic shock or persistent infection (e.g. fungal infection) per 
institutional standards. Transfusion support is allowed, and can be used at the discretion of the 
investigators. Prophylactic antibiotics can be utilized as appropriate for disease or as needed in 
the post allo-HCT setting at the discretion of the investigators.  
 
Suggested hypersensitivity precautions with ipilimumab: In the event of a hypersensitivity 
reaction, stop infusion, notify MD/NP/respiratory and pharmacy, administer oxygen as needed, 
monitor vital signs and proceed with administering hypersensitivity medications as needed.  
Medications to consider having available for hypersensitivity precautions:  
 
Suggested medications for hypersensitivity precautions:  
x Diphenhydramine 25-50mg IV  as needed (begin with 25 mg, if continued reaction then 
administer additional 25 mg) 
x Methylprednisolone or equivalent  40mg IV once as needed,  
x Meperidine injection 12.5-25mg IV as needed for rigor/fever and/or chills during 
hypersensitivity reaction (start with 12.5 mg). If patient has continued reaction, 
administer additional 12.5 mg.  
x Acetaminophen tablet 650 mg (oral) as needed for fever; hold if given already as a 
premedication 
x Famotidine 20mg/50mL in NS IVPB or equivalent as needed for hypersensitivity; hold if 
already given as premedication 
x Epinephrine IM injection 0.3mg as needed for anaphylaxis; may administer every 5 
minutes up to 3 doses) 
x Please refer to institution specific hypersensitivity reaction treatment algorithm for more 
clinical support  
 
5.5 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of progression, and tolerance. 
In the absence of treatment delays due to adverse events, treatment (including priming, induction 
and maintenance) may continue for up to 12 cycles of combination therapy or until one of the 
following criteria applies:  
 
x 
Disease progression (as defined by ELN 2017 criteria for AML and by IWG criteria 
for MDS). As T-cell infiltration of the tumor can look like progressive disease, please 

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discuss the results of radiographic assessments (for extramedullary disease) showing 
progressive disease with the overall PI before removing a patient from the study for 
disease progression.  
 
x 
Intercurrent illness that prevents further administration of treatment, 
 
x 
Unacceptable adverse event(s) requiring permanent stopping of both ipilimumab and 
decitabine  
 
x 
Patient decides to withdraw from the study 
 
x 
Pregnancy 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
x 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
x 
Termination of the study by sponsor. 
 
Ipilimumab is expected to trigger immune-mediated responses, which require activation of the 
immune system prior to the observation of clinical responses.  Such immune activation may take 
weeks to months to be evident.  For patients with a mass, some patients may have objective 
volume increase of tumor lesions or other disease parameters (based on study indication, i.e., 
hematologic malignancies) within (specific 12-24) weeks following the start of ipilimumab 
dosing.  Such patients may not have had sufficient time to develop the required immune 
activation or, in some patients, tumor volume or other disease parameter increases may represent 
infiltration of lymphocytes into the original tumor or blood.  In conventional studies, such tumor 
volume or relevant laboratory parameter increases during the first 12 weeks of the study would 
constitute disease progression and lead to discontinuation of imaging to detect response, thus 
disregarding the potential for subsequent immune-mediated clinical response. For the purposes 
of this clinical trial with AML and MDS, patients with sole extramedullary disease with evidence 
of tumor progression by PET imaging at the end of cycle 2 but without rapid clinical 
deterioration or change in performance status who do not require additional immediate therapy, 
may continue to be treated with ipilimumab and clinically observed until the next response 
evaluation (in this scenario, would then consider repeating a PET scan at the end of cycle 2) to 
allow detection of a subsequent tumor response.    
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.6 
Duration of Follow Up 
 

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Patients will be followed for up to 52 weeks (1 year) after removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. Patients will be followed every 3 
months by phone after removal from study.  
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Summary of dose delays and modifications allowed on study (please see sections below for 
detail): 
x Dose delay or modification of decitabine is allowed for patients diagnosed with MDS 
(per institutional guidelines) as described in section 6.1. If a patient with MDS is in a CR, 
due for both decitabine and ipilimumab and a dose delay of decitabine is recommended, 
then decitabine and ipilimumab can be delayed so that they can be dosed together.  
x Dose delay or modification of decitabine is allowed for patients diagnosed with AML in 
absence of disease if there are severe cytopenias after discussion with overall PI. Please 
see pre-dose requirements in section 5.1. 
x Holding ipilimumab is allowed based on recommendations in section 6.2.   
x If ipilimumab is held per recommendations in section 6.2, decitabine can continue alone.  
Ipilimumab may be re-introduced upon ipilimumab-AE resolution after discussion with 
overall PI. Delayed benefit from checkpoint blockade may occur. 
x Participants may delay ipilimumab dosing beyond 8 weeks after discussion and approval 
by the overall PI (each clinical situation will be reviewed on case by case basis).  
x Missed doses of ipilimumab are not given later.   
 
6.1 
Dose Delay Recommendations for Patients with Suspected Decitabine Related 
Toxicity 
 
If the toxicity is thought to be due to decitabine:  
 
If toxicity is thought to be due to decitabine alone, then ipilimumab dosing can be continued as 
monotherapy. This decision should be made with the overall PI.  
 
x AML:  Dose modification is not recommended for patients with AML. For cycle 4 on-
ward, if there is evidence of marrow hypocellularity with <5% blasts, then can consider 
delaying treatment cycle for up to 14 days, in absence of disease.  
 
x MDS:  Dose delay can be considered (not mandatory) in patients with MDS per FDA 
package label after evidence of marrow remission or better. Any other treatment delays 
must be discussed with the Overall PI. 
 
Patients that have grade 3 or higher thrombocytopenia (50,000/mm3 or less) OR grade 3 
or higher neutropenia (1000/mm3 or less) at the time of screening are not recommended 
for dose reduction until after response evaluation at the end of cycle 2. If there is 
evidence of marrow remission or better for patients with MDS on study, then dose delay 
may be considered for subsequent cycles per institutional guidelines. If there is evidence 
of persistent disease, then would not recommend delaying treatment unless thought to be 

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due to decitabine (and not disease).   
 
6.2 
Dose Delay Recommendations for Patients with Suspected Ipilimumab Toxicity or 
Combination Therapy   
 
Intra-patient dose modification (reductions or increases) of ipilimumab is not allowed in this 
study.  
 
Decisions to delay an ipilimumab dose must be made on specified safety criteria.  Treatment 
with ipilimumab will be delayed or discontinued if the subject experiences at least one adverse 
event, specified below, considered by the investigator to be “possibly,” probably,” or 
“definitely” related to ipilimumab treatment.  
 
Any adverse event that will prompt a delayed dose or discontinuation of ipilimumab must be 
reported.  All AEs that require dose holding (for ipilimumab) will be reviewed during regularly 
scheduled conference call with the PI and co-investigators. Calls will be planned at a minimum 
of every 4-6 weeks. A representative from the site (co-investigator, research nurse, or clinical 
trial coordinator) will be required to be present on the call. The investigator should contact the 
study PI or drug monitor to discuss any questions that may arise.  
 
Doses of ipilimumab will be referred to as dose #1, dose #2, dose #3, or dose #4 during the 
induction phase and dose #5, dose #6, dose #7 or dose #8 during the maintenance phase.  The 
induction phase will include the first four doses of ipilimumab and the maintenance phase will 
include the last four doses of ipilimumab. If there are any ipilimumab dose delays, the cycle and 
day will not change. The “study cycle” number is determined by the cycle of decitabine that the 
patient is on (with “cycle 1” starting as the first cycle of COMBINATION with ipilimumab; the 
priming phase of decitabine monotherapy could be considered “cycle 0” for purposes of this 
study). If there is a delay in ipilimumab dosing, decitabine may be continued as scheduled. 
Disease response assessments will be as scheduled regardless of how many doses of ipilimumab 
is administered. As an example, if dose #2 of ipilimumab (which would be due on cycle 2 day 1) 
is delayed for four weeks due to an ipilimumab related toxicity, decitabine can still be 
administered on cycle 2 days 1-5 and the scheduled disease response assessment will still occur 
at the end of cycle 2. If the ipilimumab related toxicity has resolved by cycle 3 day 1, then dose 
#2 of ipilimumab will be given then concurrent with decitabine. Continuing decitabine will help 
to maintain disease control given the proliferative nature of AML. We will capture how many 
doses of ipilimumab that patients are able to receive in this study. 
 
Delay window:  If ipilimumab dosing must be delayed for > 4 weeks +/- 3 days for holiday or 
scheduling logistics (more than 8 weeks [+/- 3 days] since the prior dose administration), then 
patients must come off treatment. For example, if patient cannot receive ipilimumab on cycle 2 
day 1 due to development of grade 2 colitis, then the patient’s dose will be delayed to cycle 3 day 
1. If the patient cannot be dosed on cycle 3 day 1 (and it has now been more than 8 weeks since 
last dose), then the patient must come off treatment.  
 
Exceptions may be made to hold ipilimumab for > 8 weeks after discussion with overall PI for 
grade 2 or lower ipi-induced immune related AEs and GVHD events that are less than grade III. 

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Patients may remain on decitabine alone until ipilimumab can be re-introduced if patients 
demonstrate continued benefit and resolution of suspected ipilimumab-induced AE to grade 1 or 
baseline (skin GVHD can be controlled with topical steroids).  
 
Suspicion for graft versus host disease (GVHD):  If there is a concern for GVHD, then we 
recommend consideration of a biopsy for diagnostic work-up if clinically appropriate. Evidence 
of grade III or higher acute GVHD would be considered a DLT (except for skin GVHD, must 
have at least stage 3 involvement to be a DLT) as this often triggers systemic corticosteroids. 
These patients would stop receiving study treatment (both ipilimumab and decitabine), and 
followed for up to 1 year after treatment for AE resolution, response and survival. Those with 
skin GVHD that is overall grade II with stage 1-2 involvement or less will be able to stay on 
study. Topical corticosteroids are allowed.  For GVHD events that are less than grade III, 
ipilimumab dose can be skipped (decitabine can continue) until event resolution or when the 
event is controlled without requiring systemic corticosteroids or immunosuppressive agents 
(exception: topical steroids) (missed ipilimumab doses will not be made up); these patients may 
remain on study. Please see Appendix B for resources to be used for acute and chronic GVHD 
grading. 
 
It is necessary to delay ipilimumab dosing for the following related adverse events: 
x Any ≥ Grade 2 non-skin related adverse event (including immune related AE (irAEs)), 
except for asymptomatic laboratory abnormalities, grade 2-3 fatigue, and grade 2 anorexia      
(as the latter two events can be caused by disease alone). Treatment does not need to be 
delayed for controlled (on treatment) or recently treated infections.  
x Any ≥ Grade 3 non-hematologic laboratory abnormality except for grade 3 fatigue (as can be 
caused by disease). Treatment does not need to be delayed for controlled (on treatment) or 
recently treated infections. 
x Any adverse event, laboratory abnormality or intercurrent illness that, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued dosing 
x Any ≥ Grade 3 skin related adverse event (unless considered to be related to underlying 
disease, leukemia cutis, or a drug-allergy that is not due to study drug (ie antibiotics)) 
x An event that is not considered to be necessarily related to ipilimumab but requires a brief 
course of corticosteroid therapy.  
o An example, if a patient develops Sweet’s syndrome (febrile neutrophilic dermatosis, 
confirmed by skin biopsy), then prednisone would be warranted. Patients would be 
allowed to continue decitabine to maintain disease control.  
x An event that is considered to be due to ipilimumab, such as immune related AEs that are 
grade 2 or less can receive corticosteroids if deemed clinically necessary so as long as they 
are tapered off by next dose. If ipilimumab dosing must be delayed for > 4 weeks (+/- 3 days 
for holiday or scheduling logistics) (more than 8 weeks since the prior dose administration) 
for any of the above reasons, patients must come off treatment.  
x Decitabine may continue if AE considered to be due to ipilimumab  
 
If there is a dose delay in ipilimumab: 
 

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For any dose delay, patients must re-meet laboratory criteria (including complete blood count 
with differential and platelets, comprehensive metabolic profile including liver enzymes) to 
be treated again on day of therapy (prior to dosing). 
 
Resuming ipilimumab: 
x Should coincide with day 1 of treatment cycle. 
x If the adverse event is suspected to be due to ipilimumab, then the AE must resolve to d 
grade 1 severity or returns to baseline within 4 weeks of initiating the dose delay (no 
more than 8 weeks since the most recent prior dose administration). This includes 
immune-related AE. Patients must be tapered off prednisone prior to resuming 
ipilimumab. 
x If the adverse event has resolved to ≤ grade 1, ipilimumab dosing may be restarted at the 
next scheduled time point per protocol.  Please see suggested guidelines for management 
of specific immune related adverse events (see Appendix C).  Please note that re-
initiating treatment may be associated with recurrence or exacerbation of autoimmune or 
inflammatory events.  In some instances clinical resolution of events such as colitis may 
be associated with residual pathologic changes and should require evaluation of complete 
resolution prior to restarting therapy.  
x If ipilimumab dosing must be delayed for > 4 weeks (+/- 3 days for holiday or scheduling 
logistics)  (more than 8 weeks [+/- 3 days) since the prior dose administration) for any of 
the above reasons, patients must come off treatment. 
x Autoimmune/inflammatory events are presumably related to the mechanisms of action of 
ipilimumab and potentially to a therapeutic effect.  The incidence and severity of these 
events may be dose related, but once initiated, there is no evidence that lowered doses 
can be administered without continued autoimmune activity and there has so far been no 
demonstrable benefit to continuing ipilimumab after an autoimmune event during the 
initial treatment.  The significance and benefit of toxicity or continued treatment in the 
maintenance phase has not been determined.  Typically no dose modification is used for 
ipilimumab.  
 
Permanent Discontinuation of Ipilimumab for Related Adverse Events  
If discontinuing ipilimumab, participants will have the option to continue decitabine alone on 
study if they are determined to be clinically benefitting from treatment at the investigator’s 
discretion.  
 
Permanently discontinue ipilimumab for any of the following: 
x Grade III or higher acute GVHD.  
x Persistent adverse reactions that requires holding more than 2 ipilimumab doses (exception: 
patients with a GVH event(s) that is determined to be less than a grade III who are 
benefitting from study treatment can continue on study after approval from overall PI). 
x Any persistent grade 3 or 4 event (see exceptions below in section 6.2.1).    
x Any immune related AE that is grade 3 or higher requiring systemic corticosteroids at a 
dose of 1 to 2 mg/kg/day of prednisone or equivalent. Immune related AEs that were 

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grade 2 or less are allowed to stay on study and receive corticosteroids if necessary so as 
long as they are tapered off by next scheduled dose of ipilimumab. They cannot be 
delayed by more than 4 weeks (meaning 8 weeks between doses), or they have to come 
off study.  
x Severe or life-threatening adverse reactions, including any of the following: 
o Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool 
frequency (7 or more over baseline), stool incontinence, need for IV hydration for 
more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation 
o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the 
upper limit of normal or total bilirubin >3 times the upper limit of normal 
o Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full 
thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations 
o Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis 
o Severe immune-mediated reactions involving any organ system (e.g., nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
o Immune-mediated ocular disease that is unresponsive to topical immunosuppressive 
therapy 
o Any adverse event, laboratory abnormality or intercurrent illness which, in the 
judgment of the investigator, presents organ specific injury and/or a substantial 
clinical risk to the patient with continued dosing.  
 
The following neurological adverse event requires permanent discontinuation of ipilimumab 
and defines unacceptable neurotoxicity: 
x Any motor neurologic toxicity >/= grade 3 regardless of causality 
x Any >/= grade 3 treatment related sensory neurologic toxicity 
 
Please refer to Appendix C and the Investigator Brochure for suggested specific treatment 
algorithms. 
 
6.2.1 Exceptions to Permanent Discontinuation 
 
x Potentially reversible inflammation (< grade 4), attributable to a local anti-tumor 
reaction and a potential therapeutic response. This includes inflammatory reactions at 
sites of tumor resections or in draining lymph nodes, or at sites suspicious for, but not 
diagnostic of metastasis. 
x Hospitalization for neutropenic fever evaluation (this is a common adverse event of 
underlying disease and of decitabine). 
x Hospitalization for ≤ grade 2 adverse events where the primary reason for 
hospitalization is to expedite the clinical work-up. 
x Patients with the following conditions where in the investigator’s opinion continuing 
study drug administration is justified based on the potential for continued clinical 
benefit:  

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o Patients treated with systemic steroids for less than 4 weeks without evidence of 
autoimmune disease requiring steroids treatment  
o Grade 2 skin rash treated with topical steroids for less than 4 weeks  
o Grade 2 Ocular toxicity that has completely responded to topical therapy .within 4 
weeks 
o Endocrinopathies where clinical symptoms are controlled with appropriate 
hormone replacement therapy. Note: Ipilimumab may not be restarted while the 
patient is being treated with systemic corticosteroids except for patients on stable 
doses of hormone replacement therapy such as hydrocortisone.  
 
6.2.2 Immune-Related Adverse Events (irAEs)Reactions and Immune-mediated 
Adverse Reactions: Definition, Monitoring, and Treatment 
 
These are suggested guidelines for the management of immune-related adverse events.  For the 
purposes of this study, an immune-related adverse reaction is defined as an adverse reaction of 
unknown etiology associated with drug exposure and consistent with an immune phenomenon. 
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes prior to labeling an event an irAEs.  Serolo gic, immunologic, and histologic (biopsy) data 
should be used to support the diagnosis of an immune-related toxicity. Suspected immune-
related adverse reactions must be documented on an AE or SAE form. Another term for an irAE 
is an immune-mediate adverse reaction, as it is termed in the Ipilimumab US Prescribing 
Information. Both terms may be used in this protocol document.  
 
Patients should be informed of and carefully monitored for evidence of clinically significant 
systemic immune-mediated adverse reactions (e.g., systemic lupus erythematosus-like diseases) 
or organ-specific immune-mediated adverse reaction (e.g., rash, colitis, uveitis, hepatitis or 
thyroid disease). If an immune-mediated adverse reaction is noted, appropriate work-up 
(including biopsy if possible) should be performed, and steroid therapy may be considered if 
clinically necessary.   
 
It is unknown if systemic corticosteroid therapy has an attenuating effect on ipilimumab activity. 
However, clinical anti-tumor responses have been maintained in patients treated with 
corticosteroids and discontinued from ipilimumab. If utilized, corticosteroid therapy should be 
individualized for each patient. Prior experience suggests that colitis manifested as ≥ grade 3 
diarrhea requires corticosteroid treatment. 
 
Suggested guidelines for specific immune-mediated adverse reactions are included in section 6.4 
below, in Appendix C, and the package insert.  These suggested guidelines should be utilized as 
clinically appropriate for the treatment of individual patients.  Please contact the overall PI or 
drug monitor for any questions.   
 
Overview of Management of Immune Related AE 
 
Immune related AE include dermatologic, gastrointestinal, hepatic, endocrine and other less 
common inflammatory events that resolve from general immunologic enhancement. Temporary 

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immunosuppression with corticosteroids, tumor necrosis factor-alpha antagonists, 
mycophenolate mofetil, or other agents can be effect treatment in most cases. 
 
For patients with moderate or severe immune related AE, this requires interruption of the 
ipilimumab and the use of corticosteroid immunosuppression. Treatment is based upon the 
severity of the observed toxicity: 
x For patients with grade 2 (moderate) immune-mediated toxicities, treatment with 
ipilimumab should be withheld and should not be resumed until symptoms or toxicity is 
grade 1 or less. Corticosteroids (prednisone 0.5 mg/kg/day or equivalent) should be 
started if symptoms do not resolve within a week.  
x For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated 
toxicities, treatment with ipilimumab should be permanently discontinued. High doses of 
corticosteroids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When 
symptoms subside to grade 1 or less, steroids can be gradually tapered over at least one 
month. 
 
6.3 
Other Guidance for the Treatment of Ipilimumab Associated Reactions 
 
The following guidance is provided for the management of ipilimumab treatment related events.  
These suggested guidelines, treatment algorithms in Appendix C, and further information in the 
investigator’s brochure, should be considered in the context of appropriate medical treatment for 
each patient.   
 
6.3.1 Treatment of Infusion Reactions Associated with Ipilimumab 
 
Since ipilimumab contains only human protein sequences, it is less likely that any allergic 
reaction will be seen in patients.  However, it is possible that infusion of ipilimumab will induce 
a cytokine release syndrome that could be evidenced by fever, chills, rigors, rash, pruritus, 
hypotension, hypertension, bronchospasm, or other symptoms.  No prophylactic pre-medication 
should be given unless indicated by previous experience in an individual patient. Reactions 
should be treated based upon the following recommendations.  
 
x For mild symptoms (e.g., localized cutaneous reactions such as mild pruritus, flushing, rash): 
o Decrease the rate of infusion until recovery from symptoms, remain at bedside and 
monitor patient. 
o Complete the ipilimumab infusion at the initial planned rate. 
o Diphenhydramine 50 mg IV may be administered at the discretion of the treating 
physician and patients may receive additional doses with close monitoring. 
o Premedication with diphenhydramine may be given at the discretion of the investigator 
for subsequent doses of ipilimumab. 
x For moderate symptoms (any symptom not listed above [mild symptoms] or below [severe 
symptoms] such as generalized pruritus, flushing, rash, dyspnea, hypotension with systolic 
BP >80 mmHg):  
o Interrupt ipilimumab. 
o Administer diphenhydramine 50 mg IV. 

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o Monitor patient closely until resolution of symptoms. 
o Corticosteroids may abrogate any beneficial immunologic effect, but may be 
administered at the discretion of the treating physician. 
o Resume ipilimumab infusion after recovery of symptoms. 
o At the discretion of the treating physician, ipilimumab infusion may be resumed at one 
half the initial infusion rate, then increased incrementally to the initial infusion rate. 
o If symptoms develop after resumption of the infusion, the infusion should be 
discontinued and no additional ipilimumab should be administered that day. 
o The next dose of ipilimumab will be administered at its next scheduled time and may be 
given with pre-medication (diphenhydramine and acetaminophen) and careful 
monitoring, following the same treatment guidelines outlined above. 
o At the discretion of the treating physician additional oral or IV antihistamine may be 
administered prior to dosing with ipilimumab. 
x For severe symptoms (e.g., any reaction such as bronchospasm, generalized urticaria, systolic 
blood pressure 80 mm Hg, or angioedema): 
o Immediately discontinue infusion of ipilimumab, and disconnect infusion tubing from the 
subject. 
o Consider bronchodilators, epinephrine 1 mg IV or subcutaneously, and/or 
diphenhydramine 50 mg IV, with solumedrol 100 mg IV, as needed. 
o Patients should be monitored until the investigator is comfortable that the symptoms will 
not recur. 
o No further ipilimumab will be administered. 
x In case of late-occurring hypersensitivity symptoms (e.g., appearance within one week after 
treatment of a localized or generalized pruritus), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). 
 
6.3.2 Treatment of Ipilimumab-Related Isolated Drug Fever 
 
In the event of isolated drug fever, the investigator must use clinical judgment to determine if the 
fever is related to the ipilimumab or to an infectious etiology.  If a patient experiences isolated 
drug fever, for the next dose, pre-treatment with acetaminophen or non-steroidal anti-
inflammatory agent (investigator discretion) should be instituted and a repeated antipyretic dose 
at 6 and 12 hours after ipilimumab infusion, should be administered.  The infusion rate will 
remain unchanged for future doses.  If a patient experiences recurrent isolated drug fever 
following premedication and post dosing with an appropriate antipyretic, the infusion rate for 
subsequent dosing should be decreased to 50% of the previous rate.  If fever recurs following 
infusion rate change, the investigator should assess the patient’s level of discomfort with the 
event and use clinical judgment to determine if the patient should receive further ipilimumab. 
 
6.4 
Monitoring and Management of Immune-mediated Adverse Reactions 
 

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6.4.1 Immune-mediated Enterocolitis 
The clinical presentation of GI immune-related AEs included diarrhea, increase in the frequency 
of bowel movements, abdominal pain, or hematochezia, with or without fever. However 
inflammation may occur in any part of the GI tract including esophagitis and gastritis.  Fatalities 
due to GI perforation have been reported in clinical trials of ipilimumab. Patients should be 
carefully monitored for GI symptoms that may be indicative of immune-related colitis, diarrhea, 
or GI perforation.  Diarrhea or colitis occurring after initiation of ipilimumab therapy should be 
evaluated to exclude infectious or alternate etiologies. In clinical trials, immune-related colitis 
was associated with evidence of mucosal inflammation, with or without ulcerations, and 
lymphocytic infiltration. 
 
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, 
mucus or blood in stool, with or without fever) and bowel perforation (such as peritoneal signs 
and ileus).  In symptomatic patients, rule out infectious etiologies and consider endoscopic 
evaluation to establish etiology and for persistent or severe symptoms.  C.difficile toxin has been 
detected in several patients with colitis and may be an independent entity or may co-exist with 
ipilimumab induced inflammatory colitis.   
 
Withhold ipilimumab dosing for any patients with enterocolitis pending evaluation; administer 
anti-diarrheal treatment and, if persistent evaluate with colonoscopy and initiate systemic 
corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. 
 
Permanently discontinue ipilimumab in patients with severe enterocolitis and initiate systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to 
grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In 
clinical trials, rapid corticosteroid tapering has resulted in recurrence or worsening symptoms of 
enterocolitis in some patients.  
 
Patients have been treated with anti-TNF agents for persistent colitis not responding to steroids. 
 
Please note autoimmune pancreatitis may cause abdominal pain and should be included in all 
evaluations. Enteritis may occur occasionally with other autoimmune events including hepatitis, 
pancreatitis, and endocrine insufficiency, which should be evaluated as clinically indicated.  
 
6.4.2 Immune-mediated Hepatitis and Pancreatitis  
Hepatic immune-related AEs were mostly clinically silent and manifested as transaminase or 
bilirubin laboratory abnormalities.  Fatal hepatic failure has been reported in clinical trials of 
ipilimumab.  Serum transaminase and bilirubin and lipase levels must be evaluated before 
each dose of ipilimumab as early laboratory changes may be indicative of emerging 
immune-related hepatitis/ pancreatitis and elevations in liver function tests (LFTs) may 
develop in the absence of clinical symptoms.  Increase in LFT or total bilirubin should be 
evaluated to exclude other causes of hepatic injury, including infections, disease progression, or 
other medications, and monitored until resolution.  Liver biopsies from patients who had 
immune-related hepatotoxicity showed evidence of acute inflammation (neutrophils, 
lymphocytes, and macrophages). 
 

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Monitor liver function tests (hepatic transaminase and bilirubin levels, lipase) and assess patients 
for signs and symptoms of hepatotoxicity/ pancreatitis before each dose of ipilimumab.  In 
patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of 
liver function test monitoring until resolution.  Withhold ipilimumab in patients with grade 2 
hepatotoxicity.  
 
Permanently discontinue ipilimumab in patients with grade 3–5 hepatotoxicity/pancreatitis and 
administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  
When liver function tests show sustained improvement or return to baseline, initiate 
corticosteroid tapering and continue to taper over 1 month.  Across the clinical development 
program for ipilimumab, mycophenolate treatment has been administered in patients who have 
persistent severe hepatitis despite high-dose corticosteroids.  
 
6.4.3 Immune-mediated Dermatitis 
Skin immune-related AEs presented mostly frequently as a rash and/or pruritus.  Some subjects 
reported vitiligo associated with ipilimumab administration.  Fatal toxic epidermal necrolysis has 
been reported in clinical trials of ipilimumab.  
 
Monitor patients for signs and symptoms of dermatitis such as rash and pruritus.  Unless an 
alternate etiology has been identified, signs or symptoms of dermatitis should be considered 
immune-mediated.   
 
Permanently discontinue ipilimumab in patients with Stevens-Johnson syndrome, toxic 
epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, 
bullous, or hemorrhagic manifestations.  Administer systemic corticosteroids at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent.  When dermatitis is controlled, corticosteroid tapering 
should occur over a period of at least 1 month.  Withhold ipilimumab dosing in patients with 
moderate to severe signs and symptoms.  
 
For mild to moderate dermatitis, such as grade 2 localized rash and pruritus, treat 
symptomatically. For persistent grade 2, grade 3, or greater, topical steroids may be 
administered.  Administer topical or systemic corticosteroids as indicated if there is no 
improvement of symptoms within 1 week. 
 
6.4.4 Immune-related Neurological Events  
Fatal Guillain-Barré syndrome has been reported in clinical trials of ipilimumab. Patients may 
present with muscle weakness and myasthenia gravis, cranial nerve palsy (n VII Bell’s palsy), 
and aseptic meninigits, encephalopathy.  Unexplained motor neuropathy, muscle weakness, or 
sensory neuropathy lasting more than 4 days should be evaluated and non-inflammatory causes 
such as disease progression, infections, metabolic syndromes, nerve entrapment, and medications 
should be excluded as causes.  
 
Withhold ipilimumab dosing in patients with any evidence of neuropathy pending evaluation.   
 
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, 
sensory alterations, or paresthesia.  Permanently discontinue ipilimumab in patients with severe 

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neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes.  Institute 
medical intervention as appropriate for management of neuropathy and other neurologic events.  
Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent for severe neuropathies.  
 
There have also been reports of encephalitis and myositis.  
 
6.4.5 Immune-mediated Endocrinopathies 
Ipilimumab can cause inflammation of endocrine organs including thyroid (Hashimoto’s 
thryroiditis with positive antibodies) and adrenal glands, hypophysitis, hypopituitarism, and 
resulting thyroid and adrenal insufficiency, low ADH, prolactin, FSH, LH.  Hyperthyroid with 
Graves’ disease and positive antibody has been reported.  Patients may present with subtle and 
nonspecific symptoms.  The most common clinical presentation includes headache and fatigue.  
Symptoms may also include visual field defects, behavioral changes, and electrolyte disturbances 
including hyponatremia and hypotension.  Adrenal crisis as a cause of the patient’s symptoms 
should be excluded.  Based on the available data with known outcome, most of the subjects 
symptomatically improved with hormone replacement therapy.  Long-term hormone replacement 
therapy with HC and synthroid will typically be required for subjects developing 
hypophysitis/hypopituitarism after treatment with ipilimumab.  Some patients have regained 
partial function following steroid treatment.  
 
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency 
(including adrenal crisis), and hyper- or hypothyroidism.  Headache is often the first symptoms 
of hypophysitis.  Patients may present with fatigue, headache, mental status changes, loss of 
libido, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which 
may resemble other causes such as brain metastasis or underlying disease.  Unless an alternate 
etiology has been identified, signs or symptoms of endocrinopathies should be considered 
immune-mediated and drug withheld pending evaluation.  Patients may demonstrate both central 
(hypophysitis) and peripheral adrenal and thyroid insufficiency.  Evaluation of hypophysitis 
should include pituitary MRI.  
 
Endocrine evaluation, including TSH, should be performed at baseline prior to initial 
treatment.  Monitor thyroid function tests and clinical chemistries at the start of treatment and 
hold blood for possible evaluation should clinical events require determining baseline function 
and anti-thyroid antibodies.  A plan for evaluating endocrine function at each visit either by 
history or monitoring TSH should be included in the protocol with further evaluation as 
clinically indicated.  Endocrine evaluation, including TSH, should be performed at baseline prior 
to treatment, and the protocol must include a plan for continued monitoring of endocrine and 
pituitary function.  The package insert for ipilimumab includes a recommendation for monitoring 
TSH prior to each infusion; as an early indication for pituitary dysfunction and hypophysitis, 
clinical monitoring of symptoms may be equally or more sensitive as an initial presentation.  
Clinical monitoring is required for all protocols as above, and should include any requirements 
per protocol for laboratory evaluation, both periodically or as clinically indicated, consistent with 
good medical practice.  In a limited number of patients, hypophysitis was diagnosed by imaging 
studies through enlargement of the pituitary gland.   
 

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Withhold ipilimumab dosing in patients symptomatic for hypophysitis.  Initiate systemic 
corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate 
hormone replacement therapy.  
 
6.4.6 Other Immune-mediated Adverse Reactions, Including Ocular Manifestations  
Ocular inflammation, manifested as grade 2 or grade 3 episcleritis or uveitis, was associated with 
concomitant diarrhea in a few subjects (<1%) and occasionally occurred in the absence of 
clinically apparent GI symptoms.  Other presumed immune-related AEs reported include, but 
were not limited to, arthritis/arthralgias, pneumonitis, pancreatitis, autoimmune (aseptic) 
meningitis, autoimmune nephritis, pure red cell aplasia, noninfective myocarditis, polymyositis, 
and myasthenia gravis, of which were individually reported for <1% of subjects.  
 
The following clinically significant immune-mediated adverse reactions were seen in less than 
1% of ipilimumab-treated patients in Study 1: nephritis, pneumonitis, pulmonary granuloma 
resembling sarcoidosis, meningitis, pericarditis, uveitis, iritis, ITP, neutropenia and hemolytic 
anemia. 
 
Across the clinical development program for ipilimumab, the following likely immune-mediated 
adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, 
temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, 
scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and 
autoimmune thyroiditis.   
 
Permanently discontinue ipilimumab for clinically significant or severe immune-mediated 
adverse reactions.  Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent for severe immune-mediated adverse reactions. 
 
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis.  
Permanently discontinue ipilimumab for immune-mediated ocular disease that is unresponsive to 
local immunosuppressive therapy. 
 
Overall, immune-related AEs commonly started within 3 to 10 weeks from first dose, were 
successfully managed in most instances by omitting doses, discontinuing dosing, and/or through 
administering symptomatic or immunosuppressive therapy, including corticosteroids, as 
mentioned above and detailed in Section 7.  Immune-related AEs generally resolved within days 
to weeks in the majority of subjects.  
 
There have also been reports of encephalitis. 
  
6.4.7 Cardiac  Toxicities Associated with Ipilimumab 
 
If there is any concern for ipilimumab induced cardiac toxicity, alert the Overall PI immediately, 
and consider following the management algorithm below: 
 
 
Cardiac *   
Management for Ipilimumab Cardiac Toxicities  

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≤ Grade 1  
Hold dose pending evaluation and observation.**  Evaluate for signs 
and symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain 
history EKG, CK (for concomitant myositis), CK-MB.  Repeat 
troponin, CK and EKG 2-3 days.  If troponin and labs normalize 
may resume therapy.  If labs worsen or symptoms develop then treat 
as below.  Hold pending evaluation.  
Grade >2 with suspected 
myocarditis 
 Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI 
and other causes of cardiac disease.  Cardiac Monitoring.  Cardiac 
Echo.  Consider cardiac MRI and cardiac biopsy.  Initiate high dose 
methylprednisolone.  If no improvement within 24 hours, add either 
infliximab, ATG or tacrolimus. Consult algorithm for more details.  
Resume therapy if there is a return to baseline and myocarditis is 
excluded or considered unlikely. 
Grade >2 with confirmed 
myocarditis   
Off protocol therapy.  Admit to CCU (consider transfer to nearest 
Cardiac Transplant Unit).  Treat as above.  Consider high dose 
methylprednisolone.   
Add ATG or tacrolimus if no improvement.  Off treatment. 
 
 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other 
event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been established.  
Since this toxicity has caused patient deaths, an aggressive approach is recommended.   
 
 
6.5 
Prohibited and Restricted Therapies 
 
Patients in this study may use standard vaccines.  Where possible, routine vaccination for 
influenza, pneumococcal pneumonia should be given prior to the start of therapy but may 
be administered during treatment when clinically indicated. Vaccination should be given 
when there is enough separation to distinguish any vaccine reactions from drug toxicity.  
There is no experience using live attenuated vaccination during ipilimumab therapy, so 
that live vaccine should be used cautiously during treatment.   
 
Concomitant systemic anti-cancer medications or treatments are prohibited in this study 
while receiving ipilimumab treatments. However, IT chemotherapy prophylaxis is 
allowed and can be considered after discussion with the overall PI and further these cases 
must be discussed on the safety calls. If IT chemotherapy prophylaxis is recommended, it 
can be given at any time during decitabine only lead-in cycle for patients in either dose-
escalation or dose-expansion. If IT chemotherapy prophylaxis is recommended during 
decitabine plus ipilimumab cycles, it will be considered and allowed in patients who enter 
dose-expansion and we recommend: 
 (1) To provide a 2 week window before Ipilimumab dosing (thus Ipilimumab may be 
delayed), 
 (2) consideration for IT hydrocortisone 50 mg with the IT chemotherapy of choice 
(methotrexate or cytarabine per provider),  

NCI Protocol #: 10026 
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(3) additional clinic visit for neurologic exam 3-5 days after IT chemo administration 
to ensure no additional toxicities are seen. Common toxicities experienced during IT 
chemotherapy include spinal headache and nausea; rarely arachnoiditis. Events in the 
CNS that are considered excessive beyond what is seen will be counted as an AE related 
to study drug. Platelets must be > 50 for IT chemotherapy or per institutional guidelines.   
 
Patients who remain on hydroxyurea and/or IT chemotherapy prophylaxis will be 
discussed on the safety calls to ensure new adverse events are appropriately captured if 
relevant. 
 
 
 In select cases of extensive disease involvement, palliative radiation may be 
administered to a localized problematic site during the study if there is evidence of 
disease involvement outside of the bone marrow with permission from the Protocol 
Chair. A delay of both decitabine and ipilimumab of 2 weeks is required starting the day 
that radiation is completed. Example: vertebral mass encroaching on spine with evidence 
of disease elsewhere in the body. 
 
Patients may not use any of the following therapies during the study: 
x Any non-study anti-cancer agent (investigational or non-investigational), except 
for hydroxyurea or prophylactic intrathecal chemotherapy as clinically indicated 
x Any other investigational agents 
x Any other CTLA-4 inhibitors or agonists 
x CD137 or other immunologic activation agonists 
x Immunosuppressive agents 
x Chronic systemic corticosteroids  (short courses of corticosteroids may be 
allowed while ipilimumab is delayed as discussed in section 6.2) 
 
6.5.1 Precautions 
 
Combination therapy may result in unexpected toxicity especially in novel combinations 
with other immune modifying agents.  A striking example in macaques is presented in 
Vaccari, et al. 2012. 
 
Please note that while unproven, there is a suggestion that autoimmune events, including 
hepatitis, may occur more frequently at sites of metastases or prior injury.  
 
Caution is advised when considering treatment with high-dose IL-2 in patients who have 
previously been administered ipilimumab, particularly in patients who experienced 
ipilimumab-related diarrhea/colitis.  Colonoscopy or sigmoidoscopy with biopsy may be 
advisable prior to IL-2 administration once the patient is no longer receiving ipilimumab.  
The management guidelines for general inflammatory AEs and ipilimumab-related GI 
toxicities, hepatotoxicity, endocrinopathy, and neuropathy (Investigator Brochure, 2011) 
are provided in Appendix C. 

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Patients who have received ipilimumab may potentially develop autoimmune disease 
with subsequent therapy including the appearance of colitis, hypophysitis or adrenal 
insufficiency.  

 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 
the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text.  The SPEER is a list of events that are protocol-
specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
7.1.1 Adverse Event List for Ipilimumab 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Ipilimumab (MDX-010, NSCs 732442 and 720801) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 2678 patients. Below is the CAEPR for 
Ipilimumab (MDX-010). 

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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
Version 2.10, March 29, 20191 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Blood and lymphatic 
system disorders - Other 
(acquired hemophilia) 
  
CARDIAC DISORDERS 
  
 
Atrial fibrillation 
 
  
 
 
Myocarditis2 
  
 
 
Pericardial effusion 
  
EAR AND LABYRINTH DISORDERS 
  
 
Hearing impaired 
 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
 
Testosterone deficiency2 
 
  
EYE DISORDERS 
  
 
Eye disorders - Other 
(episcleritis)2 
 
  
 
Uveitis2 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
 Colitis2 (Gr 3) 
 
 
Colonic perforation3 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Enterocolitis 
 
  
 
Esophagitis 
 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Pancreatitis2 
 
  

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Vomiting 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
 
General disorders and 
administration site 
conditions - Other 
(Systemic inflammatory 
response syndrome [SIRS]) 
  
 
 
Multi-organ failure 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - 
Other (hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder2 
 
  
 
 
Immune system disorders - 
Other (GVHD in the 
setting of allotransplant)4 
  
INFECTIONS AND INFESTATIONS 
  
 
 
 Infections and infestations 
- Other (aseptic 
meningitis)2 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
 
 
Lymphocyte count 
decreased 
  
 
Neutrophil count decreased 
 
  
 
Weight loss 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Dehydration 
 
  

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Hyperglycemia 
 
  
 
 
Metabolism and nutrition 
disorders - Other 
(exacerbation of pre-
existing diabetes mellitus) 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Arthritis 
 
  
 
 
Generalized muscle 
weakness 
  
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis)2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Ataxia 
  
 
Facial nerve disorder2 
 
  
 
Guillain-Barre syndrome2 
 
  
 
Headache 
 
  
 
Myasthenia gravis2 
 
  
 
 
Nervous system disorders - 
Other (immune-mediated 
encephalitis)2 
  
 
 
Peripheral motor 
neuropathy 
  
 
 
Peripheral sensory 
neuropathy 
  
 
Trigeminal nerve disorder 
 
  
PSYCHIATRIC DISORDERS 
  
 
 
Psychiatric disorders - 
Other (mental status 
changes) 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
 
Renal and urinary disorders - 
Other (granulomatous 
tubulointerstitial nephritis) 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis 
 
  

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
 
Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Respiratory failure 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (bronchiolitis 
obliterans with organizing 
pneumonia) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (lung infiltration) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythema multiforme 
  
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular  
 
 Rash maculo-papular (Gr 3) 
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome) 
 
  
 
 
Stevens-Johnson syndrome   
 
 
Toxic epidermal necrolysis   
 
Urticaria 
 
  
VASCULAR DISORDERS 
  
 
Hypotension 
 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-
cell activation and proliferation.  These can include (but are not limited to) autoimmune 
hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic meningitis, 
autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, 
ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, 
hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal 
insufficiency), ocular manifestations (e.g., uveitis, iritis, conjunctivitis, blepharitis, and 
episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome.  
The majority of these reactions manifested early during treatment; however, a minority occurred 
weeks to months after discontinuation of ipilimumab especially with the initiation of additional 
treatments. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in 

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association with subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients 
receving allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These 
complications may occur despite intervening therapy between receiving Ipilimumab (MDX-010) 
and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia 
gravis). 
 
6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ipilimumab 
(MDX-010) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system 
disorders - Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment 
changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; 
Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase 
increased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint 
range of motion decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 

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RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Cough; Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal 
arteritis) 
 
 
Note: Ipilimumab (MDX-010) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
 
7.1.2 Adverse Event List for Decitabine 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Decitabine (5-aza-2'-deoxycytidine, NSC 127716) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1832 patients. Below is the CAEPR for 
Decitabine (5-aza-2'-deoxycytidine).  
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
Version 2.5, March 28, 20191 
 
 Adverse Events with Possible  
 Relationship to Decitabine (5-aza-2'-deoxycytidine) 
 (CTCAE 5.0 Term) 
[n= 1832] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 

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 Adverse Events with Possible  
 Relationship to Decitabine (5-aza-2'-deoxycytidine) 
 (CTCAE 5.0 Term) 
[n= 1832] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Constipation 
 
 Constipation (Gr 2) 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 3) 
Fever 
 
 
 Fever (Gr 2) 
 
Non-cardiac chest pain 
 
  
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Autoimmune disorder 
 
 Autoimmune disorder (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Bruising 
 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
Lymphocyte count decreased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 
4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
  
 
Hyperuricemia 
 
  
 
Hypoalbuminemia 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hyponatremia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Bone pain 
 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to Decitabine (5-aza-2'-deoxycytidine) 
 (CTCAE 5.0 Term) 
[n= 1832] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
Somnolence 
 
 Somnolence (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Pharyngolaryngeal pain 
 
  
 
Respiratory hemorrhage3 
 
  
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Pruritus 
 
  
 
Purpura 
 
 Purpura (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Hematoma 
 
  
 
Phlebitis 
 
 Phlebitis (Gr 2) 
 
Vascular disorders - Other 
(hemorrhage with decreased 
platelets) 
 
 Vascular disorders - Other 
(hemorrhage with decreased 
platelets) (Gr 2) 
 
 
 
 
 
1This table will be updated as the 
toxicity profile of the agent is revised.  Updates will be distributed to all Principal Investigators 
at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent 
should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
3Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under 
the RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS SOC. 
 
4Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 

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hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
5Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, and 
Small intestinal obstruction under the GASTROINTESTINAL DISORDERS SOC. 
 
 
Adverse events reported on decitabine (5-aza-2'-deoxycytidine) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that decitabine (5-
aza-2'-deoxycytidine) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (coagulopathy); Blood and lymphatic system disorders - Other 
(lymphadenopathy); Blood and lymphatic system disorders - Other (pancytopenia); Blood and 
lymphatic system disorders - Other (spleen disorder); Bone marrow hypocellular; Eosinophilia; 
Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Atrioventricular block complete; 
Cardiac arrest; Cardiac disorders - Other (cardiac murmur); Cardiac disorders - Other (dilation 
atrial); Chest pain - cardiac; Heart failure; Myocardial infarction; Restrictive cardiomyopathy; 
Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Ear pain; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (eye hemorrhage); Eye disorders - 
Other (eye swelling); Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Ascites; 
Dyspepsia; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal reflux 
disease; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other 
(mouth ulceration); Gastrointestinal disorders - Other (oral mucosal blistering); Gastrointestinal 
hemorrhage4; Gastrointestinal obstruction5; Gastrointestinal pain; Hemorrhoids; Ileus; Oral pain; 
Periodontal disease; Proctitis; Rectal pain; Toothache; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Gait disturbance; Injection site reaction; Localized edema; Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatobiliary disorders - 
Other (cholestasis); Hepatobiliary disorders - Other (hepatomegaly) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Fracture; Infusion 
related reaction; Injury, poisoning and procedural complications - Other (catheter site pain); 
Injury, poisoning and procedural complications - Other (hernia); Injury, poisoning and 
procedural complications - Other (procedural pain); Injury, poisoning and procedural 
complications - Other (stent occlusion) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alkaline phosphatase 
increased; Blood bicarbonate decreased; Blood lactate dehydrogenase increased; CPK increased; 
Cardiac troponin I increased; Ejection fraction decreased; Electrocardiogram QT corrected 
interval prolonged; Fibrinogen decreased; GGT increased; INR increased; Investigations - Other 
(blood bicarbonate increased); Investigations - Other (blood bilirubin decreased); Investigations - 
Other (blood chloride decreased); Investigations - Other (blood chloride increased); 
Investigations - Other (blood urea increased); Investigations - Other (elevated ammonia); 

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Investigations - Other (platelet count increased); Investigations - Other (protein total decreased); 
Lipase increased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; 
Hyperkalemia; Hypermagnesemia; Hyperphosphatemia; Hypoglycemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (malnutrition) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Chest wall pain; 
Generalized muscle weakness; Muscle cramp; Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Leukemia secondary to oncology chemotherapy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Aphonia; Ataxia; Cognitive disturbance; 
Dysesthesia; Dysgeusia; Ischemia cerebrovascular; Lethargy; Paresthesia; Peripheral sensory 
neuropathy; Seizure; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis noninfective; 
Hematuria; Urinary fistula; Urinary frequency; Urinary retention; Urinary tract pain; Urinary 
urgency 
REPRODUCTIVE SYSTEM AND BREAST disorders - Breast pain; Uterine hemorrhage; 
Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory 
distress syndrome; Allergic rhinitis; Atelectasis; Bronchospasm; Hypoxia; Nasal congestion; 
Pleural effusion; Pneumonitis; Postnasal drip; Pulmonary edema; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (breath sounds abnormal /decreased); 
Respiratory, thoracic and mediastinal disorders - Other (crepitations); Respiratory, thoracic and 
mediastinal disorders - Other (pulmonary congestion); Sinus disorder; Wheezing 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin; 
Erythema multiforme; Hyperhidrosis; Hyperkeratosis; Skin and subcutaneous tissue disorders - 
Other (Sweet's syndrome); Skin hyperpigmentation; Skin hypopigmentation; Skin ulceration; 
Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Thromboembolic event; 
Vascular disorders - Other (aortic aneurysm); Vascular disorders - Other (catheter site 
hemorrhage); Vascular disorders - Other (circulatory collapse); Vascular disorders - Other 
(hemorrhage); Vascular disorders - Other (splenic infarct vs hemorrhage/rupture); Vascular 
disorders - Other (veno-occlusive disease); Vasculitis 
 
 
Note: Decitabine (5-aza-2'-deoxycytidine) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent 
 
 
7.2 
Adverse Event Characteristics  
 
x CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 

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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
x For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
x Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented 
in the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements 
for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_even
ts.htm).  These requirements are briefly outlined in the tables below (Section 
7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast.  
 
 

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7.3.3 Expedited Reporting Guidelines 
 
In addition to reporting events to NCI/ETCTN, it is mandatory for all participating sites to 
report ( informally via email) sites should notify the overall PI and the lead site study 
manager of any grade 3 or above ipilimumab related event informally via email. Any 
grade 5 event regardless of attribution should be reported to the Overall Study Chair and 
project manager within 24 hours of knowledge of the event. 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.”  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 

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NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4).  All events except those specifically mentioned the SPEER and 
listed below must be reported via CTEP AERS: 
x Grade 2 or 3 ( <3000/mm3-1000/mm3) White Blood Cell Count Decrease 
x Grade 2 or 3 (<1500/mm3-500/mm3 ) Absolute Neutrophil Count Decrease 
x Grade 2 or 3 (<75,000mm/3-25,000/mm3) Platelet Count Decrease 
 
7.3.5 Central Review of Suspected or Confirmed Adverse Events of Interest 
 
In addition to reporting requirements above, for adverse events that are suspicious for GVHD, 
confirmed to be consistent with GVHD, suspicious for an immune related AE, or confirmed to 
be consistent with immune related AE, we ask that investigators send pathology reports and 
relevant primary data including but not limited to surgical or imaging reports (e.g. colonoscopy 
report for colitis due to GVHD) for central review by the overall PI. If there is a biopsy, we also 
ask that slides be sent for central review (will be returned).  Please also include data on GVHD 
event description, grading and staging of GVHD (e.g. clinic note).  Address to send these items: 
Attn: Alexandra Savell, Research Project Manager for CTEP 10026; Dana-Farber Cancer 
Institute; 450 Brookline Avenue; LG-GC; Boston, MA 02215. If there are reports only, please 
fax to 617-632-5152 or email to: alexandrae_savell@dfci.harvard.edu. PHI must be redacted on 
reports and imaging when possible. Please see Appendix B for resource that should be used for 
acute and chronic GVHD grading. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 

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submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS)  
x Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent: Ipilimumab   (NSC 732442 IND #10200 ) 
 
 
8.1.1 Chemical Name or Amino Acid Sequence: 4 polypeptide chains, 2 identical 
heavy chains with 447 amino acids and 2 identical light chains consisting of 215 
amino acids. 
 

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8.1.2 Other Names: Anti-CTLA-4 monoclonal antibody, MDX-010, Yervoy™ 
 
8.1.3 Classification: Human monoclonal antibody 
 
8.1.4 M.W.: 147,991 Daltons 
 
8.1.5 Mode of Action: Ipilimumab is specific for the CTLA4 antigen expressed on a 
subset of activated T-cells. CTLA4 interaction with the B7 molecule, one of its 
ligands expressed on professional antigen presenting cells, can down-regulate T-
cell response. Ipilimumab is, thought to act by blocking the interaction of CTLA4 
with the B7 ligand, resulting in a blockade of the inhibitory effect of T-cell 
activation.  The CTLA4/B7 creates the interaction.  
 
8.1.6 Description: Ipilimumab is a fully human immunoglobulin (IgG1N) with two 
manufacturing processes – ongoing trials have been using substances 
manufactured using Process B.  New clinical trials will be using ipilimumab that is 
manufactured by Process C. The Process C has been developed using a higher 
producing sub-clone of the current Master Cell Bank, and modified cell culture and 
purification steps.  
  
8.1.7 How Supplied: Bristol-Myers-Squibb (BMS) supplies Ipilimumab to the 
DCTD/NCI.  Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a 
clear to slightly opalescent, colorless to pale yellow, sterile, nonpyrogenic, single-
use, isotonic aqueous solution that may contain particles. 
 
Each vial is a Type I flint glass vial with gray butyl stoppers and sealed with aluminum 
seals. 
 
 
Process C 
Component 
200 mg/ viala 
Ipilimumab 
213 mg 
Sodium Chloride, USP  
249 mg 
TRIS-hydrochloride 
134.3 mg 
Diethylenetriamine pentacetic acid 
1.67 mg 
Mannitol, USP 
426 mg 
Polysorbate 80 (plant-derived) 
4.69 mg 
Sodium Hydroxide 
QS to pH 7 
Hydrochloric acid 
QS to pH 7 
Water for Injection 
QS: 42.6 mL 
Nitrogenb 
Processing agent 
aIncludes 2.6 mL overfill. 
bNitrogen is used to transfer the bulk solution through the pre-filled and sterilizing filters into the aseptic area. 
 

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8.1.8 Preparation:  Ipilimumab is given undiluted or further diluted in 0.9% NaCl 
Injection, USP or 5% Dextrose Injection, USP in concentrations between 1 mg/mL 
and 4 mg/mL.  Ipilimumab is stable in a polyvinyl chloride (PVC), non-PVC/non 
DEHP (di-(2-ethylhexyl) phthalate) IV bag or glass container up to 24 hours 
refrigerated at (20 to 80 C) or at room temperature/ room light.  
 
Recommended safety measures for preparation and handling include protective 
clothing, gloves, and safety cabinets. 
  
8.1.9 Storage: Store intact vials refrigerated at (20 to 80 C), protected from light.  Do not 
freeze. If a storage temperature excursion is identified, promptly return ipilimumab 
to 2°C-8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the 
excursion) to PMBAfterHours@mail.nih.gov for determination of suitability. 
 
 
8.1.10 Stability: Shelf-life surveillance of the intact vials is ongoing.  Solution as 
described above is stable up to 24 hours refrigerated at (20 to 80 C) or at room 
temperature/ room light.  
 
CAUTION:  Ipilimumab does not contain antibacterial preservatives.  Use prepared IV solution 
immediately. Discard partially used vials.  
 
8.1.11 Route(s) of Administration: Intravenous infusion.  Do not administer ipilimumab 
as an IV push or bolus injection. 
 
8.1.12 Method of Administration:  Can use a volumetric pump to infuse ipilimumab at 
the protocol-specific dose(s) and rate(s) via a PVC IV infusion set with an in-line, 
sterile, non-pyrogenic, low-protein-binding filter (0.2 micron to 1.2 micron). 
 
8.1.13 Patient Care Implications:  Monitor patients for immune-related adverse events, 
e.g., rash/vitiligo, diarrhea/colitis, uveitis/episcleritis, hepatitis and 
hypothyroidism.  If you suspect toxicity, refer to the protocol guidelines for ruling 
out other causes. 
 
Post-marketing surveillance identified a fatal toxic epidermal necrolysis (TEN) event in 
a patient who received ipilimumab after experiencing a severe or life-threatening skin 
adverse reaction on a prior cancer immune stimulating therapy. Caution should be used 
when considering the use of ipilimumab in a patient who has previously experienced a 
severe or life-threatening skin adverse reaction on a prior cancer immune stimulating 
therapy. 
 
8.1.14 Availability 
 
Ipilimumab is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 

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Ipilimumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.4). 
 
8.1.15 Agent Ordering and Agent Accountability 
 
NCI -supplied agents may be requested by eligible participating investigators (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The eligible 
participating investigators at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form (IDF), and Financial Disclosure Form (FDF).  If there 
are several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead participating 
investigator at that institution. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account, the maintenance of an “active” account status, a “current” 
password, and active person registration status.  For questions about drug orders, transfers, 
returns, or accountability, call or email PMB any time.  Refer to the PMB’s website for 
specific policies and guidelines related to agent management.   
 
8.1.16 Agent Inventory Records – The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the 
CTEP forms page.  Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering 
investigator on this protocol. 
 
8.1.17 Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
x PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
x PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
x CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  
x CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 

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x PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
x IB Coordinator: IBCoordinator@mail.nih.gov 
 
8.1.18 Investigator Brochure Availability  
 
The current versions of the IBs for Ipilimumab will be accessible to site investigators 
and research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password and active person registration status.  Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
 
8.2 
Commercial Agent: Decitabine 
 
8.2.1 Product description:  Decitabine for Injection contains decitabine (5-aza-2’- 
deoxycitidine), an analogue of the natural nucleoside 2’-deoxycytidine. Decitabine 
is a fine, white to almost white powder with the molecular formula of 
C8H12N4O4 and a molecular weight of 228.21. Its chemical name is 4-amino-1-
(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin- 2(1H)-one. Decitabine is 
slightly soluble in ethanol/water (50/50), methanol/water (50/50) and methanol; 
sparingly soluble in water and soluble in dimethylsulfoxide (DMSO). Dacogen 
(decitabine) for Injection is a white to almost white sterile lyophilized powder 
supplied in a clear colorless glass vial. Each 20 mL, single dose, glass vial contains 
50 mg decitabine, 68 mg monobasic potassium phosphate (potassium dihydrogen 
phosphate) and 11.6 mg sodium hydroxide. 
 
 

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8.2.2 Solution preparation (how the dose is to be prepared):  Please refer the reader to 
the package insert for 'standard' preparation instructions in detail.  Highlights 
include the following: Decitabine is a cytotoxic drug and caution should be 
exercised when handling and preparing Decitabine. Procedures for proper handling 
and disposal of antineoplastic drugs should be applied. Several guidances on this 
subject have been published. Decitabine should be aseptically reconstituted with 
10 mL of Sterile Water for Injection (USP); upon reconstitution, each mL contains 
approximately 5.0 mg of decitabine at pH 6.7-7.3. Immediately after 
reconstitution, the solution should be further diluted with 0.9% Sodium Chloride 
Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection to a final drug 
concentration of 0.1 - 1.0 mg/mL. Unless used within 15 minutes of reconstitution, 
the diluted solution must be prepared using cold (2 ̊C - 8 ̊C) infusion fluids and 
stored at 2 ̊C - 8 ̊C (36 ̊F - 46 ̊F) for up to a maximum of 7 hours until 
administration.  Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and 
container permit. Do not use if there is evidence of particulate matter or 
discoloration. Decitabine (decitabine) for Injection is supplied as a sterile, 
lyophilized white to almost white powder, in a single-dose vial, packaged in 
cartons of 1 vial. Each vial contains 50 mg of decitabine.  
 
8.2.3 Route of administration:  Decitabine is administered at a dose of 20 mg/m2 by 
continuous intravenous infusion over 1 hour repeated daily for 5 days. This cycle 
should be repeated every 4 weeks. Patients may be premedicated with standard 
anti-emetic therapy. 
 
8.2.4 Agent Ordering:  The agent is commercially available.      
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1 
Pharmacokinetics:  
 
Not required for this present study as the PK of ipilimumab has been well established for the doses 
being used in the study.    
 
9.2 
Correlative studies: 
 
All sites will be encouraged to provide the correlative samples for analysis when possible. While 
the goal of the biomarkers is to provide supportive data for the clinical study, there may be 
circumstances when a decision is made to stop a collection, not perform, or discontinue an 
analysis due to either practical or strategic reasons (e.g., inadequate sample number, issues 
related to the quality of the sample or issues related to the assay that preclude analysis, 
impossibility to perform correlative analyses, etc). Therefore, depending on the results obtained 
during the study, sample collection/analysis may be omitted or added at the discretion of the PI. 
We highly encourage all sites to meet the collection requirements to the best of their ability 
so we can best characterize the biological activity of combination therapy in 
relapsed/refractory MDS/AML.  

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To assist with collection of correlative samples, kits will be prepared and distributed to sites 
upon activation.  
  
Summary of time points for collection: We cannot receive samples over the weekend. Please 
plan to collect samples Monday-Thursday for delivery Monday-Friday if this is done off-site 
(not Dana-Farber Cancer Institute). For patients being treated at DFCI, samples can be 
collected and delivered Monday-Friday.   
 
Peripheral blood, aspirate (bone marrow), FFPE tissue blocks will be collected for correlative 
studies following the schedule provided below and in table format in Section 10:   
 
Samples will be collected and cryopreserved at one central site (Dana Farber Cancer Institute, 
Pasquarello Laboratory) for all assays described.  Samples will be processed according to the 
accompanying laboratory study manual.  Samples will be otherwise stored and labeled (PHI 
removed, sample # assigned for HIPAA) in the Pasquarello Laboratory at temperature as 
required per sample (FFPE, at room temperature; aspirate in liquid nitrogen and plasma in -80C).  
Samples for specific assays will be appropriately delivered in batches for analysis (including for 
IHC). For the samples below, prioritization will be made for genotyping, RNA sequencing of 
immune infiltrates, flow cytometry, CYTOF, and other serial immune studies (including 
expression of checkpoint inhibitors, cytokine/chemokine patterns). All other samples will be 
saved for future studies including examination of tumor driven immune response and evaluation 
of methylation patterns underlying response.  Samples will be collected and sent from all 
participating institutions to the Pasquarello Laboratory (Hematologic Malignancies Tissue 
Banking Laboratory) at the Dana-Farber Cancer Institute, under the direction of Dr. Jerome Ritz.    
 
Address and phone number are provided:   
Dana-Farber Cancer Institute 
Pasquarello Tissue Bank-J604 
450 Brookline Ave. 
Boston, MA 02215 
Phone Number: 617-582-8214 
For more information, the Overall PI can be contacted (Jacqueline Garcia, MD) at 617-632-6349 
during business hours, and afterhours or weekends can be paged at 617-632-3352 (pager 
#44038). 
 
9.3 
Cancer Immune Monitoring and Analysis Centers ( CIMAC) Plan for Correlative 
Samples  
 
The following is a summary of assays and scientific objectives that will be performed on the 
samples collected from this study as approved by the CIMAC leadership. Assays will be 
performed subject to availability of samples: 
 
 
 
 

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Priority 
Biomarker 
Name 
Assay- CLIA: 
Y/N 
Use in protocol (integral, integrated, 
or exploratory?) Purpose 
Sample Types and 
Time points of 
sample collection 
M/
O 
Sample 
Usage 
Investigator/ 
Assay Lab  
1 
Multiplex 
IF panel4, 5 
mIF (N) with 
custom-built panel 
to identify 
leukemic myeloid 
blasts and immune 
marker CD8, CD4 
and PD-1.  
x Exploratory 
x To identify biomarkers of immune 
response if there is evidence of T Cell 
Activation 
x This is dependent on findings from 
CD4 and CD8 IHC studies.  
x If cannot create custom built then will 
use: FoxP3, PD-1, DAPI, either 
CD8/CD4/CD3 and either 
SOX10/PAX5/Cytokeratin 
 
x FFPE -Tumor 
x Pre Tx (baseline) 
x End of lead In 
x End of Cycle 2 
x End of Cycle 4 
M 
5 unstained 
FFPE slides 
at each 
timepoint 
DFCI CIMAC 
Scott Rodig, 
MD 
6 
 
 
T cell 
Receptor1,4 
TCR Sequencing  
CLIA: N 
x Integrated 
x To characterize clonality of T cell 
repertoire before/after therapy and to 
identify if T cell receptor diversity 
impacts clinical response. 
We hypothesize that high TCR 
diversity will associate with durable 
response. 
x PBMCs from 
EDTA Tubes  
x Pre Tx (baseline) 
x End of lead In 
x End of Cycle 2 
x 
M 
Minimum 1 
million 
PBMCs (1 
vial) 
DFCI 
CIMAC: 
Catherine Wu, 
MD 
7 
 
 
Somatic 
myeloid 
mutation 
analysis 
NGS  
 
CLIA:Y 
x Integrated 
x To evaluate for changes in mutational 
abundance and clonal presence and 
associate with response. 
We hypothesize that mutational 
clearance will associate with durable 
response. 
x BMMCs from 
EDTA Tubes 
x Pre Tx (baseline) 
x End of Cycle 4 
x End of Treatment / 
Progression 
M 
2cc marrow 
(1 vial) 
Non-CIMAC: 
BWH CAMD 
(Kim/M 
Baltay) 
 
8 
 
Immune 
profiling –
T cell 
immunogen
icity1 
ELISA  
CLIA: N 
x Exploratory 
x To evaluate for leukemia specific T 
cell response in responders versus 
non-responders.  
We hypothesize that decitabine will 
make blasts more visible to T cells. 
x PBMCs from 
EDTA Tubes  
x Pre Tx (baseline) 
x End of lead In 
x End of Cycle 1 
x End of Cycle 4 
M 
Minimum 3 
million 
PBMCs (1 
vial) 
Non-CIMAC: 
Catherine Wu, 
MD 
 
 
9 
Methylatio
n of 
immune 
infiltrates 
& leukemic 
blasts1,4 
 
RRBS  
CLIA: N  
x Exploratory 
x To evaluate for hypomethylation of 
immune gene sets in response to 
therapy. 
x Separate assessment of blasts and 
tumor immune infiltrates. 
We hypothesize that decitabine 
increases checkpoint inhibitor 
expression in blasts and immune gene 
set expression in tumor immune 
infiltrates. 
x BMMCs from 
EDTA Tubes 
x Pre Tx (baseline) 
x End of Lead In 
x End of Cycle 2 
M 
Minimum 1 
million 
BMMCs (1 
vial) 
Non-CIMAC: 
Catherine Wu, 
MD 

NCI Protocol #: 10026 
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92 
 
 
 
10 
 
Open 
chromatin 
at immune 
gene sets1,4 
ATAC-Seq  
CLIA: N  
x Exploratory 
x To evaluate for open chromatic at 
immune gene sets in response to 
therapy using tumor immune 
infiltrates 
We hypothesize that open chromatin 
at immune gene sets will inform 
responsiveness. 
x BMMCs from 
EDTA Tubes 
x Pre Tx (baseline) 
x End of Lead In 
x End of Cycle 2 
M 
Minimum 1 
million 
BMMCs (1 
vial) 
Non-CIMAC: 
Catherine Wu, 
MD 
 
11 
 
 
Sequencing 
of immune 
infiltrates 
& leukemic 
blasts1,4 
RNA-seq 
CLIA: N 
x Exploratory 
x To evaluate for biomarkers of 
responsiveness in tumor versus 
immune infiltrates as it relates to 
alloreactive tumor environment 
(transplant naïve vs post-transplant) 
x Separate assessment of blasts and 
tumor immune infiltrates  
We hypothesize that there will be 
genetic biomarkers of responsiveness 
that are unique to post-transplant 
environment. 
x BMMCs from 
EDTA Tubes 
x Pre Tx (baseline) 
x End of Lead In 
x End of Cycle 2 
M 
Minimum 1 
million 
BMMCs (1 
vial) 
DFCI CIMAC 
Catherine Wu, 
MD 
12 
Immune 
profiling1,4 
 
CyTOF 
CLIA: N 
 
x Exploratory 
x To quantify and determine the 
functional activation of immune and 
myeloid markers as it relates to 
response. 
x Using a custom myeloid/immune 
panel (developed by laboratory of 
DFCI Dr. Jerome Ritz lab). 
We hypothesize there will be a 
relative increased T cell presence and 
decreased T regulatory cells in 
responders compared to non-
responders. 
x PBMCs from 
EDTA Tubes  
x Pre Tx (baseline) 
x End of lead In 
x End of Cycle 4 
M 
3-5 million 
PBMCs (1 
vial) 
DFCI CIMAC 
Steve Hodi, 
MD 
13 
Sequencin1,
3 
WES  
CLIA: N  
 
 
x Exploratory 
x To identify for expression of novel 
antigens after combination 
decitabine/ipilimumab that correlates 
with response. 
We hypothesized that responders to 
treatment will express novel 
neoantigens as a consequence of 
combination decitabine and 
ipilimumab exposure. 
x Germline Skin and 
Tumor and BMMC 
x At any time 
collected for 
disease assessment, 
or for evaluation of 
toxicity (paired) 
O 
Minimum 1 
million 
BMMCs (1 
vial) 
DFCI CIMAC 
Catherine Wu, 
MD 
14 
Cytokine 
profile 
Olink  
CLIA: N 
 
x Exploratory 
x To evaluate cytokine profiles as a 
marker of T cell activation in 
responders versus non-responders.  
We hypothesize that there will be 
increased interferon gamma and 
chemokines that enable leukocyte 
trafficking in patients with increased T 
cell infiltrates. 
x Plasma from 
EDTA Tubes  
x Pre Tx (baseline) 
x End of Cycle 1 
x End of Cycle 2 
M 
1 vial 
(plasma) 
Mt Sinai 
CIMAC 

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15 
 
MDSC2 
and tumor 
specific 
immunity 
(cytolytic 
capacity) 
Flow  
CLIA: N 
 
x Exploratory 
x To evaluate presence of MDSCs as it 
relates to T cell response 
We hypothesize that decitabine will 
decrease MDSC presence resulting in 
increased T cells in presence of 
ipilimumab.    
x PBMCs from 
EDTA Tubes  
x Pre Tx (baseline) 
x End of lead In 
x End of Cycle 2 
M 
5-10 million 
PBMCs 
Avigan Lab – 
BIDMC  
 
1 Provided there will be specimen available  
2MDSC and leukemia specific immunity (cytolytic capacity) will be performed by the laboratory of Dr. David Avigan at Beth 
Israel Deaconess. PBMCs from AML patients will be isolated by Ficoll density-gradient centrifugation and stained with 
antibodies for CD11b, HLA-DR, CD14, CD15, and CD33 expression. The cells will then be analyzed with flow cytometry. If 
present, tumor cells will be gated out on the basis of forward scatter/side scatter and known blast phenotype, and total MDSCs 
(CD33+CD15− or CD33+CD15+) will be quantified as a percentage of total cells and as a percentage of gated immature 
CD11b+/HLA-DR− myeloid cells. MDSCs will be further characterized as granulocytic, by the presence of CD15+, or monocytic, 
by CD15− and side scatter  
3 Tumor and germline controls for WES will be patient-specific. PBMCs will be used as a tumor specimen if there is 
a leukemic burden in the blood. Otherwise, FFPE tumor tissue will be used if available. Germline DNA samples 
(used for WES) may be bone-marrow-derived mesenchymal stromal cells, or, if not available, tissue/PBMCs from 
archival pre-transplant remission timepoint. From the latter source of germline DNA, computational tools may be 
used to estimate the amount of tumor contamination of normal tissue (e.g. DeTiN from Taylor-Weiner A, et al. Nat 
Methods 2018) to improve mutation detection. 
4 Additional timepoints may be analyzed for blood-based assays if specimens are available and the CIMAC and trial 
PI agree. 
5 Leukemia based assays will be performed on leukemia cells in the peripheral blood, bone marrow aspirates, or in 
FFPE-preserved tissue biopsies ( bone marrow, lymph node, skin, etc) depending on the assay type and location of 
the leukemia burden in the participant 
6 Mandatory or Optional 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10026 
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9.3.1 Bone Marrow Aspirates 
 
From each bone marrow aspirate, ~10 x 107 mononuclear cells, divided into aliquots of 1 x 107 
cells, will be RBC lysed and then snap frozen as cell pellets.  Pellets will be stored in liquid 
nitrogen at -80C.  We anticipate that following will be isolated from the cell pellets: 
 
1. RNA, including mRNA, to be used for (in order of priority): 
a. RNA-sequencing of immune cells (CD3+), tumor (CD34+), and TCR-sequencing 
2. Genomic DNA to be used for (in order or priority): 
a. Through CIMAC-independent process: NGS to determine somatic mutations (will 
use Rapid Heme Panel at the Brigham & Women Hospital with the Center for 
Advanced Molecular Diagnostics (CAMD) that evaluates 95 genes (includes most 
common myeloid mutations) and hot spot codons for oncogenes and entire coding 
regions for tumor suppressors using an NGS platform) 
b. Through CIMAC-independent process: DNA methylation sequencing  
c. Through CIMAC-independent process: Cytolytic capacity of tumor immune cells 
in collaboration with the Avigan Laboratory at the Beth Isreal Deaconness 
Medicla Center   
d. Whole Exome DNA sequencing, for serial tracking of mutation load and 
development of new mutations which may be associated with resistance  
 
Remaining aspirate may be used for additional assays of potentially relevant biomarkers, 
depending upon reagent and/or tissue availability, and on responses seen in patients.   
 
9.3.2 Whole Blood - Peripheral blood mononuclear cells 
 
Peripheral blood mononuclear cells will be purified using the standard Ficoll gradient method 
and if not used immediately, cryopreserved in standard freezing media and stored in liquid 
nitrogen. 
 
1. Flow cytometry to examine markers related to myeloid differentiation and T cell subsets 
including isolating specific cell populations of interest (CD34+ blasts, T cells) 
2. Mass cytometry (CyTOF) analysis 
3. Through CIMAC-independent process: Cytolytic capacity of tumor immune cells and 
phenotyping of MDSCs in collaboration with the Avigan Laboratory at the Beth Isreal 
Deaconness Medicla Center   
 
Remaining peripheral blood may be used for additional assays of potentially relevant 
biomarkers, depending upon reagent and/or tissue availability, and on responses seen in patients.   
 

NCI Protocol #: 10026 
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9.3.3 FFPE tissue blocks 
In collaboration with the Brigham and Women Pathology Core Facility and DFCI CIMAC 
Tissue Biomarker laboratory of Dr. Scott Rodig, minimum IHC staining for CD34, CD3, CD8, 
granzymeB, CD4. A second panel of IHC staining will be recommended following initial IHC 
panel analysis, which may include but is not limited to pending findings: PD-1, PD-L1, CTLA-4 
or markers of CD4 subsets. Formalin Fixed Paraffin Embedded (FFPE) samples of bone marrow 
core (or extramedullary tumor where it applies) or unstained slides will also be obtained from the 
Brigham and Women’s pathology department that have been archived as part of standard tissue 
banking and tandem sample collection protocols. The FFPE samples collected for the purpose of 
the clinical trial and as part of parallel tissue banking are stored at the Brigham and Women’s 
Pathology department.  
 
9.3.4 Plasma 
Plasma will be stored at -80C.  Plasma samples will be used to measure cytokines serially using 
the multiplex protein assays and ELISAs on Luminex platforms and Olink platform. 
 
 
9.3.5 Skin biopsies 
 
Skin biopsies for (1) leukemia cutis and (2) germline DNA assessment will be requested from 
exceptional responders (from any part of the study) and from some non-responders (at dose-
expansion) to allow for paired analysis with tumor DNA after approval from overall PI. This is 
optional and individual cases that will be requested will be determined by the overall PI. 
 
9.4 
Pharmacodynamic Study 
 
Objective #1: Measuring absolute lymphocyte count as a potential biomarker for response 
to ipilimumab. We will compare measured levels at baseline (defined as prior to dosing on cycle 
1 day 1) and at pre-determined time points (end of cycles 1, 2, and 4) and we will also compare 
changes in ALC from baseline (defined as prior to dosing on cycle 1 day 1) to the pre-
determined time point (end of cycle 2) for survival differences given the evidence that ALC after 
two cycles may be a predictor of clinical response.  As decitabine may cause myelosuppression, 
ALC elevation may not be reliable. We will compare measured levels at baseline (defined as 
prior to dosing on cycle 1 day 1) and at pre-determined time points (end of cycles 1, 2, and 4) 
and we will also compare changes in ALC from baseline (defined as prior to dosing on cycle 1 
day 1) to the pre-determined time point (end of cycle 2) for survival differences given the 
evidence that ALC after two cycles may be a predictor of clinical response.   
-Time-points:  baseline, end of cycles 1, 2, and 4 
 
9.5 
Exploratory/Ancillary Correlative Studies 
 
Please see Rationale for correlative studies provided in section 2.  
 
Correlative study objective 
Objective 1: To determine clonal patterns of patients on treatment 
Whole exome sequencing will be performed on the baseline bone marrow aspirate samples and 

NCI Protocol #: 10026 
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bone marrow-derived fibroblasts for germline tissue to determine 1) the presence of known 
recurrent mutations in AML and 2) presence of novel mutations not previously associated with 
AML.  The response to therapy will be correlated with presence of known recurrent mutations, 
with particular attention paid to mutations associated with baseline treatment resistance or 
exceptional response. If no correlation is found between treatment response and known recurrent 
mutations, we will extend our analysis to include any novel mutations found in either patients 
with resistant disease or those with exceptional response.  We will also identify neoantigens to 
determine if neoantigen load correlates with clinical and/or immunologic response.  If we are 
unable to perform WES, we will use the Rapid Heme Panel as a way to capture common myeloid 
mutations and variant allele frequency.  This assay is routinely used as standard of care testing 
for newly diagnosed or relapsed patients with hematologic malignancies. Mutation variant allele 
frequency for both those mutations present at screening and those arising during treatment will 
be followed serially, given the known role of mutation frequency with treatment response in 
other contexts. This will be performed on baseline samples, after four cycles of combination 
therapy and at time of relapse if relevant.  
-Time-points for collection: baseline (screening), end of cycle 4, and time of relapse  
 
Objective 2: To determine histopathologic patterns of response 
We hypothesize that infiltrating T cells at the site of tumor microenvironment is critical to tumor 
control.  Samples to be tested include marrow and extramedullary site (if amenable to biopsy) 
including skin in leukemia cutis. Using immunohistochemistry, we will evaluate for activated T-
cells by CD8/granzyme B double IHC at baseline and post-treatment. We will also evaluate for 
CD4, PD-1, and PD-L1 expression.  We will collaborate with Dr. Scott Rodig and his core 
laboratory at the Brigham and Women’s Hospital to perform these evaluations. As biopsies will 
otherwise be required per protocol at additional time points, we will capture IHC responses at 
later time points if we see evidence for delayed biological activity. Archival tissue from patients 
on study may be utilized or requested as necessary. 
-Sample type: formalin-fixed, paraffin-embedded (FFPE) samples for analysis including core 
biopsies, skin biopsies and tumor biopsies (extramedullary)  
-Time-points for collection:  baseline (screening), on treatment (proposed: end of cycle 2 and 
end of cycle 4), time of relapse if relevant 
-Correlative to be performed in: Laboratory of Dr. Scott Rodig ( Brigham and Women’s 
Hospital, Attn: Rodig Lab, Thorn Building #603B, 20 Shattuck Street, Boston, MA 02115).    
-Total anticipated # samples: ~ up to 4 per patient  
 
Objective 3: To evaluate the phenotype of immunologic consequences of combination 
treatment     
CTLA-4 expression is induced upon T cell activation. We hypothesize that epigenetic therapy 
may modulate T cell activation and that the addition of immunotherapy will give rise to an 
increased number of CD4 and CD8 T cells infiltrating the tumor sites. Further, there is limited 
data available on the immune response to epigenetic therapy. Exploratory studies from the recent 
ipilimumab study in the post allo-HCT setting showed that CD4 Tregs were decreased and CD4 
Tcons (effector cells) were increased in responders 8 weeks after ipilimumab. Further 
characterization of both dcreased Treg and increased Tcon at 8 weeks showed that they were 
compromised predominantly by the most mature subsets (effective memory).  Naive and central 
memory (CM) subsets of Treg and Tcon were decreased in responders at 8 weeks. Further 

NCI Protocol #: 10026 
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97 
 
studies are thus needed to understand these changes in T cell subsets and to correlate these 
changes with response. 
(A) Flow cytometry: Proliferation, cytokine, and immune checkpoint inhibitor 
induction by T-cells will be serially examined.  Fluorochrome conjugated antibodies 
will be added to each reaction tube followed by the addition of 100ul of whole blood. 
After incubation, BD FACSLyse will be added to each reaction tube, and the sample 
will be vortexed and incubated. Antibody-labeled cells will then be fixed using 
formaldehyde and analyzed using a BD FACSCanto II plus with BD FACSDiva 
software.  If by conventional flow cytometry we see evidence of T cell activation, we 
will then move those samples forward for further interrogation using CyTOF to 
explore subpopulations. 
(B) CyTOF: IWe hypothesize that epigenetic therapy and checkpoint inhibition may 
result in at least partial restoration of normal hematopoietic developmental programs 
and subsequent reversal of the aberrant immunophenotype.  AML cells also have 
altered intracellular signaling which can be measured by mass cytometry. The DFCI 
CIMAC Immune Assessment Lab offers CyTOF; a single-cell proteomic technology that 
allows for the analysis of 40+ cellular parameters using antibodies tagged with heavy 
metal isotopes to elucidate complex phenotypic and functional characteristics of 
heterogeneous immune populations.  We will use a custom designed panel of surface 
membrane and intracellular markers to assess the number and activation status of 
Treg, TEM, TCM, Tnaive, and NK cells, including but not limited to CTLA-4, ICOS, 
PDL-1, TIM-3. The CyTOF panel that is available is included below: 
 
 
CyTOF Panel – Focus on Treg and cytokine signaling pathways 
 
  TARGET 
SPECIES 
CLONE 
ISOTOPE 
Manufacturer 
  Surface  
  
  
  
 
1 CD45 
Human 
HI30 
154Sm 
Fluidigm 
2 HLA-DR 
Cross 
L243 
141Pr 
Biolegend 
3 CD95 
Human 
DX2 
164Dy 
Fluidigm 
4 CD3 
Human 
UCHT1 
170Er 
Fluidigm 
5 CD4 
Human 
SK3 
174Yb 
Fluidigm 
6 CD8 
Human 
SK1 
168Er 
Fluidigm 
7 CD25 
Human 
2A3 
149Sm 
Fluidigm 
8 CD127 
Human 
A019D5 
176Yb 
Fluidigm 
9 CD45RA 
Human 
HI100 
169Tm 
Fluidigm 
10 CD122 (IL2Rβ) 
Human 
Tu27 
143Nd 
BioLegend 
11 CD132 (IL2Rγ) 
Human 
TUGΧ4 
166Er 
BioLegend 
12 CCR7 
Human 
G043H7 
173Tb 
BioLegend 
13 CD62L 
Human 
DREG-56 
153Eu 
Fluidigm 
14 CD31 
Human 
WM59 
145Nd 
Fluidigm 
15 CD279(PD1) 
Human 
EH12.2H7 
175Lu 
Fluidigm 
16 CD19 
Human 
HIB19 
142Nd 
Fluidigm 
17 IgD 
Human 
IA6-2 
146Nd 
Fluidigm 
18 CD38 
Human 
HIT2 
144Nd 
Fluidigm 

NCI Protocol #: 10026 
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98 
 
19 CD27 
Human 
L128 
155Gd  
Fluidigm 
20 BAFF-R(CD268) 
Human 
11C1 
160Gd 
Biolegend 
21 CD56 
Human 
HCD56 
162Dy 
Biolegend 
22 CD16 
Human 
3G8 
148Nd 
Fluidigm 
23 NKG2D（CD314） 
Human 
1D11 
161Dy 
Fluidigm 
24 ICOS (CD278) 
Human 
DX29 
147sm 
BD 
  Intracellular  
  
  
  
25 Foxp3 
Human 
PCH101 
165Ho 
eBioscience 
26 BCL-2 
Human 
Bcl-2/100 
171Yb 
BD Bioscience 
27 Ki67 
Cross 
B56 
151Eu 
BD Bioscience 
28 BIM 
Cross 
Polyclonal  
159Tb  
BD Bioscience 
29 Helios 
Cross 
22F6 
156Gd 
Biolegend 
30 CD152(CTLA4) 
Human 
14D3 
163Dy 
eBioscience 
  Signaling  
  
  
  
 
31 pStat5 [Y694] 
Cross 
47 
150Nd 
Fluidigm 
32 pStat3 [Y705] 
Cross 
4/P-Stat3 
158Gd 
Fluidigm 
33 pERK 1/2 [T202/Y204] 
Cross 
D13.14.4E 
167Er 
Fluidigm 
34 pS6 Ribo(S235/236) 
Cross 
N7-548 
172Yb 
Fluidigm 
35 p-AKT 
Cross 
S473 
152Sm 
Fluidigm 
 
(C) Chemokine and cytokine profiling:  Levels of cytokines involved in 
inflammation, tolerance and Th1, Th2 and Th17 responses will be measured in 
plasma samples using Luminex and Olink platforms.  From whole blood, we will 
perform serial immunophenotypic analysis of immune cells using ELISA to assess 
chemokine/cytokine profiles (CXCL2, CXCL5, MICA, and others) to assess whether 
we observe similar results in patients treated with combination ipilimumab/ 
decitabine. The Proseek Olink Proteomics platform operating on a Fluidigm Biomark 
HD microfluidic PCR system is a quantitative and reproducible assay to measure 
levels cytokines, chemokines, growth factors, in addition to detection of circulating 
immune co-stimulatory and inhibitory molecules, and other relevant immune-
oncology markers, in a 92-plex format known as the Olink Immuno-Onology panel, 
which only requires 1 micro-liter of sample.  
-Sample type: whole blood or aspirate (flow cytometry and CYTOF), plasma 
(Luminex) 
-Time-points for collection:  baseline (screening), end of the lead in, end of cycle 1, 
end of cycle 2 and end of cycle 4 
-Correlative to be performed in:  
x Flow cytometry and CyTOF: Laboratory of Dr. Jerome Ritz (Dana-Farber Cancer 
Institute Pasquarello Tissue Bank-J604, 450 Brookline Ave., Boston, MA 02215)  
x Chemokine and cytokine multiplex assays: Center for Immuno-Oncology (Dana-
Farber Cancer Institute, D2-131, 450 Brookline Avenue, Boston, MA 02215) 
x Olink Immuno-Onology panel:  Mount Sinai CIMAC, Icahn School of Medicine 
at Mount Sinai;Hess Center for Science and Medicine, 5th floor, rooms 310/313 
Human Immune Monitoring Center (HIMC), 1470 Madison Avenue, New York, 
NY 10029 
 

NCI Protocol #: 10026 
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99 
 
-Total anticipated # samples: ~ up to 4-5 per patient  
 
Objective 4: To characterize the genotypic immunologic consequences of combination 
treatment   
Epigenetic priming and checkpoint blockade have been shown to have a variety of immunologic 
effects as described above. We hypothesize that any observed therapeutic effect may be partially 
due to immunomodulatory effects on lymphocytes in addition to effects on the AML cells.  We 
will evaluate these changes by evaluation of the leukemic transcriptome to infer changes to 
immune response.  We will utilize whole exome sequencing or bulk versus single cell 
transcriptomics to elucidate the heterogeneity of immune and cancer cell populations before and 
after therapy to understand how leukemic and immune populations co-evolve during response or 
resistance. We will evaluate the gene expression pattern of immune infiltrates to understand 
differences in the tumor microenvironment in situ.  We will evaluate samples collected at 
baseline (prior to dosing on study) and on treatment (at the end of cycles 2). 
-Sample type: aspirate   
-Time-points for collection:  baseline (screening), end of cycle 1 and end of cycle 2 (will collect 
and hold samples from cycle 4 for analysis depending on findings) 
-Correlative to be performed in: The DFCI CIMAC translational immuno-genomics laboratory 
of Dr. Catherine Wu (Dana-Farber Cancer Institute, Dana 540B, 450 Brookline Avenue, 
Boston, MA 02215) will prepare the respective DNA/RNA, and sequencing will be 
performed at the following external lab: 
 
Broad Institute Genomics Services 
320 Charles Street 
Cambridge, MA 02141 
 
Sequencing data will then be provided back to the Wu Lab and in the form of BAM files. The 
samples that are sent for analysis are exhausted during the process, and thus not able to be returned.  
 
-Total anticipated # samples: ~ up to 4 per patient  
 
Objective 5:  To quantitate regulatory T cell subsets and to evaluate for tumor reactive 
lymphocytes activity and for tetramer binding. 
 In collaboration with Drs. David Avigan and Jacalyn Rosenblatt, we will perform flow 
cytometry-based analysis of peripheral-blood mononuclear cells to evaluate for (1) T cell subsets 
and expression of inhibitory immune receptors on different immune cells, (2) quantification of 
circulating CD4/CD8 populations, and (3) levels of circulating regulatory T cells and tumor 
reactive lymphocytes (collaboration with Dr. Ritz and Drs. Avigan/Rosenblatt). Peripheral blood 
samples will be analyzed by FACS-gating to determine the percentage of activated effector cells 
(using CD4/CD25+ fraction and CD69 expression) and regulatory T cells (measuring expression 
of Foxp3, GITR, CTLA-4, CD127, and CD62L on the CD4/CD25+ population). We will then 
stain for CD45RA to evaluate for the naive memory cell prevalence and CD45RO, CCR7 and 
CD28 for memory cell response. We will evaluate if ex vivo immunologic response correlates 
with levels of memory effector and regulatory T cells. We will evaluate the immunomodulatory 
effect of decitabine alone and in conjunction with checkpoint blockade in AML by evaluating for 
(1) transcriptional induction of and (2) binding to leukemia-associated antigens as suggestion of 

NCI Protocol #: 10026 
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enhanced presentation of leukemia antigens to T cells. We will evaluate if decitabine enhances 
antigen presentation. There is preclinical evidence that HMA therapy enhances MHC class I and 
co-stimulatory molecule expression which may increase recognition of leukemia-associated 
antigens (LAA). We will use real-time quantitative polymerase chain reaction to measure 
leukemia-associated antigens such as WT1, MUC1, and PR3, which may be targets for AML 
immunotherapy. In collaboration with Drs. Avigan/Rosenblatt, we will evaluate the percentage 
of CD8+ T cells binding tetramers constructed from these antigens and for functional activity in 
the tetramer-positive population by measuring corresponding levels of IFN-gamma, granzyme, 
IL-4, and IL-10 expression by FACS staining.  
-Sample type: aspirate and peripheral blood  
-Time-points for collection: baseline (screening), end of the lead in, and end of cycle 2.  
-Correlative to be performed in: 
 Dr. David Avigan’s laboratory at Beth Israel Deaconess Medical Center 
Address: 3 Blackfan Circle CLS 724 Boston, MA 02215 
-Total anticipated # samples: up to 3 per patient  
  
Similar tests will also be run on tissue samples for any patient requiring a lymph node or bone 
marrow biopsy for clinical reasons. No extra procedures will be done for the purpose of this 
study, but if these tests are being done for standard of care evaluations, an extra sample may be 
taken to use for the above research evaluations. Extra pull of aspirate (~5cc) at any non-
scheduled bone marrow evaluation will be accepted for future studies. 
 
Objective 6: To evaluate the genomic and epigenomic state of tumor immune infiltrates 
and leukemic blasts before and after decitabine priming and after ipilimumab 
treatment.  
From paired samples, we will perform reduced representation bisulfite sequencing to evaluate 
DNA methylation changes and ATAC-sequencing to evaluate for chromatin accessibility. 
These assays will be performed in Dr. Catherine Wu’s laboratory.  
-Sample Type: aspirate 
-Time Points for collection: baseline (screening), end of decitabine monotherapy lead in month, 
end of cycles 1 or 2. 
-Correlative to be performed in: Dr. Wu’s laboratory at Dana-Farber Cancer Institute will 
prepare the DNA library, and sequencing will be performed at the following external lab: 
 
Broad Institute Genomics Services 
320 Charles Street 
Cambridge, MA 02141 
 
Sequencing data will then be provided back to the Wu Lab in the form of BAM files. The samples 
that are sent for analysis are exhausted during the process, and thus not able to be returned.  
 
 
 
 
 
-Total anticipated # samples: up to 4 per patient  
 
10. STUDY CALENDAR 
 

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10.1 
 Study Schedule  
 
Baseline evaluations and screening labs/procedures performed are to be conducted within 2 
weeks prior to start of protocol therapy except for serum pregnancy in women of childbearing 
potential which must be repeated if resulted > 72 hours prior to treatment start. Baseline 
evaluation can be used as screening for eligibility if performed within 1 week of starting protocol 
therapy.  If treatment start occurs within 48 hours of registration, then baseline evaluation does 
NOT need to be repeated to confirm eligibility.  Scans, EKG and echocardiogram (or MUGA 
scan) are allowed within 4 weeks of treatment start (day 1 of the lead in period).  In the event 
that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy. Please see screening table below for specific 
windows for diagnostic tests including bone marrow and PET.  
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10026 
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Screening, Priming and Induction Period 
 
Pre-
Study 
Lead In 
D1 
Lead In 
D15b 
Lead In 
D24a 
C1 D1b 
C1 D15 b 
C1 
D24a 
C2 D1b C2 D24a 
C3 D1b 
C4 D1b 
C4 
D24a 
IpilimumabA 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
DecitabineB 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Physical Exam 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Vital signs 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Performance status 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryc 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Immune-related 
labsd  
X 
 
 
 
X 
 
 
 
 
 
X 
 
Adverse event 
evaluatione,q,r 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
GVHD Assessment 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
PETf 
Xf 
 
 
 
 
 
 
 
Xf 
 
 
Xg 
B-HCGh 
Xh 
 
 
 
 
 
 
 
 
 
 
 
Bone marrowi 
X 
 
 
Xj 
 
 
Xi 
 
Xi 
 
 
Xi 
Skin biopsyk  
Xk 
 
 
 
 
 
Xk 
 
Xk 
 
 
Xk 
T cell chimerisml 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
Hepatitis Panelm 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV testingn 
X 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogramo,q,s 
X 
 
 
 
 
 
 
 
 
 
 
 
EKGo,q 
X 
 
 
 
 
 
 
 
 
 
 
 
Correlative studiesp 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
A:  Ipilimumab:  Dose as assigned by dose level. Administered every 4 weeks. Dosed per weight on day 1 of a cycle. 
B:  Decitabine:  20 mg/m2 daily IV for 5 consecutive days on days 1-5. Dosed per weight on day 1 of the lead in period 
a:   Can be done any time between day 24-28  
b:  +/- 3 days. If there is evidence of persistent disease or blood counts meet criteria to treat, final bone marrow results are not required prior to dosing on day 1 of next 
cycle.  
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
uric acid, magnesium, phosphorus. 
d:   Every 3 months unless clinically indicated: gamma-GT, direct bilirubin, LDH, TSH, and lipase 
e:  Please see Appendix F for helpful study check list including immune related AE evaluation 
f:  PET scans are required only for those with sole extramedullary disease (no marrow involvement by morphology) and optional for those with extramedullary and 
marrow involved AML. PET scans are standard imaging tests for those with extramedullary disease involvement. Study can be performed any time between day 
24-28 at the end of cycles 2 and 4 (suggested time frame). However as clinical scenario may vary with patients with sole extramedullary disease, we will allow 
imaging window of +/- 4 weeks based on clinical scenario or scheduling logistics. Please send report and imaging (on CD) with redacted PHI for central review of 
extramedullary AML events to Attn: Alexandra Savell, Research Project Manager for CTEP 10026; Dana-Farber Cancer Institute; 450 Brookline Avenue; LG-GC; 
Boston, MA 02215. If there are reports only, please fax to 617-632-5152 or email to: alexandrae_savell@dfci.harvard.edu   
g:  If patient has sole extramedullary disease and there was no resolution of FDG-avid disease by the end of cycle 2, then patients should have a repeat PET at the end of 
cycle 4 per standard of care- Study can be performed any time between day 24-28 at the end of cycles 2 and 4 (suggested time frame). However as clinical scenario 
may vary with patients with sole extramedullary disease, we will allow imaging window of +/- 4 weeks based on clinical scenario or scheduling logistics. Please 
send report and imaging (on CD) with redacted PHI for central review of extramedullary AML events to Attn: Alexandra Savell, Research Project Manager for 

NCI Protocol #: 10026 
6/30/2020 
103 
 
CTEP 10026; Dana-Farber Cancer Institute; 450 Brookline Avenue; LG-GC; Boston, MA 02215. If there are reports only, please fax to 617-632-5152 or email to: 
alexandrae_savell@dfci.harvard.edu  
h:  Serum pregnancy test (women of childbearing potential).- Negative results required within 72 hours of treatment start  
i:  For bone marrow biopsies, the minimum requested includes (1) aspirate (if aspirable), (2) core, (3) flow cytometry (if sufficient blasts; may not be possible in setting 
of low blasts or remission; if MRD flow cytometry is an option we will accept this data in lieu of standard flow cytometry if this test is available at the time of 
suspected remission), (4) cytogenetics if possible, (5) molecular testing per institutional guidelines (suggested at minimum at time of screening and relapse but not 
required; correlatives will include genotyping leukemic blasts). Core biopsy is mandatory at screening, at the end of cycles 2 and 4- See sample collection table in 
section 10.2 for details. If a diagnostic bone marrow biopsy was performed within 4 weeks of treatment start and no anti-leukemic therapy has been given (except 
for hydrea and radiation), then flow cytometry and cytogenetics do not need to be repeated. If a diagnostic bone marrow was performed within 2 weeks of 
treatment start, then only a research aspirate and research core are required to be collected during screening. In cases of persistent leukemic blood, bone marrow 
biopsy can be performed on day 1 of subsequent cycle prior to treatment. 
j:  Aspirate ONLY for correlative study (unless inaspirable). See Correlative studies.     
k: For those with leukemia cutis only - repeat evaluation at end of cycles 1, 2 and/or 4 (pending response)-  If there is suspected resolution or response based on skin 
exam, biopsy may occur sooner as clinically indicated. After confirmation of resolution of lesion, there does not need to be a repeat biopsy at the same site. If there is 
concern for persistence of disease based on skin examination, then repeat biopsy is recommended at the end of cycles 1, 2 and/or 4 if it can be safely performed.   
l: Routine response evaluation for patients in Arm A who are status post allo-HCT only. Peripheral blood source only. Can be performed locally and if not available 
locally then should be analyzed at site where patient’s transplant was performed. 
m:  For those with known HBV they should get an HBV viral load (PCR). For those with known HCV they should get an HCV viral load (PCR). It is recommended that 
patients with known HBV get monthly (+/- 14 days) HBV viral load assessments after ipilimumab is initiated. Please update overall PI if there is significant or clinical 
concern for HBV re-activation despite anti-viral therapy.  
n:  For those with known HIV they must get a CD4 count and an HIV viral load (PCR). 
o:  Baseline echocardiogram and EKG required for screening (if done within 4 weeks of treatment start does not need to repeat unless there is a clinical concern) and at 
any other time that is clinically indicated during the trial as it relates to footnote q 
p:  Peripheral blood, aspirate, core biopsy, or FFPE to be collected per schedule described correlatives table below.  
q:  Alert PI if there is concern for cardiac toxicity (minimum assessment: cardiology consult, EKG, echocardiogram, and labs CPK and troponin; refer to section 6.4.7) 
r:  Please see section 7.3.5 of the protocol for reporting requirements for GVHD and suspected immune related AEs to enable central review 
s: MUGA scan is a suitable alternative to an echocardiogram  
t: For participants enrolled on Arm A ( post transplant), a formal GVHD assessment is required at minimum on Day 1 of each cycle utilizing the GVHD assessment 
worksheet provided in Appendix B 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #: 10026 
6/30/2020 
104 
 
 
Maintenance cycles and end of study 
 
C5 D1b C6 D1b 
C7 D1b 
C7 D24a 
C8 D1b 
C9 D1b 
C10 D1b 
C10 D24a C11 D1b C12 D1b 
End of 
studyi,j 
IpilimumabA 
X 
 
X 
 
 
X 
 
 
X 
 
 
DecitabineB 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Concurrent meds 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Physical Exam 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Xk 
Vital signs 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Performance status 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryc 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Immune-related labsd  
 
 
X 
 
 
 
X 
 
 
 
X 
Adverse event 
evaluatione,l,m 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Xk 
GVHD Assessment 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Bone marrowf 
 
 
 
Xf 
 
 
 
X 
 
 
Xf 
T cell chimerismg 
 
 
 
 
 
 
 
 
 
 
X 
Correlative studiesh 
 
 
 
X 
 
 
 
X 
 
 
X 
A:  Ipilimumab:  Dose as assigned by dose level. Administered every 8 weeks. Dosed per weight on day 1 of a cycle. 
B:  Decitabine:  20 mg/m2 daily IV for 5 consecutive days on days 1-5. Dosed per weight on day 1 of the lead in 
a:   Can be done any time between day 24-28  
b:  +/- 3 days 
c: Albumin, alkaline phosphatase, total bilirubin,  bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, 
uric acid, magnesium, phosphorus. 
d:   At baseline, C1D1, and then every 3 cycles thereafter or more frequently when clinically indicated: gamma-GT, direct bilirubin, LDH, TSH, and lipase 
e:  Please see Appendix F for helpful study check list including immune related AE evaluation 
f:  For bone marrow biopsies, the minimum requested includes (1) aspirate (if aspirable), (2) core, (3) flow cytometry (if sufficient blasts; may not be possible in setting of 
low blasts or remission; if MRD flow cytometry is an option we will accept this data in lieu of standard flow cytometry if this test is available at the time of 
suspected remission), (4) cytogenetics if possible, (5) molecular testing per institutional guidelines (suggested at minimum at time of screening and relapse; but not 
required correlatives will include genotyping leukemic blasts).  If concern for relapse after a response is achieved, patient should get marrow per routine clinical 
standards.  At the end of treatment (either completion of therapy or at time of suspected relapse), encourage marrow sampling unless clinical condition precludes 
this. In cases of persistent leukemic blood, bone marrow biopsy can be performed on day 1 of subsequent cycle prior to treatment. 
g: Routine response evaluation for patients in Arm A who are status post allo-HCT only. Peripheral blood source. Can be performed locally and if not available locally 
then should be analyzed at site where patient’s transplant was performed. 
h:  Peripheral blood, aspirate, core biopsy, or FFPE to be collected per schedule described correlatives table below.  
i:  End of study includes patients who: complete 12 combination cycles, come off study for toxicity, or have disease progression.   
j: Quarterly phone call for survival follow-up for up to 1 year after treatment is complete. All efforts to contact the patient should be made.  
k: As there can be a delay in the presentation of an immune-related adverse event, patients will be asked to come back for a clinical exam 3 months (+/-1 month) after 
their last treatment on study. 
l: Alert PI if there is concern for cardiac toxicity (minimum assessment: cardiology consult, EKG, echocardiogram, and labs  CPK and troponin; refer to section 6.4.7) 
m: Please see section 7.3.5 of the protocol for reporting requirements for GVHD and suspected immune related AEs to enable central review 
n: For participants enrolled on Arm A ( post transplant), a formal GVHD assessment is required at minimum on Day 1 of each cycle utilizing the GVHD assessment 
worksheet provided in Appendix B 
 
 
 
 
 
 
 
 

NCI Protocol #: 10026 
6/30/2020 
105 
 
 
 
 
10.2 
Correlative Sample Schedule  
 
All sites will send samples to Dana-Farber Cancer Institute at the following address:  
 
Dana-Farber Cancer Institute 
Smith Receiving  
Pasquarello Tissue Bank- CMCF 
1 Jimmy Fund Way- DA-L181A 
Boston, MA 02115 
 
Time Point1 
Sample Type To 
Collect1 
Sample Tube/Container2, 
Amount Requested (Proposed 
Processing Site3) 
Shipping 
Method4,5 
Shipping 
Address 
Screening or pre-
treatment 
 
(T0) 
Marrow Aspirate 
1 x 10 mL green top (P) 
1 x 5 mL green top (A)  
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
 
Marrow Aspirate 
 
2 mL lavender top (C) 
Peripheral blood10 
4 x 10 mL lavender top (P)  
1x 10mL green top (A) 
Extramedullary FFPE 
Tissue Block5 
No specific size; standard paraffin 
blocks or unstained glass slides 
(R) 
FedEx Priority 
overnight or 
same day RT 
(Mandatory) Bone 
Marrow Core9 
No specific size; 10% buffered 
formalin 
End8 of Lead-In 
 
(T1) 
Marrow Aspirate7 
1 x 10 mL green top (P) 
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
Peripheral blood 
3 x 10 mL lavender top (P) 
1x 10 mL green top (A) 
End8 of Cycle 112  
 
(T2) 
Marrow Aspirate 
 
1 x 10 mL green top (P) 
 
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
 
Marrow Core 
 
5-8 Unstained Slides 
 
Peripheral Blood 
 
4 x 10 mL lavender top (P)  
Extramedullary FFPE 
Tissue Block5 
No specific size; standard paraffin 
blocks or unstained glass slides 
(R) 
FedEx Priority 
overnight or 
same day RT 
End8 of Cycle 212  
 
(T3) 
Marrow Aspirate 
1 x 10 mL green top (P) 
1 x 5 mL green top (A) 
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
Peripheral Blood10 
4 x 10 mL lavender top (P)  
1x 10 mL green top (A) 
 
Extramedullary FFPE 
Tissue Block5 
No specific size; standard paraffin 
blocks or unstained glass slides 
(R) 
FedEx Priority 
overnight or 
same day RT 
(Mandatory) Bone 
Marrow Core9 
No specific size; 10% buffered 
formalin (R) 
End8 of Cycle 412  
 
Marrow Aspirate 
 
1 x 10 mL green top (P) 
FedEx Priority 
overnight with 
Dana-Farber 
Cancer Institute 

NCI Protocol #: 10026 
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106 
 
(T4) 
Marrow Aspirate6 
 
2 mL lavender top (C) 
cool pack4 
 
Peripheral Blood 
3 x10 mL lavender top (P) 
  
Extramedullary FFPE 
Tissue Block5 
No specific size; standard paraffin 
blocks or unstained glass slides 
(R) 
FedEx Priority 
overnight or 
same day RT 
(Mandatory) Bone 
Marrow Core9 
No specific size; 10% buffered 
formalin 
 
End8 of Cycle 7   
 
(T5) 
 
Marrow Aspirate 
 
1 x 5 mL green top (P) 
 
FedEx Priority 
overnight with 
cool pack4 
 
Dana-Farber 
Cancer Institute 
 
Peripheral Blood 
2 x 10 mL lavender top (P)  
End8 of Cycle 10 
 
(T6) 
Marrow Aspirate 
1 x 5 mL green top (P) 
 
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
Peripheral Blood 
2 x 10 mL lavender top (P) 
 
End of Treatment 
or Suspected 
Relapse 
 
(T7)12 
Marrow Aspirate 
1 x 5 mL green top (P) 
 
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
Marrow Aspirate6 
2 mL lavender top (C)  
 
Peripheral Blood 
2 x 10 mL lavender top (P) 
 
Extramedullary FFPE 
Tissue Block5 
No specific size; standard paraffin 
blocks or unstained glass slides 
(R) 
FedEx Priority 
overnight or 
same day RT 
 
 
(Optional) Bone 
Marrow Core9 
No specific size; 10% buffered 
formalin 
Clinically indicated 
(unscheduled) 
 
(Tx) 
Marrow Aspirate 
1 x 5 mL green top (P) 
 
FedEx Priority 
overnight with 
cool pack4 
Dana-Farber 
Cancer Institute 
 
Peripheral Blood 
2 x 10 mL lavender top (P) 
 
One-time for 
germline DNA 
assessment11 
(Optiona)  
 
 
Skin biopsy  
 
 
Punch 4 mm in sterile container 
with saline.  
 
Fed Ex Priority 
overnight 
Frozen  
 
Dana-Farber 
Cancer Institute 
 
Suspected Ipi-
induced Toxicity 
(Optional)13 
 
 
Skin biopsy  
 
Punch 4 mm in sterile container 
with saline.   
 
Fed Ex Priority 
overnight 
Frozen  
 
Dana-Farber 
Cancer Institute 
 
1All efforts should be made to collect correlative samples unless there are unforeseen clinical circumstances, or patient refusal. 
2Containers/Tubes: Green top= sodium heparin tube; Lavender top = EDTA tube. Any tube size combination is acceptable to 
collect the approximate requested volume of blood or aspirate, however please use what is included in kits if possible to reduce 
missed samples. 
3Proposed Processing +/- Storage Sites for samples: (P) Pasquarello Heme Tissue Bank Lab (Dana-Farber Cancer Institute, 
Pasquarello Tissue Bank - J614, Smith Receiving, 1 Jimmy Fund Way, Boston, MA 02215); (R) Rodig Laboratory, Attn: Evisa 
Gjini/Sara Abdelrahman, Thorn Building, Room 603B, Brigham & Women’s Hospital, 20 Shattuck Street, Boston, MA 02115; 
(A) Avigan Laboratory (Beth Israel Deaconess Medical Center), 3 Blackfan Circle CLS 724 Boston, MA 02215; (C) Center 
for Advanced Molecular Diagnostics, 75 Francis Street, Boston, MA 02115  
4Shipping: Aspirate and peripheral blood should be shipped with a cool pack if coming overnight (FedEx) and received Monday-
Thursday ONLY for processing. Samples coming from participants at the corresponding organization (site: Dana-Farber Cancer 
Institute) must be submitted before 4 pm Monday-Friday.     
5FFPE Tissue Block (including extramedullary disease biopsies including but not limited to leukemia cutis): At the screening 
time point, FFPE of extramedullary sites are required for patients enrolling with extramedullary AML only and optional for those 
enrolling with extramedullary plus marrow involved AML. FFPE samples at screening may be archival (if performed within 12 
weeks, then biopsy does not need to be repeated unless a patient received anti-leukemic treatment (such as chemotherapy or 
radiation) after the biopsy with the exception of hydrea).  These extramedullary FFPE tissue block samples can be shipped 
Monday-Friday at room temperature. These samples do NOT need to be sent with the kit (peripheral blood and aspirate) unless 
immediately ready; may be sent separately.  
6Rapid Heme Panel Sample: This 1cc aspirate sample will only be collected for all patients in both Arm A and Arm B to 
perform research-based molecular testing with a Rapid Heme Panel (RHP) (performed in Center for Advanced Molecular 

NCI Protocol #: 10026 
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107 
 
Diagnostics at the Brigham & Women’s Hospital, Boston, MA).  If a patient has a dry aspirate, then RHP may be drawn from 
peripheral blood if there are circulating blasts in setting of AML (circulating blasts are not required for a peripheral blood draw in 
setting of MDS). However, prefer sample to come from aspirate to allow for proper intra-patient and inter-patient comparison. In 
the event the “end of treatment” time point falls within the first 3 months on study treatment (+/- 2 weeks), this sample is optional 
7End of lead-in marrow aspirate sample: This is a research aspirate only; no formal submission for pathology review is 
required.   
8End of cycle samples: can be collected any time between Days 24-28. 
9Bone Marrow Core: At the screening time point, submission of bone marrow biopsy core will be mandatory (to be fixed in 
10% buffered formalin prior to sending using materials provided in kit) (this extra core should be collected at time of screening 
marrow for the purpose of IHC correlative studies). Mandatory submission of bone marrow biopsy core or 6-8 unstained slides 
will be collected at the end of cycles1, 2 and 4. For the end of treatment/suspected relapse timepoint, a core is requested, but not 
mandatory. At the EOT/suspected relapse timepoint, 6-8 unstained slides may be sent in leiu of a fresh core sample. Cores 
arriving in formalin will be transferred to 70% ethanol and decalcified in the Brigham & Women’s Hospital Pathology Core 
laboratory in preparation for staining with IHC in the Rodig Laboratory. These bone marrow core samples should be shipped 
Monday-Thursday at room temperature.  Archival tissue (FFPE) from participants who are consented on the clinical trial 
including bone marrow biopsies (tissue blocks or slides) performed at other time points where a bone marrow is clinically 
indicated (while on study) may be requested at a later time for IHC analysis in the Rodig laboratory 
10  PB sample for PD studies: It is preferred that the PB is drawn at one visit. However, depending on scenario, the peripheral 
blood PD sample can be collected over two visits if clinically necessary (e.g. for the “screening/pre-treatment” collection, PB can 
be collected at screening up until day 1 of lead-in cycle as long as it’s prior to decitabine dosing; for the “end of cycle 2” 
collection, PB can be collected on days 24-28 of cycle 2 up until day 1 of cycle 3 as long as it’s prior to decitabine and 
ipilimumab dosing). If this is the case, please update the study team to anticipate and plan on two sample deliveries.  
11Germline assessment: Skin biopsies will be performed on patients who are identified to be exceptional responders (at any 
point of the trial) and some non-responders (in dose expansion cohort) after discussion with the overall PI. Samples are to be sent 
in normal saline in appropriate leakproof container to BWH CAMD by way of Dana-Farber. If sent from outside of DFCI, the 
sample should be sent frozen (both saline and tissue) and shipped to the Pasquarello Tissue Bank at Dana-Farber Cancer Institute. 
DNA will be extracted in batches in Brigham and Women’s Hospital CAMD. This is optional. 
12FFPE bone marrow core slide or tissue block may be requested if sample available for IHC comparison at this time point.   
13  Optional, if  sample is being taken for clinical reasons, and it is safe to do so, we are requesting a small sample be sent to 
Dana-Farber Cancer Institute for analysis.  
   
11. MEASUREMENT OF EFFECT 
 
Although the clinical benefit of combination ipilimumab and decitabine has not yet been 
established, the intent of offering this treatment is to provide a possible therapeutic benefit, and 
thus the patient will be carefully monitored for tumor response and symptom relief in addition to 
safety and tolerability.  Patients with MDS/AML will be assessed by standard criteria.  For the 
purposes of this study, patients should be re-evaluated at the end of cycles 1, 2 and 4, and then 
every 3 cycles on treatment, and then at time of suspected relapse if relevant.  The aspirate 
sample collected at the end of cycle 1 is for correlative research only.  In addition to a baseline 
PET scan (for those with extramedullary disease, not required for those with leukemia cutis 
only), follow-up response scans will also be obtained at the end of four cycles of combination 
therapy following initial documentation of an objective response. 
 
11.1 
Antitumor Effect – Hematologic Tumors 
 
Please see Appendix D for IWG Response Criteria for AML [6]. Disease progression will be 
determined by European LeukemiaNet 2017 criteria (Appendix H). 
 
Please see Appendix E for IWG Response Criteria for MDS [7]. 
 
Bone marrow biopsy and aspirate will be performed at screening (will serve as baseline) and end 
of cycles 1, 2 and 4, and every 3 cycles thereafter (end of cycles 7 and 10).  If there is evidence 
or clinical concern for disease progression, then a bone marrow biopsy and aspirate will be 

NCI Protocol #: 10026 
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collected.  At each evaluation the patient should have aspirate (if aspirable), cytogenetics and 
flow cytometry performed. Genotyping will be performed as a part of study correlates.   
 
Hematologic evaluations will be performed with CBC with differential at a minimum of once per 
cycle. Response assessments may be determined by labs (CBC with differential, particularly 
platelet count and absolute neutrophil count) within 2 weeks of a bone marrow biopsy as long as 
it is obtained prior to day 1 of the next cycle.  
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence.   
x For those with AML: Best overall response including CR and CRi will be recorded. 
Patients may remain on study if they have evidence of clinical benefit, stable disease, 
partial remission, complete remission or complete remission with incomplete count 
recovery.  
x For those with MDS: Best overall response rate will include CR, marrow CR, PR, and 
hematologic improvement. 
 
11.1.1 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR or HI (for those with MDS) (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively documented.  
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
11.1.2 Progression-Free Survival 
 
Overall Survival:  Overall Survival (OS) is defined as the time from time of registration to death 
due to any cause, or censored at date last known alive. We will evaluate for survival differences 
among patients that respond based on transplant status.  
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from time of 
registration to the earlier of progression or death due to any cause. Participants alive without 
disease progression are censored at date of last disease evaluation.   
 
12.  STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 

NCI Protocol #: 10026 
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109 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For Phase 1 studies, all decisions regarding dose escalation/expansion/de-escalation require sign-
off by the Protocol Principal Investigator through the CTMS/IWRS.  In addition, for the Phase 1 
portion, the Protocol Principal Investigator will have at least monthly, or more frequently, 
conference calls with the Study Investigators and the CTEP Medical Officer(s) to review accrual, 
progress, and adverse events and unanticipated problems. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
 In addition to reporting to NCI/ETCN, it is mandatory for all participating sites to report all 
grade 4 events within 24 hours if possible, no more than 72 hours, to the Overall Study Chair 
except for those mentioned in section 7.3.4. All grade 5 events should be reported to the Overall 
Study Chair within 24 hours.  
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Read-Only, Rave CRA (Lab Admin), Rave SLA, or Rave 
Investigator) on either the LPO or participating organization roster at the enrolling site. To hold 
the Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an AP 
registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave. 
  
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 

NCI Protocol #: 10026 
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the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  
For CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 799-7580 or by email at CTMSSupport@theradex.com for 
additional support with Rave and completion of CRFs. 
 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 

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An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry 
and Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
12.3 
CTEP Multicenter Guidelines 
 
N/A 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 

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2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 

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releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5 
Genomic Data Sharing Plan   
 
Correlative studies proposed will aim to include genotyping patient leukemic blasts.  If genomic 
data will be studied, analyzed, and collected, then we will plan to share and store this data in an 
NIH/NCI Genomic Data Biorepository (e.g., dbGaP, Cancer Genomic Database, other) 
following the genomic data sharing policy.   
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
    
This is an open-label phase 1 study using a standard 3+3 dose-escalation design with planned 
dose escalation of ipilimumab in combination with decitabine, to define the safety profile and 
MTD (RP2D) in patients with R/R MDSAML with and without previous allogeneic HSCT. Two 
arms are planned. Arm A will include a cohort of patients who are post-transplant (patients who 
were transplanted by allogeneic HSCT at any time). Arm B will include a cohort of patients who 
are transplant naive (patients who never received allo-HSCT). Both cohorts will be tested at 
three different ipilimumab dose levels (dose level 0 (starting dose; first dose level): 3 mg/kg, 
dose level 1: 5 mg/kg, and dose level 2: 10 mg/kg).  Three to six patients will be evaluated at 
each dose level per arm.  
 
Please see section 5.1 for details on patient enrollment.  We will demonstrate safety in the first 
dose level in patients on Arm B prior to enrolling patients onto Arm A. After safety is 
demonstrated at this first dose level, enrollment can then occur simultaneously without further 
delay or observation period.  A dose de-escalation level (-1) will be allowed with ipilimumab at 
1 mg/kg. Arm A does not need to complete dose escalation before Arm B if Arm B is able to 
move to dose-expansion; and vice versa. In the event that 0 of 3 patients in a dose level 
experience a DLT, the dose level may still be expanded to 6 evaluable patients based on 
observed toxicity at the current dose level at the discretion of the overall PI to capture patient 
safety prior to expanding. 
  
 
Dose escalation will follow a standard 3+3 design exploring 3 dose levels of ipilimumab 
(starting at dose level 0, at 3 mg/kg) with decitabine (20 mg/m2 daily x 5 consecutive doses).  
We will escalate to next dose cohort if 0/3 or 1/6 participants have a DLT during the first two 
cycles of combination therapy (cycles 1+2; first 8 weeks of combination therapy).  If the rate of 
dose limiting toxicity (DLT) exceeds 30%, it is less likely that the dose of ipilimumab will be 

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dose-escalated. The table below provides the probability that the dose will be escalated, i.e., that 
0 in 3 or 1 in 6 patients experience a DLT, given the true but unknown rate of DLT.  
 
 
 
True but unknown probability of 
DLT 
 
0.10 
0.20 
0.30 
0.40 
0.50 
P(escalate) 
0.91 
0.71 
0.49 
0.31 
0.17 
The MTD will be the highest dose at which 1 or fewer of 6 patients experience a DLT. If no 
MTD has been established, then dose level 2 will be used in the dose expansion cohort as the 
recommended phase 2 dose (RP2D).  Once an MTD (or RP2D) has been established an 
expansion cohort will be enrolled for each arm. For a given arm, if all 3 dose cohorts are filled to 
6 patients, then a 6 patient expansion will be added. If 2 or fewer dose cohorts are filled to 6 
patients, then a 12 patient expansion will be added so that no more than 24 patients (dose 
escalation + expansion) will be treated on a given arm. Patients will be monitored for DLTs 
during the first 8 weeks of combination therapy (56 days from start of combination) during 
the induction phase only. If a patient experiences disease progression in cycle 1, the patient will 
be evaluable for DLT if the patient completes a minimum of 28 days. Any patient who does not 
complete cycle 1 for any reason other than DLT will be considered non-evaluable for 
dose escalation decisions and will be replaced by an additional patient at that same dose level. 
Patients in cycle 2 will be assessed for DLT. 
Safety and tolerability of decitabine plus ipilimumab will be evaluated by means of drug related 
DLT (defined as first 8 weeks of combination treatment with decitabine and ipilimumab), AE 
reports (following CTCAE V.5 criteria), physical examinations, and laboratory safety 
evaluations.  These results will be tabulated overall and by dose level to examine their frequency, 
organ systems affected, severity, and relationship to study drugs.  
 
The goal of the expansion cohort will be to further assess the tolerability of decitabine plus 
ipilimumab. Frequency of grade 3 or higher non-hematologic toxicities will be reported by arm 
and frequency of all grade immune-related adverse events will be reported by arm. Additionally, 
GVHD for the patients on the post-transplant arm will be estimated and reported with a 90% 
exact binomial confidence interval.  
 
Additionally, efficacy of decitabine plus ipilimumab will be assessed for the total number of 
patients enrolled at the MTD/RP2D for each arm. Anti-leukemic activity will be described in 
terms of best overall response rate (for AML, to include CR+CRi; for MDS, to include 
CR+marrow CR+PR+HI). Assuming 6 patients are enrolled at the MTD/RP2D from the dose 
escalation phase and an additional 6 patients for the cohort expansion, the 90% exact binomial 
confidence interval will be within +/- 25%. Assuming 6 patients are enrolled at the MTD/RP2D 
from the dose escalation phase and an additional 12 patients from the cohort expansion, the 90% 
exact binomial confidence interval will be within +/- 21%. 
 
Overall survival (OS) is defined as the time from registration to death due to any cause or 
censored at the date last known alive. Progression-free survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Survival outcomes will be 

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estimated by the method of Kaplan and Meier. OS and PFS will be evaluated within each arm. 
 
13.2 
Sample Size/Accrual Rate 
 
For each arm (Arm A and Arm B), assuming all dose cohorts are filled, the estimated sample 
will be at most 24. Hence the total estimated total sample size is at most 48 patients. The 
expansion cohort will be set at the MTD/RP2D.  After the first dose level is assessed in Arm B 
(transplant naive), then we will then allow enrollment of patients onto Arm A.  Further 
enrollment will occur in parallel with no observation period or delay between the start of therapy 
for each enrolled patient in either arm. We anticipate completing accrual within 24 months. 1-2 
patients per month will be accrued. 
 
Up to an additional 12 months of follow-up will be required on the last participant to observe the 
participant’s survival; for total study duration of 3 years.  
 
 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
2 
0 
0 
4 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
4 
0 
0 
8 
White 
11 
11 
4 
4 
30 
More Than One Race 
2 
2 
1 
1 
6 
Total 
19 
19 
5 
5 
48 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
13.3 
Stratification Factors 
 
N/A 

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13.4 
Analysis of Primary Endpoints 
 
We will determine the MTD/RP2D of dose escalated ipilimumab in combination with decitabine 
in patients who are post allo-HCT and in patients who are transplant naive.    
 
13.5 
Analysis of Secondary Endpoints 
 
Safety analyses will be based on the safety population, defined as all enrolled patients receiving 
at least 1 dose of ipilimumab.  Categorical data will be presented as frequencies and percentages. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated. All tests of interactions will be conducted at a 2-sided alpha level of 0.1, and all CIs will 
be given at a 2-sided 95% level, unless otherwise stated.  Patients who are registered to the study 
and have received at least one dose of ipilimumab on study will be evaluable for response. 
Clinical response to treatment will be assessed following the 2003 IWG criteria for AML [6] and 
the 2006 IWG criteria for MDS [7]. Anti-leukemic activity will be described in terms of best 
overall response rate (for AML, to include CR+CRi; for MDS, to include CR+marrow 
CR+PR+HI), PFS, OS, and remission duration. Time to event summaries will use the Kaplan-
Meier method. We will separately evaluate the incidence of acute GVHD and chronic GVHD in 
patients in the post-allo-HCT cohort, and compare these events with response to treatment. 
 
The focus of this trial is to establish the safety and RP2D of the combination; thus the biomarker 
studies should be considered exploratory. We will evaluate whether or not absolute lymphocyte 
count can predict for response for patients who receive combination treatment. ALC levels will 
be divided into: low (<1000 cells/ul) and normal/high (greater than or equal to 1000 cells/ul). We 
will compare the response and overall survival of patients with low ALC versus normal/high 
ALC using Kaplan-Meier estimates and differences will be assessed using log-rank test. We will 
further capture the absolute change in ALC level measured at baseline to end of cycle 2 
(collected prior to dosing on cycle 3 day 1) for response and survival differences. For correlative 
laboratory tests, we will compare nonrandom measurements in an individual patient either across 
time (pre-treatment versus on-treatment) with a paired Student t test. OS will be censored at the 
date of last contacts.  
 
 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, 
but unable to carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 

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APPENDIX B1 
ACUTE GRAFT VERSUS HOST DISEASE WORKSHEET 
 
  Acute GVHD Worksheet 
Consensus Conference on Acute GVHD Grading  
Reference: Przepiorka, DD et al., Bone Marrow Transplant, 825-828. 
 
Instructions:  
1. Is acute GVHD present (circle): YES or NO 
2. If yes, please circle below the Overall Grade (and the Individual Stages as Relevant) 
 
GVHD Classification 
Overall Grade 
(please circle) 
Skin 
Liver 
Gut 
I 
Stage 1-2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
 
Stage 2-3 or 
Stage 2-4 
IV 
Stage 4 or 
Stage 4 
 
For each overall grade of acute GVHD, an assessment of skin disease plus liver and/or gut is required.  
 
Individual organ staging  
Clinical manifestations and staging of acute GVHD 
Organ 
Clinical Manifestation 
Staging 
Tips to Investigator 
Skin 
 
 
 
Erythematous, 
maculopapular rash 
involving palms and soles; 
may become confluence; 
severe disease: bullae 
Stage 1: < 25% rash 
Stage 2: 25-50% rash 
Stage 3: generalized 
erythroderma 
Stage 4: bullae 
Use rule of 9s to determine 
extent of rash 
Liver 
Painless jaundice with 
conjugated 
hyperbilirubinemia and 
increased alkaline 
phosphatase 
Stage 1: bilirubin 2-3 mg/dL 
Stage 2: bilirubin 3.1-6 mg/dL 
Stage 3: bilirubin 6.1-15 mg/dL 
Stage 4: bilirubin > 15 mg/dL 
Range given is for total 
bilirubin; downgrade one 
stage if a cause of elevated 
bilirubin other than GvHD 
has been documented 
GI  
Upper: nausea, vomiting, 
anorexia 
 
Loewr: diarrhea, abdominal 
cramps, distention, ileus, 
bleeding 
Stage 1: diarrhea > 500 mL/day 
or persistent nausea or anorexia 
Stage 2: diarrhea > 1000 mL/day 
Stage 3: diarrhea > 1500 mL/day 
Stage 4: large volume diarrhea 
and severe abdominal pain +/- 
ileus 
Downgrade one stage if a 
cause of diarrhea other than 
GvHD has been 
documented; downgrade 
upper GI one stage if biopsy 
result is negative; or if no 
biopsy is done and gVHD is 
not etiology or if biops is 
equivocal and GVHD is not 
an etiology 
 
 
 
Subject ID:  
 
 
 
Site: 
Signature of Treating Investigator:  
 
 
Date of evaluation:  
Cycle/Day:  
 
 
 
 
 

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APPENDIX B2 
CHRONIC GRAFT VERSUS HOST DISEASE WORKSHEET 
 
 
Chronic GVHD Worksheet 
Consensus Conference on Acute GVHD Grading  
Reference: Jagasia MH et al., Biol Blood Marrow Transplant, 2015, 389-401. 
 
Instructions:  
1. Is chronic GVHD present (circle): YES or NO 
2. If yes, please circle global severity below (mild, moderate or 
severe). See sheets on Scoring per organ 
  
 
 
Subject ID: 
Site: 
Signature of Treating Investigator:  
Date of evaluation:  
Cycle/Day:  
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
PERFORMANCE 
SCORE: 
 
KPS ECOG LPS 
b Asymptomatic 
and fully active 
(ECOG 0; KPS or 
LPS 100%) 
b Symptomatic, 
fully 
ambulatory, 
restricted only 
in physically 
strenuous 
activity (ECOG 
1, KPS 
or LPS 80-90%) 
b Symptomatic, 
ambulatory, 
capabl of self-
care, >50% of 
waking hours ou 
of bed (ECOG 2, 
KPS or LPS 60- 
70%) 
b Symptomatic, 
limited self-
care, 
>50% of waking 
hours in bed 
(ECOG 3-4, KPS or 
LPS 
<60%) 
 
 
SKIN† 
SCORE % BSA 
 
 
GVHD features to be 
scored by BSA: 
Check all that apply: 
b Maculopapular 
rash/erythema 
b Lichen planus-like features 
b Sclerotic features 
b Papulosquamous 
lesions or ichthyosis 
b Keratosis pilaris-like GVHD 
b No BSA 
involve
d 
b 1-18% BSA 
b 19-50% BSA 
b >50% BSA 
SKIN FEATURES 
SCORE: 
 
 
b No sclerotic 
features 
b Superficial 
sclerotic 
features “not 
hidebound” 
(able to pinch) 
Check all that apply: 
b Deep 
sclerotic 
features 
b “Hidebound” 
(unable to 
pinch) 
b Impaired mobility 
b Ulceration
 
Other skin GVHD features (NOT scored by BSA) 
Check all that apply: 
b Hyperpigmentation 
b Hypopigmentation 
b Poikiloderma 
b Severe or generalized pruritus 
b Hair involvement 
b Nail involvement 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 
MOUTH 
Lichen planus-
like features 
present: 
b Yes 
b No 
b No symptoms 
b Mild symptoms 
with 
disease 
signs but not 
limiting 
oral intake 
significantl
y 
b Moderate 
symptoms with 
disease signs 
with 
partial 
limitation of 
oral intake 
b Severe symptoms with 
disease signs on 
examination with major 
limitation of oral intake 
b Abnormality present but explained entirely by non-GVHD documented cause (specify):  

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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
EYES 
 
Keratoconjunctivitis 
sicca (KCS) 
confirmed by 
ophthalmologist: 
b Yes 
b No 
b Not examined 
b No symptoms 
b Mild dry eye 
symptoms 
not affecting 
ADL 
(requirement 
of lubricant 
eye drops < 3 
x per day) 
b Moderate dry eye 
symptoms 
partially affecting 
ADL (requiring 
lubricant eye 
drops > 3 x per 
day or punctal 
plugs), WITHOUT 
new vision 
impairment due 
to KCS 
b Severe dry eye 
symptoms 
significantly affecting 
ADL (special eyeware 
to relieve pain) OR 
unable to work 
because of ocular 
symptoms OR loss of 
vision due to KCS 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
GI Tract 
Check all that apply: 
b Esophageal 
web/ proximal 
stricture or ring 
b Dysphagia 
b Anorexia 
b Nausea 
b Vomiting 
b Diarrhea 
b Weight loss >5%* 
b Failure to thrive 
b No symptoms 
b Symptoms 
without 
significant 
weight loss* 
(<5%) 
b Symptoms 
associated with 
mild to 
moderate 
weight loss* 
(5-15%) OR 
moderate 
diarrhea 
without 
significant 
interference 
with daily living 
b Symptoms associated 
with significant weight 
loss* >15%, requires 
nutritional supplement 
for most calorie needs 
OR esophageal dilation 
OR severe diarrhea with 
significant interference 
with daily living 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 
 
LIVER 
b Normal total 
bilirubin 
and ALT or 
AP 
< 3 x ULN 
b Normal total 
bilirubin with ALT 
>3 to 5 x ULN 
or AP > 3 x ULN 
b Elevated total 
bilirubin but 
<3 mg/dL or 
ALT > 5 ULN 
b Elevated total 
bilirubin > 3 
mg/dL 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
LUNGS** 
Symptom score: 
 
b No symptoms 
 
b Mild symptoms 
(shortness of 
breath after 
climbing one 
flight of steps) 
b Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground) 
b Severe symptoms 
(shortness of breath 
at rest; requiring 02) 
Lung score: 
% FEV1 
b FEV1≥80% 
b FEV1 60-79% 
b FEV1 40-59% 
b FEV1 <39% 
 
Pulmonary function 
tests 
b Not performed 
 
 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 

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JOINTS AND FASCIA 
 
P-ROM score 
(see below) 
Shoulder (1-7):  
 
Elbow (1-7): 
 
Wrist/finger (1-
7): Ankle (1-4):   
b No 
sympto
ms 
b Mild tightness of 
arms or legs, 
normal or mild 
decreased 
range of motion 
(ROM) AND not 
affecting ADL 
b Tightness of arms 
or legs OR joint 
contractures, 
erythema 
thought due to 
fasciitis, 
moderate 
decrease ROM 
AND mild to 
moderate 
limitation of ADL 
b Contractures WITH 
significant decrease 
of ROM AND 
significant 
limitation of ADL 
(unable to tie 
shoes, button 
shirts, dress self 
etc.) 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
 
 
GENITAL TRACT 
(See Supplemental 
figure‡) 
b Not examined 
Currently sexually 
active 
b Yes 
b No 
 
b No signs 
b Mild signs‡ and 
females with or 
without 
discomfort on 
exam 
b Moderate signs‡ 
and may have 
symptoms with 
discomfort on 
exam 
b Severe signs‡ with 
or without 
symptoms 
b Abnormality present but explained entirely by non-GVHD documented cause (specify): 
 
Other indicators, clinical features or complications related to chronic GVHD (check all that apply and 
assign a score to severity (0-3) based on functional impact where applicable none – 0,mild -1, 
moderate -2, severe – 3) 
b Ascites (serositis) 
 
 
b  Myasthenia Gravis  
 
b Pericardial Effusion 
 
b  Peripheral Neuropathy 
 
 
b   Eosinophilia > 500/μl  
 
b Pleural Effusion(s) 
 
 
b Polymyositis  
 
b   Platelets <100,000/μl   
 
b Nephrotic syndrome 
 
b  Weight loss>5%* without GI symptoms  
 
 
b   Others (specify): 
 
 
 
 
Overall GVHD Severity 
(Opinion of the 
evaluator) 
 
 No GVHD 
 Mild 
 Moderate 
 Severe 
 
 
 
 
 

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Photographic Range of Motion (P-ROM) 
† Skin scoring should use both percentage of BSA involved by disease signs and the cutaneous 
features scales. When a discrepancy exists between the percentage of total body surface (BSA) 
score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there 
is impaired mobility or ulceration (Score 3), the higher level should be used for the final skin 
scoring. 
* Weight loss within 3 months. 
**Lung scoring should be performed using both the symptoms and FEV1 scores whenever possible. 
FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and 
FEV1 scores. 
Abbreviations: ECOG (Eastern Cooperative Oncology Group), KPS (Karnofsky 
Performance Status), LPS (Lansky Performance Status); BSA (body surface area); 
ADL (activities of daily living); LFTs (liver function tests); AP (alkaline 
phosphatase); ALT (alanine aminotransferase); ULN (normal upper limit). 
‡ To be completed by specialist or trained medical providers (see Supplemental Figure). 
 
 

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APPENDIX C 
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS, 
DIARRHEA, HEPATOTOXICITY, ENDOCRINOPATHY, SKIN 
AND NEUROPATHY * 
 
*Investigator’s Brochure (March 2016) 
General Recommendations for Management of Suspected Inflammatory Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caution: With the appearance of any 
generalized rash, discontinue and avoid 
any concomitant medications 
(e.g. antibiotics, anticonvulsants, or proton 
pump inhibitors) that may be associated 
with severe skin reactions 
+ Definition: irAEs are associated with 
ipilimumab exposure and are consistent 
with immune phenomenon 
 
Examples of possible irAEs (common 
and rare): rash, pruritus, diarrhea/colitis, 
hepatitis/elevated liver function tests, 
hypopituitarism, hypo/hyperthyroidism, 
uveitis, pneumonitis, nephritis, 
pancreatitis, aseptic meningitis, toxic 
epidermal necrolysis, myopathy/myositis 
or neuromuscular disorder (e.g. 
Myasthenia gravis, Guillain-Barre 
Syndrome)  
Suspicion of 
an immune 
related 
adverse event
Rule-out non-immune related causes 
If symptoms have a GI, Liver, or Endocrine etiology, then refer 
To ‘Diarrhea”, “Hepatotoxicity”, or “Endocrinopathy” 
Management Algorithm for more specific guidance 
Low grade 
(Grade 1 or 2) 
What is the 
severity of the 
adverse event? 
(NCI CTCAE 
High grade 
(Grade 3 or 4) 
 
- Increase monitoring 
- Symptomatic treatment  
- Consider skipping next dose until 
event resolves 
- Consider oral steroid therapy* for 
persistent or recurring Grade 2 irAEs 
- If symptoms worsen or do not 
improve with treatment after 1-2 weeks 
then consider managing as a high 
grade event 
- Increase monitoring 
- Strongly consider high dose steroid 
therapy* 
- Hold further dosing until adverse event 
resolves 
- Consider specialist consult 
- If steroid therapy is initiated and symptoms 
improve, then consider a gradual steroid 
taper over 4 weeks 
- If symptoms do not respond within 5-7 days 
of intervention, then consider alternative 
immunosuppression therapy (e.g., 
mycophenolate mofetil, tacrolimus, 
infliximab) 
* Based on clinical experience to date, systemic steroids for 
treatment of irAEs do not appear to impact the development or 
maintenance of ipilimumab clinical activity in advanced melanoma.  

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Diarrhea Management Algorithm 
 
 
 
 
 
 
 
Diarrhea 
GRADE 1 
Increase of <4 stools per 
day over baseline; 
mild increase in ostomy 
output compared with 
baseline 
GRADE 2 
Increase of 4-6 stools per day 
over baseline; IV fluids 
indicated < 24 hrs; moderate 
increase in ostomy output 
compared to baseline; not 
interfering with  activities of 
daily living (ADL) 
GRADE 3 
Increase of 侔7 stools per day over 
baseline; incontinence; IV fluids 侔
24 hrs; hospitalization; 
severe increase in ostomy output 
compared to baseline; interfering 
with ADL 
GRADE 4 
Life-threatening 
consequences 
(e.g., 
hemodynamic 
collapse) 
GRADE 5 
Death 
 
 
 

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Hepatoxicity Management Algorithm 
 
Situation: rising liver function tests (LFTs) >8X ULN or suspected immune-mediated 
hepatitis 
1) 
Admit subject to hospital for evaluation and close monitoring 
2) 
Stop further ipilimumab dosing until hepatotoxicity is resolved. Consider permanent 
discontinuation of ipilimumab per protocol  
3) 
Start at least 120 mg methylprednisolone sodium succinate per day, given IV as a 
single or divided dose 
4) 
Check liver laboratory test values (LFTs, T-bilirubin) daily until stable or showing 
signs of improvement for at least 3 consecutive days 
5) 
If no decrease in LFTs after 3 days or rebound hepatitis occurs despite treatment with 
corticosteroids, then add mycophenolate mofetil 1g BID per institutional guidelines 
for immunosuppression of liver transplants (supportive treatment as required, 
including prophylaxis for opportunistic infections per institutional guidelines) 
6) 
If no improvement after 5 to 7 days, consider adding 0.10 to 0.15 mg/kg/day of 
tacrolimus (trough level 5-20 ng/mL) 
7) 
If target trough level is achieved with tacrolimus but no improvement is observed 
after 5 to 7 days, consider infliximab, 5 mg/kg, once 
8) 
Continue to check LFTs daily for at least 2 weeks to monitor sustained response to 
treatment 
 
A flow chart of the algorithm is depicted on the following page. 
 

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APPENDIX D    
ACUTE MYELOID LEUKEMIA RESPONSE CRITERIA  
  
Cheson, B et al., J Clin Oncol, 2003, 4642-9. 
 
Morphological Complete Remission (CR): 
-Normalization of the peripheral blood absolute neutrophil count > 1.0x109/L, platelets > than 
100x109/L no residual evidence of extramedullary disease and bone marrow aspirate with ≤ 
5% blasts, no blasts with Auer rods  
 
Morphological Complete Remission with incomplete blood count recovery (CRi): 
-Same as CR but without normalization of the peripheral blood absolute neutrophil and platelet 
count 
 
Relapse from CR or CRi: 
-Reappearance of leukemic blasts in the peripheral blood; or> 5% blasts in the bone marrow 
not attributable to another cause (e.g. recovery of normal cells following treatment –induced 
aplasia or use of growth factors) OR 
-Appearance or reappearance of extramedullary disease. 
-If there are no circulating blasts and no extramedullary disease and the bone marrow blast 
percentage is >5% but <20%, then a repeat bone marrow performed at least 7 days after the 
first marrow examination and documenting bone marrow blast percentage >5% is necessary 
to establish relapse. 
 
Partial Remission (PR): 
-Normalization of the peripheral blood absolute neutrophil count 1.0x109/L, platelets > than 
100x109/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25% , 
or marrow blasts <5% with Auer rods. 
 
Cytogenetic Responses 
Complete cytogenetic response: An abnormal clone is detected in all metaphases prior to 
treatment and only normal metaphases are observed in all metaphases following treatment. 
 
Partial cytogenetic response: An abnormal clone is detected in all metaphases prior to 
treatment and the post-treatment sample has 50% or fewer abnormal metaphases compared to the 
pretreatment value. 
 
Cytogenetic non-response: An abnormal clone is detected in all metaphases prior to treatment 
and neither complete nor partial cytogenetic response is observed in post-treatment specimens 
Specimens with normal cytogenetic results before treatment will not be evaluated for cytogenetic 
response. The method used to determine cytogenetic response will be standard metaphase 
cytogenetics. 
 
Stable disease: 
-Subjects who fail to achieve CR, Cri, or PR and who do not have criteria for PD will be 
defined as having the stable disease. If the subject dies prior to response assessment at the end of 
Cycle 1, then they will be classified as “indeterminate”. 

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Progressive disease (PD): may be defined as ONE of the following: 
->50% increase in peripheral blood or bone marrow blasts from best assessment with 
minimum threshold of 20% blasts in the marrow or 1.0x109/L blasts in peripheral blood. 
-Development of biopsy proven extramedullary leukemia (if the subject has extramedullary 
disease at baseline, then PD will be defined by blood and marrow criteria or if new sites of 
extramedullary disease appear). 
-If subject who present with an initial marrow blast percentage sufficiently high to preclude the 
ability to base disease progression on a >50% increase in marrow blast percentage, disease 
progression should be based on peripheral blood criteria or development of extramedullary 
leukemia as above. 
 
Persistent Disease 
Hematologic Persistence – Bone marrow or peripheral blasts >5% after d+30 following 
alloSCT 
 

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APPENDIX E  MDS RESPONSE CRITERIA 
 
Table below from IWG 2006 criteria (Cheson B, Blood, 2006, 419-425) 
 
 
 
 

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 APPENDIX F ADVERSE EVENT GUIDANCEAND PRE TREATMENT CRITERIA 
CHECKLIST 
 
(Note: this is not all inclusive for all visits, but for general study visit only) 
 
x Clinic Visit 
x Physical exam 
x ECOG score 
x Medication review 
x Adverse event evaluation and grading if appropriate 
x Immune-related adverse event evaluation: 
o Immediately alert Overall PI (required) if there is concern for cardiac toxicity 
at any time during treatment including clinical signs or concerns for heart 
failure, myocardial infarction, cardiomyopathy, or myositis. If there is 
concern for this, obtain at minimum CPK and troponin, cardiology consult, 
and EKG and echocardiogram, if it is clinically relevant. Please refer to 
section 6.4.7 for guidance on cardiac toxicity management for ipilimumab. 
o Prior to initiating treatment, always assess stool frequency (bowel movements 
per 24 hours). 
o Change in bowel habits (colitis)? 
o Blood in the stool, abdominal pain (colitis)? 
o Headache, especially frontal (hypophysitis)? 
o Unusual fatigue, impaired libido (hypophysitis)? 
o Cough, dyspnea (pneumonitis)? 
x Labs including minimum of complete blood counts with differential and 
comprehensive metabolic panel 
x Additional immune related labs every 3 months including: gamma GT, direct 
bilirubin, LDH, TSH and lipase 
x If due for ipilimumab: LFTs must be reviewed and must be: 
o d3.0 x institutional ULN for AST and ALT 
o d1.5 x institutional ULN for total bilirubin 
o If elevated total bilirubin is due Gilbert’s disease or disease-related 
hemolysis then total bilirubin ≤ 3.0 x institutional ULN 
o If, during the course of treatment abnormal LFT values are detected, 
ipilimumab should not be administered. The subject should be evaluated and 
recommendations for management are in section 6 of the protocol with helpful 
algorithms in Appendix C, as clinically appropriate. 
 
 
 
 
 
 
 

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APPENDIX G PATIENT SAFETY WALLET MEDICATION CARD  

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APPENDIX H EUROPEAN LEUKEMIA NET CRITERIA 
 
 
 

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APPENDIX I:  IPSS  AND IPSS-R  
 
International Prognostic Scoring System -Revised  (Greenberg PL et al., Blood, 2012, 2454-
2465).  
 
 
 

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International Prognostic Scoring System- (Greenberg P et al., Blood, 1997, 2079-2088)