Clinical trial NCT02712905
Conditions: Solid Tumors and Hematologic Malignancy
Keywords: Acute myeloid leukemia (AML) myelodysplastic syndrome (MDS) small cell lung cancer (SCLC) myelofibrosis (MF) solid tumor, lysine-specific demethylase 1 (LSD1) inhibitor
Sponsor: Incyte Corporation
Start date: 2016-05-05; Completion date: 2022-04-14
Enrollment: 116 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, dose-escalation/dose-expansion study of INCB059872 in subjects with advanced malignancies. The study will be conducted in 4 parts. Part 1 (mono therapy dose escalation) will determine the recommended dose(s) of INCB059872 for dose expansion, based on maximum tolerated dose and/or a tolerated pharmacologically active dose. Part 2 (dose expansion) will further determine the safety, tolerability, efficacy, PK, and PD of the selected monotherapy dose(s) in AML/MDS, SCLC, myelofibrosis, Ewing sarcoma, and poorly differentiated neuroendocrine tumors. Part 3 will determine the recommended dose(s) of INCB059872 in combination with azacitadine and all-trans retinoic acid in AML and in combination with nivolumab in SCLC. Part 4 will further determine the safety, tolerability, efficacy, PK, and PD of the selected combination dose(s) in Part 3.

Detailed description:

Arms: arm 1: None arm 2: Initial cohort dose of INCB059872 to evaluate different doses of INCB0599872 in combination with other therapies in the following treatment groups:

* Combination with all-trans retinoic acid (ATRA) in subjects with relapsed/refractory AML.
* Combination with azacitidine in subjects with newly diagnosed, treatment-naive AML
* Combination with nivolumab in subjects with advanced SCLC previously progressed on platinum-based treatment.

Upon identification of the recommended dose(s) for each treatment combination, expansion cohorts of approximately 30 subjects in each treatment group may begin enrollment to further determine safety, tolerability, efficacy, PK, and PD of the selected dose(s).
Interventions: intervention 1: INCB059872 intervention 2: all-trans retinoic acid (ATRA) intervention 3: azacitidine intervention 4: nivolumab
Intervention descriptions: intervention 1: Initial cohort dose of INCB059872 monotherapy at the protocol-specified starting dose, with subsequent cohort escalations based on protocol-specific criteria. The recommended dose(s) will be taken forward into expansion cohorts.

INCB059872 tablets to be administered by mouth. intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_000.pdf: 
Official Title: 
 A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, 
Safety and Tolerability Study of INCB059872 in Subjects With 
Advanced Malignancies 
NCT Number: 
NCT02712905 
 Document Date: 
Clinical Study Protocol Version 8: 15-June-2020 


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Protocol INCB 59872-101 Am 8 
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CONFIDENTIAL 
 
Clinical Study Protocol 
 
INCB 59872-101 
A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety 
and Tolerability Study of INCB059872 in Subjects With 
Advanced Malignancies 
 
 
Product: 
INCB059872 
IND Number: 
 
EudraCT Number 
2017-001710-28 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
15 DEC 2015 
Amendment (Version) 1: 
19 JAN 2016 
Amendment (Version) 2: 
28 JUL 2016 
Amendment (Version) 3: 
22 SEP 2017 
Amendment (Version) 4: 
06 NOV 2017 
Amendment (Version) 5: 
30 JUL 2018 
Amendment (Version) 6: 
19 APR 2019 
Amendment (Version) 7: 
13 JUN 2019 
Amendment (Version) 8: 
15 JUN 2020 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 


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INVESTIGATOR'S AGREEMENT 
I have read the INCB 59872-101 Protocol Amendment 8 (Version 8 dated 15 JUN 2020) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 


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SYNOPSIS 
Name of Investigational Product:  INCB059872 (Lysine Specific Demethylase 1 Inhibitor) 
Title of Study:  A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability 
Study of INCB059872 in Subjects With Advanced Malignancies 
Protocol Number:  INCB 59872-101 
Study Phase:  1/2 
Indication:  Advanced Malignancies 
Primary Objectives: 
• Part 1:  To evaluate the safety and tolerability and determine the recommended dose(s) of 
INCB059872 for further study in advanced malignancies. 
• Part 2:  To further evaluate the safety and tolerability of INCB059872 for further study in advanced 
malignancies. 
• Part 3:  To evaluate the safety and tolerability and determine the recommended dose of INCB059872 
in combination with other therapies for further study in advanced malignancies. 
• Part 4:  To further evaluate the safety and tolerability of INCB059872 in combination with other 
therapies in advanced malignancies. 
Secondary Objectives: 
• Parts 1 and 2:  To assess preliminary antitumor activity of INCB059872 as a monotherapy in subjects 
with advanced malignancies. 
• Parts 3 and 4:  To assess preliminary antitumor activity of INCB059872 in combination with other 
therapies in subjects with advanced malignancies. 
• To evaluate the pharmacokinetics (PK) of INCB059872 and assess the effect of food (Treatment 
Group [TG] B1 only) on the PK of INCB059872. 
Primary Endpoints: 
• Parts 1 and 2:  Safety and tolerability as assessed by monitoring frequency, duration, and severity of 
adverse events (AEs) through physical examinations, by evaluating changes in vital signs and 
electrocardiograms (ECGs), and through clinical laboratory blood and urine sample evaluations. 
• Parts 3 and 4:  Safety and tolerability as assessed by monitoring frequency, duration, and severity of 
AEs through physical examinations, by evaluating changes in vital signs and ECGs, and through 
clinical laboratory blood and urine sample evaluations in combinations therapies. 
 
 


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Secondary Endpoints: 
• Parts 1 and 2:  Tumor response rates in those subjects with measurable disease or spleen volume 
changes as determined by investigator assessment of response per disease-specific guidelines. 
− Solid tumors:  Objective response rate (ORR), defined as the percentage of subjects having complete 
response (CR) or partial response (PR) will be determined by the investigator assessment of 
radiographic disease assessments per RECIST v1.1. 
− Acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS):  ORR, defined as the proportion 
of subjects who achieve CR or complete remission with incomplete hematologic recovery (CRi) per 
the International Working Group Response Criteria for Acute Myeloid Leukemia or the International 
Working Group Response Criteria for MDS, as applicable. 
− MF:  Change and percentage change in spleen volume reduction (SVR) as measured by magnetic 
resonance imaging (MRI; computed tomography [CT] scan in subjects who are not a candidate for 
MRI or when MRI is not readily available) at Week 12 when compared with baseline. 
• Parts 3 and 4:  Tumor response rates in those subjects with measurable disease as determined by 
investigator assessment of response per disease-specific guidelines. 
− Small cell lung cancer (SCLC):  ORR, defined as the percentage of subjects having CR or PR will be 
determined by the investigator assessment of radiographic disease assessments per RECIST v1.1. 
− AML/MDS:  ORR, defined as the proportion of subjects who achieve CR or CRi per the International 
Working Group Response Criteria for Acute Myeloid Leukemia or the International Working Group 
Response Criteria for MDS, as applicable. 
• PK parameters of INCB059872 in plasma:  Cmax, Tmax, Cmin, AUC0-t, t½, and Cl/F. 
Overall Study Design: 
This is an open-label, dose-escalation/dose-expansion study of the lysine-specific demethylase 1 (LSD1) 
inhibitor INCB059872 as a monotherapy and combination therapy in subjects with advanced 
malignancies.  Subjects will receive INCB059872 doses once every other day (QOD) on a 28-day 
continuous therapy schedule; if QOD is well-tolerated, the next dose may be administered at a different 
dosing regimen (ie, once daily [QD]) but will not exceed the 100% dose escalation for a total daily dose.  
The study will be conducted in 4 parts:  Parts 1 and 2 will evaluate INCB059872 as monotherapy, with 
Part 1 for dose escalation and Part 2 for dose expansion, and Parts 3 and 4 will evaluate INCB059872 in 
combination with select therapies, with Part 3 for combination dose escalation and Part 4 for combination 
dose expansion.  Part 1 (monotherapy dose escalation) will determine the starting dose(s) of INCB059872 


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for dose expansion, based on maximum tolerated dose (MTD).  The recommended dose(s) will be taken 
forward into Part 2 (monotherapy dose expansion).  It is important to note that there may be a different 
MTD in different treatment groups.  The initiation of Part 2 will be based on further review of the 
ongoing clinical study and preclinical data of INCB059872 and information from literature.  Part 3 (dose 
escalation of INCB059872 in combination therapy) will be initiated after the MTD in Part 1 is 
determined.  Part 4 (dose expansion of INCB059872 in combination therapy) will explore the dose(s) 
confirmed in Part 3 and the dose(s) may be different based on combination therapy and/or tumor type. 
Monotherapy Dose Escalation (Part 1) 
Approximately 24 subjects will be enrolled into each dose-escalation treatment group. 
Treatment Group A will enroll subjects with AML or MDS.  The enrollment in TG B is prioritized for 
SCLC.  Enrollment of subjects with other solid malignancies (eg, endocrine tumors) is allowed with the 
sponsor medical monitor approval. 
Dose escalation for TG A and TG B in Part 1 will proceed independently, with each treatment group 
following a 3 + 3 design.  The starting dose of INCB059872 for TG A and TG B will be 2 mg QOD.  A 
minimum of 3 subjects will initially be enrolled in each treatment group in Part 1, and each subject will be 
observed for a dose-limiting toxicity (DLT) observation period of 1 cycle (28 days) before the next dose 
cohort begins enrollment.  Subjects must have taken at least 75% of the cohort-specific dose (at least 
11 doses for QOD schedule or at least 21 doses for QD schedule) in the first 28 days of study treatment or 
have had a DLT to be considered evaluable.  Subjects who are not evaluable will be replaced.  The dose 
will be escalated by up to 100% if none (0) of the first 3 evaluable subjects enrolled has a DLT.  Dose 
escalation should proceed in smaller increments (ie, by no more than 50%) if a DLT is observed, or if 2 or 
more subjects at a given dose level experience Grade 2 or higher AEs (unless they are clearly and 
incontrovertibly due to an alternative cause).   
If 1 of the first 3 evaluable subjects enrolled has a DLT, the cohort will be expanded to include 
3 additional evaluable subjects, and if no DLT occurs in the additional 3 subjects, then the dose will be 
escalated by up to 100%.  Otherwise, if 2 subjects in a cohort of 3 or 6 subjects experience DLTs, the 
MTD will be deemed to be exceeded.  An interim lower dose level may be explored if the dose increment 
has been 100%.  The MTD will be defined as one dose level below the dose level at which one-third or 
more subjects experience DLTs.  Upon the aggregate review of overall safety, PK, 
and efficacy, a 
recommended dose (per tumor type) will be determined to maximize the clinical benefit/risk margin. 
Monotherapy Dose Expansion (Part 2) 
Upon identification of the recommended dose(s), up to 4 expansion cohorts per tumor type of 
approximately 15 subjects each may begin enrollment to further determine safety, tolerability, efficacy, 
PK, 
 of the selected dose(s).  Treatment Group A1 will enroll subjects with AML or MDS and 
subjects in this cohort will have an opportunity to switch their treatment to a combination dose that is 
tested and found safe.  Only subjects who have stable disease or better response for ≥ 3 months on 
monotherapy will be allowed to do so.  Treatment Group A2 will enroll subjects with primary 
myelofibrosis (PMF) or secondary MF (post–polycythemia vera myelofibrosis [PPV-MF] or post–
essential thrombocythemia myelofibrosis [PET-MF]).  Treatment Group B1 will enroll subjects with 
SCLC.  Treatment Group B2 will enroll subjects with Ewing's sarcoma and poorly differentiated 
neuroendocrine tumors.  The selected doses for each treatment group are as follows: 
• 
TG A1 dose will be 4 mg QD based on the safety and tolerability assessment in TG A. 
• 
TG A2, TG B1, and TG B2 doses will be 3 mg QOD based on the safety and tolerability assessment 
in TG B (Part 1). 
A study of the effect of food on the PK of INCB059872 will be conducted in Part 2, TG B1 only. 
Note:  Based on emerging data, the sponsor may decide to enroll specific subtypes of AML in TG A1.   
 
If ≥ 5 subjects in the first 15 subjects of any cohort cumulatively (or more than 33% of subjects in cohorts 


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larger than 15 subjects) experience DLTs during Cycle 1, then further enrollment to the cohort will be 
stopped, and a lower dose level may be explored. 
Individual dose titration will be permitted according to Protocol-defined safety parameters.  Subjects will 
continue to receive INCB059872 in 28-day cycles until a withdrawal criterion is met.   
Combination Dose-Finding (Part 3) 
Part 3 enrollment will be initiated after the MTD has been determined in Part 1 and will include 
dose-finding to evaluate safety and tolerability of the combinations.  Enrollment of Part 3 will occur in 
parallel with Part 2.  Dose-finding will use a 3 + 3 design to evaluate different doses of INCB059872 in 
combination with other therapies in the following treatment groups:  
• 
Combination TG C:  INCB059872 in combination with all-trans retinoic acid (ATRA) in subjects 
with relapsed/refractory AML.  The starting dose for INCB059872 in this cohort will be 2 mg QD 
(2 dose levels below the recommended dose for monotherapy expansion in TG A1). 
• 
Combination TG D:  INCB059872 in combination with azacitidine in subjects with newly diagnosed, 
treatment-naive AML or MDS with at least 5% bone marrow blasts and IPSS-R intermediate or 
higher risk disease who are unfit to tolerate standard intensive chemotherapy at study entry and who 
are eligible to receive azacitidine as first-line therapy for the disease under study.  The starting dose 
for INCB059872 in this cohort will be 2 mg QD (2 dose levels below the recommended dose for 
monotherapy expansion in TG A1). 
• 
Combination TG E:  INCB059872 in combination with nivolumab in subjects with advanced SCLC 
previously progressed on platinum-based treatment.  The starting dose for INCB059872 in this cohort 
will be 3 mg QOD (the recommended dose for monotherapy expansion in TG B1). 
The starting dose of INCB059872 in the combination treatment groups will be based upon the tolerability 
of INCB059872 monotherapy identified in Part 1 of this study.  Doses of the combination agents will be 
selected from conventional dose regimens and will remain the same for all dose-finding and 
dose-expansion cohorts.  INCB059872 doses will not exceed the monotherapy MTD identified in Part 1.  
A minimum of 3 subjects will initially be enrolled in each treatment group in Part 3, and each subject will 
be observed for a DLT observation period of 1 cycle (28 days) before the next dose cohort or expansion 
to Part 4 begins enrollment.  Subjects must have taken at least 75% of the cohort-specific dose (at least 
11 doses for QOD schedule or at least 21 doses for QD schedule) in the first 28 days of study treatment or 
have had a DLT to be considered evaluable.  Subjects who are not evaluable will be replaced. 
If tolerated, the combination treatment groups will escalate independently and in parallel until the MTD 
or optimal doses of the combinations are identified and will be followed by independent expansion 
cohorts at the selected dose(s).  If the starting dose is not tolerated in any of the combination treatment 
groups, a lower dose of INCB059872 may be explored; otherwise, higher doses found to be safe and 
tolerable in Part 1 may be explored.  The sponsor, in consultation with participating investigators, may 
elect to expand a dose cohort(s) deemed tolerable, to up to 12 subjects, in order to obtain supplemental 
PK, 
, and safety data. 
Combination Dose Expansion (Part 4) 
Upon identification of the recommended dose(s) for each treatment combination in Part 3, expansion 
cohorts of approximately 30 subjects in each treatment group may begin enrollment to further determine 
safety, tolerability, efficacy, PK, 
 of the selected dose(s). 
• 
Combination TG C1:  INCB059872 in combination with ATRA using the regimen identified in Part 3 
in subjects with relapsed/refractory AML. 
• 
Combination TG D1:  INCB059872 in combination with azacitidine using the regimen identified in 
Part 3 in subjects with newly diagnosed, treatment-naive AML or MDS with at least 5% bone marrow 
blasts and IPSS-R intermediate or higher risk who are unfit to tolerate standard intensive 
chemotherapy at study entry and who are eligible to receive azacitidine as first-line therapy for the 
disease under study. 


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• 
Combination TG E1:  INCB059872 in combination with nivolumab using the regimen identified in 
Part 3 in subjects with advanced SCLC who previously progressed on platinum based treatment. 
In Part 4, a stopping rule for futility is planned for each combination dose expansion treatment group.  
The futility analyses for combination TGs will be conducted when 15 subjects for each disease type have 
been treated and evaluated for response or have permanently discontinued study treatment because of 
disease progression, withdrawal of consent, or death.  The futility analyses for TG D1 will be conducted 
when the first 15 subjects with AML or when the first 15 subjects with MDS have been treated.   
Study Population: 
Potential subjects include those with advanced or metastatic malignancies who are ineligible for all 
therapeutic options that are standard of care or known to confer clinical benefit, or who refuse these 
treatments. 
Key Inclusion Criteria: 
• 
Male or female subjects, age 18 years or older. 
• 
Presence of measurable disease that has been confirmed by histology or cytology.  Myelofibrosis 
subjects must have palpable spleen of ≥ 5 cm below the left subcostal margin on physical examination 
at the screening visit. 
• 
The following malignancy types will be included in each of the treatment groups: 
 
Treatment 
Group 
Malignancy Histology 
Part 1 
(Dose Escalation) 
A 
AML or MDS  
B 
SCLC (other solid tumors, eg, endocrine tumors, are 
allowed with medical monitor approval) 
Part 2 
(Dose Expansion) 
A1 
Relapsed/refractory AML or MDS 
A2 
MF (PMF, PPV-MF, and PET-MF) 
B1 
SCLC 
B2 
Ewing's sarcoma and poorly differentiated neuroendocrine 
tumors 
Parts 3 and 4 
(Combination Dose 
Escalation/Expansion) 
C/C1 
Relapsed/refractory AML 
D/D1 
Newly diagnosed, treatment-naive AML, or MDS who are 
unfit to tolerate standard intensive chemotherapy at study 
entry and who are eligible to receive azacitidine as first-line 
therapy for the disease under study.   
E/E1 
SCLC previously progressed on platinum-based treatment 
• 
Subjects must meet specific disease and treatment criteria as follows: 
− TG A/A1/A2, TG B/B1/B2, C/C1, and TG E/E1:  The subject must not be a candidate for 
potentially curative therapy or standard-of-care approved therapy.  
− TG A2:  The subjects must have confirmed diagnosis of PMF, PPV-MF, or PET-MF according to 
revised WHO 2016 criteria. 
− TG D/D1:   
Subjects with newly diagnosed, treatment-naive AML who are unfit to tolerate standard intensive 
chemotherapy at study entry based on at least 1 of the following criteria: 
 Age ≥ 75 years old. 
 History of congestive heart failure or documented ejection fraction ≤ 50%. 
 Pulmonary disease with diffusing capacity of the lungs for carbon monoxide ≤ 65% or FEVI 
≤ 65%, or dyspnea at rest or requiring, oxygen. 
 Any other comorbidity that the physician judges to be incompatible with intensive 
chemotherapy. 


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OR  
Subjects with newly diagnosed, treatment-naive MDS with at least 5% bone marrow blasts and 
IPSS-R intermediate or higher risk disease who are unfit to tolerate standard intensive 
chemotherapy at study entry and who are eligible to receive azacitidine as first-line therapy for 
the disease under study. 
 The following treatments for prior lower risk MDS are acceptable:  Revlimid®, low-dose 
cytarabine, and growth factors. 
− TG E/E1:  The subjects in TG E must have previously received platinum-based therapy, but 
additional lines of therapies are allowed.  The subjects in TG E1 must not have received more 
than 1 previous line of therapy for locally advanced or metastatic SCLC.  The previous line of 
therapy must be a platinum-based therapy, and the subjects must have progressed on or after this 
treatment. 
• 
Willingness to undergo a pretreatment bone marrow biopsy or aspirate (AML/MDS/MF) during 
screening (requirement may be waived with medical monitor approval).  Subjects with solid 
malignancies must have baseline archival tumor specimen available:  a tumor block or approximately 
15 slides from biopsy or resection of primary tumor or metastasis that are < 2 years old (specimens 
> 2 years old may be accepted with medical monitor approval). 
• 
ECOG performance status 0 to 2. 
• 
Willingness to avoid pregnancy or fathering children based on the following criteria: 
− Woman of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral 
oophorectomy, ≥ 12 months of amenorrhea.) 
− Woman of childbearing potential who has a negative serum pregnancy test at screening and 
before the first dose on Day 1 and who agrees to take appropriate precautions to avoid pregnancy 
(with at least 99% certainty) from screening through safety follow-up.  Permitted methods that are 
at least 99% effective in preventing pregnancy should be communicated to the subjects and their 
understanding confirmed. 
− Man who agrees to take appropriate precautions to avoid fathering children (with at least 
99% certainty) from screening through safety follow-up.  Permitted methods that are at least 
99% effective in preventing pregnancy should be communicated to the subjects and their 
understanding confirmed. 
Key Exclusion Criteria: 
• 
Receipt of anticancer medications, anticancer therapies, or investigational drugs within the following 
interval before the first administration of study drug (requirement may be waived with medical 
monitor approval): 
− < 5 half-lives or 14 days, whichever is longer, for any investigational agent 
− < 5 half-lives for all other anticancer medications 
− < 6 weeks for mitomycin-C or nitrosoureas 
• 
Any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable chronic 
toxicities (≤ Grade 2) not expected to resolve. 
• 
All treatment groups:  prior receipt of an LSD1 inhibitor therapy.  Parts 3 and 4 TG E/E1:  prior 
receipt of anti–programmed cell death-1, anti–programmed death ligand 1, or anti–PD-L2 antibody. 
• 
Any of the following laboratory results at screening without transfusions and hematopoietic growth 
factor support in solid tumors (no lower limits in AML and MDS, or in MF with medical monitor 
approval): 
Laboratory Parameter 
Value 
Absolute neutrophil count (× 109/L) 
< 1.5 
Hemoglobin (g/dL) 
< 9.0 
Platelet count (× 109/L) 
< 100 


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• 
Laboratory and medical history parameters outside Protocol-defined range unless associated with 
primary malignancy or metastatic disease and with medical monitor approval: 
− 
Total bilirubin > 1.5 × institutional upper limit of normal (ULN) if no liver metastases or 
> 3 × ULN in the presence of liver metastases or presence of documented Gilbert syndrome 
(unconjugated hyperbilirubinemia). 
− Aspartate aminotransferase or alanine aminotransferase > 2.0 × institutional ULN. 
− Creatinine clearance < 60 mL/min based on the institutional formula. 
• 
History or evidence of bleeding disorder requiring treatment. 
• 
History or presence of an abnormal ECG that in the investigator's opinion is clinically meaningful.  A 
screening QTc interval > 470 milliseconds, as corrected by Fridericia, is excluded.  For subjects with 
an intraventricular conduction delay (QRS interval 120 milliseconds), the JTc interval may be used in 
place of the QTc with sponsor approval.  Subjects with left bundle branch block are excluded. 
• 
Prior radiotherapy within 2 weeks of study treatment.  Subjects must have recovered from all 
radiation-related toxicities, including radiation pneumonitis, and not require corticosteroids.  Evidence 
of fibrosis within a radiation field from prior radiotherapy is permitted with medical monitor 
approval.  A 1-week washout period is permitted for palliative radiation to non–central nervous 
system (CNS) disease with medical monitor approval. 
• 
Unless approved by the medical monitor, allogeneic hematopoietic stem cell transplant within 
6 months before treatment, or active graft-versus-host-disease following allogeneic transplant, or 
receipt of immunosuppressive therapy following allogeneic transplant within 2 weeks of Cycle 1 
Day 1 (prednisone ≤ 10 mg/day is allowed). 
• 
Unless approved by the medical monitor, autologous hematopoietic stem cell transplant within 
3 months before treatment. 
• 
History of human immunodeficiency virus infection. 
• 
Untreated brain or CNS metastases or brain/CNS metastases that have progressed (eg, evidence of 
new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS 
metastases).  Subjects with previously treated and clinically stable brain/CNS metastases and who are 
off all corticosteroids for ≥ 4 weeks are eligible. 
• 
History of clinically significant or uncontrolled cardiac disease, including recent history (within 
6 months) of unstable angina, acute myocardial infarction, New York Heart Association Class III or 
IV congestive heart failure, or arrhythmia requiring therapy. 
• 
Pregnant or nursing women or subjects expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through completion of safety follow-up visit. 
• 
Known additional malignancy that is progressing or requires active treatment.  Exceptions include 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that 
has undergone potentially curative therapy. 
• 
Chronic or current active infectious disease requiring systemic antibiotics or antifungal or antiviral 
treatment, unless approved by sponsor medical monitor. 
• 
Current use of prohibited medications. 
• 
Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of the 
investigator. 
• 
Inadequate recovery from toxicity and/or complications from a major surgery before starting therapy. 
• 
Any condition that would, in the investigator's judgment, interfere with full participation in the study, 
including administration of study drug and attending required study visits; pose a significant risk to 
the subject; or interfere with interpretation of study data. 
• 
Inability to comprehend or unwilling to sign the informed consent form (ICF). 


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• 
Inability to swallow and retain oral medication. 
• 
Evidence of active hepatitis B virus or hepatitis C virus infection. 
• 
TG E/E1:  Active, known or suspected autoimmune disease.  Subjects are permitted to enroll with 
vitiligo, diabetes mellitus, resolved childhood asthma/atopy, residual hypothyroidism due to an 
autoimmune immune condition only requiring thyroid hormone replacement, psoriasis not requiring 
systemic treatment, or conditions not expected to recur in the absence of an external trigger. 
• 
TG C/C1:  known allergy or reaction to any component of ATRA. 
• 
TG D/D1:  known allergy or reaction to any component of azacitidine.   
• 
TG E/E1:  known allergy or reaction to any component of nivolumab. 
INCB059872/Study Drug, Dosage, and Mode of Administration: 
INCB059872 will be self-administered orally QOD or QD on a 28-day cycle.  In each cycle of the QOD 
dosing schedule, subjects should receive 14 doses of INCB059872.  In each cycle of the QD dosing 
schedule, subjects should receive 28 doses of INCB059872.  Tablets will be available in 1 mg strength.  
The initial starting dose for Part 1 will be 2 mg QOD.  The initial starting dose for other parts of the study 
will be based on the aggregate data review of Part 1. 
For QOD administration, if a dose is missed by more than 24 hours, the subject should skip the dose and 
take the next scheduled dose at the usual time.  For QD administration, if a dose is missed by more than 
4 hours, the subject should skip the dose and take the next scheduled dose at the usual time.  INCB059872 
tablet should be taken on an empty stomach if possible (refrain from food consumption during the period 
2 hours before and 1 hour after taking INCB059872).  For subjects participating in the food-effect portion 
of the study in Part 2, TG B1, a high-fat, high-calorie meal will be consumed within 30 minutes before 
taking INCB059872 on Cycle 2 Day 1. 
Alternative dosing regimens (ie, once daily) may be explored based on emerging PK/
 and safety 
data. 
Reference Therapy, Dosage, and Mode of Administration:   
Conventional regimens of the standard of care combination agents or nivolumab will be used throughout 
Parts 3 and 4 of the study.  Tretinoin capsules (ATRA) will be administered as an open-label commercial 
product at a starting dose of 45 mg/m2 per day as 2 evenly divided doses.  
Azacitidine will be administered as an open-label commercial product at a starting dose of 75 mg/m2 
subcutaneously or intravenously for 7 days during the first 9-day or less period (ie, a 2-day break allowed 
on weekend, if needed) of each 28-day treatment cycle.  
Nivolumab will be administered at a dose of 3 mg/kg as an intravenous infusion over 60 minutes every 
2 weeks.  
Premedications should be administered per standard-of-care guidelines. 
Study Schedule/Procedures: 
Subjects will have regularly scheduled study visits at the clinical site as part of a 28-day cycle.  Study 
visits are as follows: 
• 
Screening:  Day -28 through Day -1 
• 
Cycle 1:  Day 1, 4, 8, 11, 15, 22 
• 
Subsequent cycles:  Day 1 (± 2 days; note that Day 1 must be a day with INCB059872 treatment) and 
Day 15 (± 2 days) 
• 
End of treatment:  Subjects must be seen and have blood drawn 2 times per week for 2 weeks after 
last dose.  
• 
Safety follow-up:  30 days (+ 5 days) after the EOT visit or last dose of study drug if EOT visit not 
performed (or until toxicities resolve, return to baseline, are deemed irreversible, or the subject 
receives another anticancer therapy, whichever is shorter). 




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Combination TG E1 will be terminated for futility if ≤ 1 of the 15 subjects responded (ie, CR or PR) 
based on assessments provided by investigator. 
Data Monitoring Committee:   
No independent Data Monitoring Committee is planned for this study.  Decisions to continue the 
enrollment in subsequent dose level cohort, dose level to be tested, as well as number of subjects to be 
evaluated, will be made after the appropriate data are collected and reviewed by sponsor representatives 
(eg, medical monitor) and investigators or designees.  The group of sponsor representatives and 
investigators or designees will convene regularly (eg, once weekly) or ad hoc for specific discussions.  
Meeting minutes will be documented. 
An internal Data Safety Monitoring Board (iDSMB) will review safety data at regular intervals 
throughout the study.  The frequency of meetings will be contingent upon enrollment and availability of 
safety data for analysis and review.  Details regarding membership, roles, and responsibilities of the 
committee are specified in the iDSMB charter. 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................20 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Background .................................................................................................................23 
1.1.1. 
Lysine Demethylase 1 Inhibitor in Oncology .............................................................23 
1.2. 
Overview of INCB059872 ..........................................................................................24 
1.2.1. 
Pharmacology of INCB059872 ..................................................................................24 
1.2.2. 
Nonclinical Drug Metabolism and Pharmacokinetics of INCB059872 .....................26 
1.3. 
Overview of Conventional Care Agents .....................................................................27 
1.3.1. 
All-Trans Retinoic Acid .............................................................................................27 
1.3.2. 
Azacitidine ..................................................................................................................27 
1.3.3. 
Overview of Nivolumab .............................................................................................28 
1.4. 
Study Rationale ...........................................................................................................29 
1.5. 
Justification of Route, Dose Regimen, and Treatment Period ....................................29 
1.6. 
Potential Risks and Benefits of the Treatment Regimen ............................................30 
1.6.1. 
Potential Risks of INCB059872 Based on Preclinical Safety ....................................30 
1.6.2. 
Clinical Experience With INCB059872 .....................................................................31 
1.6.3. 
Potential Risks of All-Trans Retinoic Acid ................................................................34 
1.6.4. 
Potential Risks of Azacitidine ....................................................................................35 
1.6.5. 
Potential Risks Associated With Nivolumab ..............................................................35 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................36 
2.1. 
Study Objectives .........................................................................................................36 
2.1.1. 
Primary Objectives .....................................................................................................36 
2.1.2. 
Secondary Objectives .................................................................................................36 
 
 ...............................................................................................36 
2.2. 
Study Endpoints ..........................................................................................................37 
2.2.1. 
Primary Endpoints ......................................................................................................37 
2.2.2. 
Secondary Endpoints ..................................................................................................37 
 
 ................................................................................................38 
3. 
SUBJECT ELIGIBILITY ...........................................................................................39 
3.1. 
Subject Inclusion Criteria ...........................................................................................39 


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3.2. 
Subject Exclusion Criteria ..........................................................................................41 
4. 
INVESTIGATIONAL PLAN .....................................................................................43 
4.1. 
Overall Study Design ..................................................................................................43 
4.1.1. 
Monotherapy Dose Escalation (Part 1) .......................................................................43 
4.1.2. 
Monotherapy Dose Expansion (Part 2) .......................................................................44 
4.1.3. 
Combination Dose-Finding (Part 3) ...........................................................................44 
4.1.4. 
Combination Dose Expansion (Part 4) .......................................................................45 
4.2. 
Measures Taken to Avoid Bias ...................................................................................46 
4.3. 
Number of Subjects ....................................................................................................47 
4.3.1. 
Planned Number of Subjects ......................................................................................47 
4.3.2. 
Replacement of Subjects .............................................................................................47 
4.4. 
Duration of Treatment and Subject Participation .......................................................47 
4.5. 
Overall Study Duration ...............................................................................................47 
4.6. 
Study Termination ......................................................................................................48 
5. 
TREATMENT ............................................................................................................48 
5.1. 
Treatment Assignment ................................................................................................48 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................48 
5.1.2. 
Randomization and Blinding ......................................................................................49 
5.2. 
Study Drug Materials and Management .....................................................................49 
5.2.1. 
INCB059872 ...............................................................................................................49 
5.2.1.1. 
Supply, Packaging, and Labeling ...............................................................................49 
5.2.1.2. 
Storage ........................................................................................................................49 
5.2.1.3. 
Instruction to Subjects for Handling Study Drug (INCB059872) ..............................49 
5.2.2. 
Conventional Care Drugs ...........................................................................................50 
5.2.2.1. 
Tretinoin Capsules ......................................................................................................50 
5.2.2.2. 
Azacitidine ..................................................................................................................50 
5.2.2.3. 
Nivolumab ..................................................................................................................50 
5.3. 
Treatment Compliance ................................................................................................50 
5.3.1. 
Treatment Compliance With INCB059872 ................................................................50 
5.3.2. 
Treatment Compliance With ATRA, Azacitidine, and Nivolumab ...........................51 
5.4. 
Treatment Interruptions and Adjustments ..................................................................51 
5.4.1. 
Dose Modifications of INCB059872 ..........................................................................51 
5.4.2. 
Dose Modifications of Conventional Care Agents .....................................................51 


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5.4.3. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose of 
INCB059872 ...............................................................................................................52 
5.4.4. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................53 
5.4.5. 
Follow-Up of Dose-Limiting Toxicities .....................................................................53 
5.4.6. 
Procedures for Cohort Review and Dose Escalation ..................................................53 
5.4.7. 
Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB059872 ...............................................................................................................53 
5.4.8. 
Management of Immune-Related Adverse Events .....................................................55 
5.4.9. 
Management of Infusion Reactions ............................................................................57 
5.4.10. 
Criteria for Permanent Discontinuation of INCB059872 ...........................................57 
5.4.11. 
Criteria and Procedures for Dose Increases of INCB059872 .....................................57 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................58 
5.5.1. 
Withdrawal Criteria ....................................................................................................58 
5.5.2. 
Withdrawal Procedures ...............................................................................................58 
5.6. 
Concomitant Medications ...........................................................................................59 
5.6.1. 
Restricted Medications ...............................................................................................59 
5.6.2. 
Prohibited Medications ...............................................................................................59 
6. 
STUDY ASSESSMENTS ..........................................................................................59 
6.1. 
Screening ....................................................................................................................66 
6.2. 
Treatment ....................................................................................................................66 
6.3. 
End of Treatment ........................................................................................................66 
6.4. 
Follow-Up ...................................................................................................................67 
6.4.1. 
Safety Follow-Up ........................................................................................................67 
6.4.2. 
Disease Status Follow-Up ...........................................................................................67 
6.5. 
End of Study ...............................................................................................................67 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................68 
7.1. 
Administration of Informed Consent Form ................................................................68 
7.2. 
Interactive Response Technology Procedure ..............................................................68 
7.3. 
Demography and Medical History ..............................................................................68 
7.3.1. 
Demographics and General Medical History .............................................................68 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................68 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................68 
7.5. 
Safety Assessments .....................................................................................................68 


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7.5.1. 
Adverse Events ...........................................................................................................68 
7.5.2. 
Physical Examinations ................................................................................................69 
7.5.2.1. 
Comprehensive Physical Examination .......................................................................69 
7.5.2.2. 
Targeted Physical Examination ..................................................................................69 
7.5.3. 
Vital Signs ..................................................................................................................69 
7.5.4. 
Electrocardiograms .....................................................................................................69 
7.5.5. 
Laboratory Assessments .............................................................................................70 
7.5.5.1. 
Pregnancy Testing ......................................................................................................70 
7.6. 
Efficacy Assessments .................................................................................................70 
 
 .......................72 
 
 ......................................................................................72 
 
 ............................................................72 
7.8. 
Pharmacokinetic Assessments ....................................................................................72 
7.8.1. 
Blood Sample Collection ............................................................................................72 
7.8.1.1. 
Timed Pharmacokinetic Testing .................................................................................72 
7.8.2. 
Urine Sample Collection .............................................................................................73 
7.8.3. 
Bioanalytical Methodology and Analysis ...................................................................73 
7.8.4. 
Food-Effect Pharmacokinetic Testing ........................................................................73 
 
 .................................................................................74 
7.10. 
Other Study Procedures ..............................................................................................74 
7.10.1. 
Distribution of Subject Reminder Cards .....................................................................74 
8. 
SAFETY MONITORING AND REPORTING .........................................................75 
8.1. 
Adverse Events ...........................................................................................................75 
8.1.1. 
Definitions ..................................................................................................................75 
8.1.2. 
Reporting ....................................................................................................................75 
8.2. 
Laboratory Test Abnormalities ...................................................................................77 
8.3. 
Serious Adverse Events ..............................................................................................77 
8.3.1. 
Definitions ..................................................................................................................77 
8.3.2. 
Reporting ....................................................................................................................78 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................78 
8.5. 
Pregnancy ...................................................................................................................79 
8.6. 
Warnings and Precautions ..........................................................................................79 
8.7. 
Data Monitoring Committee .......................................................................................79 


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8.8. 
Product Complaints ....................................................................................................80 
9. 
STATISTICS ..............................................................................................................80 
9.1. 
Study Populations .......................................................................................................80 
9.2. 
Selection of Sample Size ............................................................................................80 
9.3. 
Level of Significance ..................................................................................................81 
9.4. 
Statistical Analyses .....................................................................................................81 
9.4.1. 
Efficacy Analyses .......................................................................................................81 
 
 ............................................................................................................81 
9.4.3. 
Safety Analyses ..........................................................................................................81 
9.4.3.1. 
Adverse Events ...........................................................................................................81 
9.4.3.2. 
Clinical Laboratory Tests ...........................................................................................82 
9.4.3.3. 
Vital Signs ..................................................................................................................82 
9.4.3.4. 
Electrocardiograms .....................................................................................................82 
9.4.3.5. 
Adverse Events of Special Interest .............................................................................83 
9.4.4. 
Pharmacokinetic Analysis ..........................................................................................83 
 
 ....................................................................................................83 
9.5. 
Analyses for the Data Monitoring Committee ............................................................83 
9.6. 
Interim Analysis ..........................................................................................................83 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................84 
10.1. 
Investigator Responsibilities .......................................................................................84 
10.2. 
Accountability, Handling, and Disposal of Study Drug .............................................85 
10.3. 
Data Management .......................................................................................................86 
10.4. 
Data Privacy and Confidentiality of Study Records ...................................................86 
10.5. 
Financial Disclosure ...................................................................................................87 
10.6. 
Publication Policy .......................................................................................................87 
11. 
REFERENCES ...........................................................................................................88 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................93 
APPENDIX B. POTENT CYP2D6 INHIBITORS AND POTENT CYP3A4 
INHIBITORS AND INDUCERS ...............................................................................94 
APPENDIX C. PHARMACOKINETIC ANALYTICAL PARAMETERS...............................96 
APPENDIX D. INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR ACUTE MYELOID LEUKEMIA .....................................................................97 






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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
APL 
acute promyelocytic leukemia 
AST 
aspartate aminotransferase 
ATRA 
all-trans retinoic acid 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CRi 
complete remission with incomplete hematologic recovery 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNMT1 
DNA methyltransferase 1 
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
median effective dose 
EOT 
end of treatment 
FAB 
French-American-British 
FAD 
flavin adenine dinucleotide 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDAC 
histone deacetylase 
hERG 
human ether-à-go-go-related gene 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HNSTD 
highest non−severely toxic dose 
HR 
hazard ratio 
IC50 
half maximal inhibition 


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Abbreviation 
Definition 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
iDSMB 
internal data safety monitoring board 
IEC 
independent ethics committee 
IN 
Investigator Notification 
IPSS-R 
Revised International Prognostic Scoring System 
IRB 
institutional review board 
IRT 
Interactive Response Technology 
IV 
intravenous 
L-DAC 
low-dose cytarabine 
LSC 
leukemia stem cell 
LSD1 
lysine-specific demethylase 1 
MAO 
monoamine oxidase 
MDS 
myelodysplastic syndrome 
MDS-EB 
myelodysplastic syndrome with excess blasts 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis  
MLFS 
morphologic leukemia-free state 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NSCLC 
non–small cell lung cancer 
ORR 
objective response rate 
PD 
pharmacodynamic 
PD-1 
programmed cell death-1 
PD-L1 
programmed death ligand 1 
PET-MF 
post–essential thrombocythemia myelofibrosis 
PK 
pharmacokinetic 
PMF 
primary myelofibrosis 
PPV-MF 
post–polycythemia vera myelofibrosis 
PR 
partial response 
Pro-GRP 
pro−gastrin-releasing peptide 
Q2W 
every 2 weeks 
QD 
once daily 
QOD 
every other day 


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Abbreviation 
Definition 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
subcutaneous 
SCLC 
small cell lung cancer 
STD10 
severely toxic dose in 10% 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TG 
Treatment Group 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1. 
Background 
INCB059872 is a covalent flavin adenine dinucleotide (FAD)-directed inhibitor of 
lysine-specific demethylase 1 (LSD1) that is proposed for the treatment of advance 
malignancies.  LSD1 regulates gene expression epigenetically by removing methylation marks 
from lysine 4 or 9 of histone H3.  Target genes of LSD1 are involved in may biological 
processes, including cell growth, survival, differentiation, and stem cell homeostasis.  Studies 
have shown that deregulated LSD1 activity is associated with human diseases, including cancer, 
where overexpression of LSD1 is frequently associated with poor clinical outcomes.  Refer to the 
Investigator's Brochure (IB) for additional background information on INCB059872. 
1.1.1. 
Lysine Demethylase 1 Inhibitor in Oncology 
Epigenetic modifications significantly contribute to the development of various cancers 
(Dawson and Kouzarides 2012).  Analyses of cancer genomes have revealed that multiple 
epigenetic regulatory genes are often overexpressed or mutated in a variety of cancers 
(Shen and Laird 2013).  One particular epigenetic enzyme that is associated with human cancer 
is LSD1, the first discovered histone demethylase and a key epigenetic regulator of chromatin 
architecture (Shi et al 2004).  Methylated histone marks on H3K4 and H3K9 are coupled with 
transcriptional activation and repression, respectively.  As part of the corepressor complex (eg, as 
corepressor of RE1 silencing transcription factor) (Stavropoulos et al 2006), LSD1 has been 
reported to demethylate H3K4 and represses transcription, whereas LSD1 in the nuclear 
hormone receptor complex (eg, androgen receptor) may demethylate H3K9 to activate gene 
expression (Metzger et al 2005).  This suggests that the substrate specificity of LSD1 can be 
determined by associated factors, thereby regulating alternative gene expression in a 
context-dependent manner.  In addition to histone proteins, LSD1 demethylates several 
nonhistone proteins critical in the regulation of cell growth, differentiation, and survival 
pathways.  These include p53 (Huang et al 2007), E2F (Kontaki and Talianidis 2010), STAT3 
(Yang et al 2010), Tat (Sakane et al 2011), and myosin phosphatase target subunit 1 
(Cho et al 2011).  These findings suggest the potential for additional oncogenic roles of LSD1 
beyond its epigenetic role in regulating chromatin remodeling.  LSD1 also associates with other 
epigenetic regulators, such as DNA methyltransferase 1 (DNMT1) (Wang et al 2009) and histone 
deacetylase (HDAC) (You et al 2001).  These associations augment the activities of DNMT or 
HDACs.  LSD1 inhibitors may therefore potentiate the effects of HDAC or DNMT inhibitors 
(Han et al 2013, Singh et al 2011). 
LSD1 contributes to a variety of biological processes, including the regulation of cell 
proliferation, the epithelial-mesenchymal transition, cellular transformation of somatic cells, and 
self-renewal and differentiation, the latter impacting stem cell biology both in embryonic stem 
cells and in cancer stem cells (Chen et al 2012, Adamo et al 2011).  These cancer stem cells may 
render cancer cells resistant to conventional therapies, such as chemotherapy or radiotherapy, 
and promote tumor recurrence after treatment (Beck and Blanpain 2013).  In this regard, LSD1 
functions in maintaining an undifferentiated tumor initiating or cancer stem cell phenotype in a 
spectrum of cancers (Wang et al 2011, Zhang et al 2013).  Notably, acute myeloid 


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leukemia (AML) cells retain a less differentiated stem cell−like phenotype or leukemia stem 
cell (LSC) potential.  Genome-wide gene expression analyses have revealed that LSD1 regulates 
a subset of genes involved in multiple oncogenic programs to maintain the LSC phenotype in 
AML, and inhibition of LSD1 has demonstrated therapeutic benefit in preclinical models of 
murine and human AML (Harris et al 2012, Schenk et al 2012).  A variety of additional 
hematologic cancers also overexpress LSD1, including significant subsets of high-grade B-cell 
and T-cell non-Hodgkin's lymphomas and Hodgkin's lymphomas (Niebel et al 2014), although 
the therapeutic benefit of LSD1 inhibition in these cancers has not yet been evaluated.  
In addition to hematologic malignancies, overexpression of LSD1 is frequently observed in 
many types of solid tumors, and its expression is associated with a more clinically aggressive 
phenotype and poor prognostic outcome.  Cancers in which overexpression of LSD1 has been 
documented include  bladder cancer (Hayami et al 2011), small cell lung cancer (SCLC) 
(Mohammad et al 2015), non-SCLC (Lv et al 2012), breast cancer (Lim et al 2010), ovarian 
cancer (Konovalov and Garcia-Bassets 2013), glioma (Sareddy et al 2013), colorectal cancer 
(Hayami et al 2011, Ding et al 2013), a variety of sarcomas (Bennani-Baiti et al 2012),  
neuroblastoma (Schulte et al 2009), prostate cancer (Suikki et al 2010), esophageal squamous 
cell cancer (Yu et al 2013), papillary thyroid cancer (Kong et al 2013), and Ewing sarcoma 
(Sankar et al 2014).  In these studies, either genetic knockdown of LSD1 expression or treatment 
with small-molecule inhibitors of LSD1 resulted in decreased cancer cell proliferation and/or 
induction of apoptosis both in vitro and in vivo.  These findings suggest a potential therapeutic 
benefit of LSD1 inhibitors in a broad range of cancers beyond AML. 
1.2. 
Overview of INCB059872 
INCB059872 is a cyclopropylamine derivative.  Other cyclopropylamine analogs covalently 
modify the cofactor FAD to inhibit the enzymatic activity of LSD1 (Ueda et al 2009, 
Suzuki and Miyata 2011).  INCB059872 potently inhibited the enzymatic activity of LSD1, with 
an average half maximal inhibition (IC50) value of 18 ± 3 nM.  INCB059872 was highly specific 
for LSD1, as it did not inhibit LSD2 at 5 μM, nor monoamine oxidase-A (MAO-A) and MOA-B 
at concentrations as high as 20 μM. 
1.2.1. 
Pharmacology of INCB059872 
In enzyme-based assays, INCB059872 potently inhibited LSD1, with IC50 values of 18 ± 3 
(average ± SD), while INCB059872 did not inhibit LSD2 and MAO-A/B.  Both biochemical and 
in vitro pharmacodynamic (PD) assays consistently demonstrated that INCB059872 was a 
FAD-directed inhibitor of LSD1.  In cellular assays, INCB059872 inhibition resulted in the 
upregulated expression of the differentiation markers, CD86 and CD11b, in multiple AML cell 
lines and human primary AML cells across the different French-American-British (FAB) 
subtypes.  Using the human acute monocytic leukemia cell line, THP-1, spiked into human 
whole blood to estimate potency in the presence of human serum proteins, INCB059872 induced 
CD86 protein, with a half maximal effective concentration (EC50) value of 23 ± 8 nM.  Human 
AML cell lines showed various degrees of sensitivity to INCB059872 in cell proliferation assays, 
with EC50 values ranging from 17 to 314 nM, and treated cells underwent G1 cell cycle arrest.  
The antitumor activity of INCB059872 was further evaluated in human primary AML cells 
ex vivo. 


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The proliferation of a number of SCLC cell lines was also inhibited by INCB059872, with IC50 
values ranging from 47 to 377 nM.  Nontumorigenic cells, by contrast, were significantly less 
sensitive to INCB059872, with IC50 values > 10 μM in interleukin-2–stimulated T cells from 
normal donors.  INCB059872 also demonstrated no significant effects on cellular proliferation or 
survival in HEK293 human embryonic kidney cells at concentrations up to 20 μM.  These data 
demonstrate that INCB059872 inhibits LSD1 activity in vitro, and that inhibition of LSD1 results 
in the growth arrest and differentiation of cancer cells compared to normal cells.  In vitro PD 
assays for LSD1 inhibition in AML cells showed that induction of the CD86 myeloid 
differentiation marker by INCB059872 was sustained for 5 days after removal of INCB059872 
in culture.  These results confirm that INCB059872 is a covalent FAD-directed inhibitor in cells. 
In vivo, oral administration of INCB059872 demonstrated PD activity and efficacy in several 
models of human and murine AML and in human SCLC xenograft models in mice.  Tumor PD 
analyses conducted in both the Molm-13 human AML systemic xenograft model and the THP-1 
human AML subcutaneous (SC) xenograft model demonstrated induction of CD86 and CD11b 
expression, consistent with in vitro data.  In these models, the PD activity of INCB059872 was 
marginal at a dose of 0.1 mg/kg and maximal at doses ≥ 0.5 mg/kg, demonstrating an in vivo 
median effective dose (ED50) for CD86 induction of approximately 0.3 mg/kg.  In addition, 
tumor PD responses were sustained for over 48 to 72 hours after dosing, suggesting a possible 
irreversible inhibition of LSD1 by covalent modification of FAD.  Consistent with in vivo PD 
studies, once daily (QD) doses of INCB059872 greater than the in vivo ED50 showed significant 
and comparable antitumor effects in human AML cell line xenograft models, while doses less 
than the in vivo ED50 exhibited either no efficacy or marginal tumor growth inhibition in these 
tumor xenograft models.  Similar effects of QD dosing regimens on tumor growth inhibition 
were observed in human SCLC tumor xenograft models (NCI-H562 and NCI-H1417), with a 
marked reduction in plasma pro−gastrin-releasing peptide (Pro-GRP) levels in 
INCB059872-treated NCI-H1417 tumor-bearing mice relative to vehicle controls.  Alternative 
oral dosing regimens of INCB059872, including every other day (QOD), generally were 
comparably efficacious as a QD dosing regimen in these AML and SCLC xenograft models, 
consistent with the prolonged PD effects associated with INCB059872. 
In the MLL-AF9 murine leukemia engraftment model in C57BL/6mice, the median survival of 
leukemic animals was significantly prolonged in mice receiving doses greater than or equal to a 
pharmacodynamically active oral dose of INCB059872 over a 14-day dosing period.  These 
survival effects of INCB059872 in the MLL-AF9 murine AML model were associated with an 
expansion of the percentage of normal bone marrow cells, a reduction in LSCs, a decrease in the 
number of AML blast cells, the induction of myeloid differentiation, and a normalization of 
hematologic parameters to those of nonleukemic mice. 
INCB059872 was evaluated against a panel of targets to assess the potential for unintended 
pharmacological activity.  There was no significant cross-reactivity against any of the 55 in vitro 
binding assays in which INCB059872 was tested.  INCB059872 was evaluated in kinase 
profiling assays at concentrations up to 20 μM, and no inhibitory activity for any of the 
56 kinases tested was noted.  INCB059872 was evaluated against a panel of selected ion cardiac 
channels (L-type calcium, human ether-à-go-go-related gene [hERG] potassium, hKir2.1 
potassium, hKvLQT1/hminK potassium, hKv4.3 potassium, hNav1.5 sodium) in an automatic 
parallel patch clamp system; none of these channels was inhibited by more than 25% at 30 μM.  


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INCB059872 was also evaluated in the Good Laboratory Practice (GLP) in vitro hERG channel 
assay.  The IC50 for hERG inhibition was 149.3 μM, which is > 4000-fold higher than the 
anticipated steady-state free Cmax in humans.  Collectively, these in vitro and functional results 
support the conclusion that the risk of unintended pharmacological activity is expected to be low. 
1.2.2. 
Nonclinical Drug Metabolism and Pharmacokinetics of INCB059872 
The absorption, distribution, metabolism, and excretion of INCB059872, a covalent 
FAD-directed inhibitor for LSD1, have been characterized in rats, dogs, and monkeys.  
Following intravenous (IV) administration, the systemic clearance was low in monkeys and dogs 
(23% and 29% of hepatic blood flow, respectively) and moderate in rats (37% of hepatic blood 
flow).  The clearance mechanisms of INCB059872 include both cytochrome P450 
(CYP)-dependent metabolism and non−enzyme-dependent catabolism.  The administered dose 
excreted in urine as intact INCB059872 varied from approximately 9.9% in rats to 7.8% in dogs 
and 3.5% in monkeys, indicating renal clearance as minor elimination pathways.  INCB059872 
exhibited a moderate steady-state volume of distribution in all 3 species (0.9-1.5 L/kg), 
suggesting moderate distribution.  After oral administration, oral bioavailability was moderate in 
monkeys (37%) but high in rats (70%) and dogs (100%).  The terminal elimination half-life was 
1.0 hour in rats, 1.2 hours in dogs, and 3.3 hours in monkeys.  Despite a short half-life, sustained 
pharmacological activity was observed in vitro and in vivo, presumably a result of irreversible or 
covalent inhibition of LSD1, ie, a pharmacokinetic (PK)-PD divergence is expected for this 
mode of inhibition by INCB059872.  Based on allometric scaling, the terminal elimination 
half-life in human is projected to be approximately 3 hours, and the oral bioavailability is 
projected to be 70%.  Significant antitumor effects were observed in mice when peak plasma 
concentration exceeded the EC50 in the whole blood assay with either QD or QOD dosing.  
Based on preclinical PK-PD relationship assessment, the projected clinical dose for efficacy in 
patients is 2 mg QOD, which is expected to provide plasma concentrations exceeding the EC50 of 
0.023 μM (based on THP-1 spiked whole blood assay with CD86 induction) for 2 hours, the total 
steady-state plasma AUC0-48 and Cmax is estimated to be approximately 0.2 μM∙h and 0.05 μM, 
respectively. 
INCB059872 exhibits moderate in vitro permeability across Caco-2 monolayers 
(3.8 × 10-6 cm/sec) and high aqueous solubility (20 mg/mL).  In vitro transport studies indicate 
that INCB059872 is a weak substrate of efflux transporter P-glycoprotein, but not of breast 
cancer resistance protein.  INCB059872 has limited penetration across the rat blood-brain 
barrier, with a steady-state brain-to-plasma ratio of 0.1.  In vitro human protein binding of 
INCB059872 was low (unbound fraction of 73.5%), similar to that in preclinical species. 
INCB059872 did not inhibit hepatic uptake transporters (OATP1B1 and OATP1B3).  While 
INCB059872 was a weak inhibitor of renal uptake transporters (OCT2, OAT1, and OAT3), no 
drug-drug interactions are expected based on the projected steady-state human plasma Cmax 
value.  Moreover, INCB059872 did not inhibit P-glycoprotein or breast cancer resistance protein 
efflux transporters.  Reaction phenotyping using recombinant human CYPs indicated that 
INCB059872 was metabolized by CYP2D6 and CYP3A4, and therefore it is possible that the PK 
of INCB059872 will be affected by coadministration of potent CYP2D6 inhibitors or CYP3A4 
inhibitors/inducers.  INCB059872 is not an inhibitor of the 6 CYPs evaluated, and therefore no 
drug-drug interaction is expected based on INCB059872 CYP inhibitory activities at 
pharmacologically relevant exposures of INCB059872.  The metabolism profile of INCB059872 


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in rat, dog, monkey, and human in vitro liver preparations was qualitatively similar, with M1 
(INCB061984) generated at levels > 10% of INCB059872 across all species.  However, M1 was 
also generated in buffer or buffer fortified with rat bile, bilirubin, and FAD, indicating that 
nonenzymatic mechanisms are also involved in the formation of M1.  There was no evidence of 
any human-specific metabolites.  In vivo, parent INCB059872 was the most abundant component 
in rat and dog plasma, and M1 (INCB061984) was identified in rat plasma (approximately 4% of 
INCB059872) and dog plasma (approximately 40% of INCB059872). 
1.3. 
Overview of Conventional Care Agents 
1.3.1. 
All-Trans Retinoic Acid 
All-trans retinoic acid (ATRA) is the acid form of vitamin A.  It induces cell differentiation and 
decreases proliferation of acute promyelocytic leukemia (APL) cells by interrupting oncogenic 
transcriptional activities of retinoic acid receptor-alpha.  It is currently indicated for use in 
patients with acute APL (Vesanoid PI 2010).  Monotherapy of ATRA is associated with high 
complete remission rate, ranging from 70% to 85% (Huang et al 1988, Tallman et al 1997, 
Tallman et al 2002). 
The intended use of ATRA in the proposed study is to assess safety and preliminary clinical 
benefit of the combination therapy with INCB059872.  ATRA-based therapies have shown 
utility in clinical studies (Hoffman et al 2012).  However, ATRA-based therapies have not been 
effective in non-APL AML, but the combination of ATRA and tranylcypromine (a nonspecific 
LSD1 inhibitor) unlocked the ATRA-driven therapeutic response and diminished the 
engraftment of primary human non-APL AML (Schenk et al 2012).  Synergistic inhibition of 
leukemia cell viability was observed when ATRA was combined with INCB059872 in 
preclinical study.  ATRA in combination with other agents, particularly those targeting 
epigenetics, has been shown to be potentially beneficial in myelodysplastic syndrome (MDS; 
Kuendgen et al 2005).  ATRA metabolism is not affected by P450 enzyme, and its metabolic 
drug-drug interaction with INCB059872 is not anticipated. 
1.3.2. 
Azacitidine 
Azacitidine is a nucleoside metabolic inhibitor that is approved by the FDA and EMA for the 
treatment of patients with several different subtypes of MDS (Vidaza PI 2014).  Azacitidine is 
thought to have 2 main mechanisms of antineoplastic action:  cytotoxicity, resulting from 
incorporation into RNA and DNA, and DNA hypomethylation, restoring normal growth control 
and differentiation in hematopoietic cells (Kaminskas et al 2005).  Several clinical studies have 
demonstrated the efficacy of azacitidine in MDS.  In a Phase 2 clinical study evaluating 
azacitidine versus supportive care in high-risk MDS, Silverman et al (2002) reported a 60% 
overall response rate (including hematologic improvement) for azacitidine as compared with 5% 
receiving supportive care.  Additionally, a Phase 3 study (Al-Ali et al 2012, Fenaux et al 2009) 
evaluating azacitidine versus conventional care in higher risk MDS revealed superior rates of 
hematologic response (29% vs 12%) and hematologic improvement (49% vs 29%) in the 
azacitidine group. 


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Azacitidine is recommended as a low-intensity induction therapy in AML, primarily in patients 
who are unfit for high- or intermediate-intensity regimens, especially in patients ≥ 60 years 
(NCCN 2017).  In the AZA-AML-001 study (Dombret et al 2015), azacitidine (n = 241) was 
compared with conventional therapies (best supportive care, low-dose cytarabine [L-DAC], and 
standard induction therapy; n = 247) in patients age ≥ 65 years with newly diagnosed AML with 
> 30% bone marrow blasts.  Median OS was improved (10.4 months vs 6.5 months, hazard ratio 
[HR] = 0.85, p = 0.10009) but did not reach statistical significance; mOS did reach statistical 
significance (12.1 months vs 6.9 months, HR = 0.76, p = 0.019) when the patients were censored 
at the start of subsequent AML therapy by prespecified sensitivity analysis.  Also, patients with 
poor-risk cytogenetics (HR = 0.68) and with myelodysplasia-related changes (HR = 0.69) 
benefited significantly from azacitidine.  Even though the study was not powered to compare 
azacitidine with individual conventional therapy, the OS of patients treated with azacitidine or 
L-DAC (n = 154 vs 158) did not differ significantly, and comparable survival rates were also 
observed comparing azacitidine with standard induction therapy (n = 43 vs 44), and azacitidine is 
superior to best supportive care by post hoc analysis.  Azacitidine achieved a complete response 
(CR) of 19.5% versus 21.9% with conventional therapies, CR/complete remission with 
incomplete hematologic recovery (CRi) 27.8% versus 25.1%.  The most common 
treatment-emergent adverse events (TEAEs) ≥ G3 occurring in ≥ 20% of patients in the 
azacitidine arm were febrile neutropenia, neutropenia, thrombocytopenia, pneumonia, and 
anemia.  Although there has been limited investigation into the use of azacitidine in 
relapsed/refractory AML, Al-Ali et al (2012) reported a 10% overall response rate (including 
hematologic improvement) in subjects who were resistant to primary chemotherapy.  Azacitidine 
undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase.  
Cytochrome P450 enzyme induction or inhibition by azacitidine at clinically achievable plasma 
concentrations is unlikely, and metabolic drug-drug interaction between INCB059872 and 
azacitidine is not anticipated. 
1.3.3. 
Overview of Nivolumab 
Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that selectively inhibits 
programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor to block the ligands 
programmed death ligand 1 (PD-L1) and PD-L2 from binding.  The negative PD-1 receptor 
signaling that regulates T-cell activation and proliferation is therefore disrupted 
(Robert et al 2015).  This releases PD-1 pathway-mediated inhibition of the immune response, 
including the antitumor immune response.  Nivolumab has demonstrated activity in early phase 
clinical studies, and Phase 3 studies (including CheckMate 331) are ongoing to evaluate the role 
of nivolumab in the management of relapsed SCLC.  In the Phase 1/2 study CheckMate 032 
(NCT01928394), multiple regimens of nivolumab were evaluated with (n = 61) or without 
(n = 98) ipilimumab in solid tumors, including SCLC.  Durable responses were observed in both 
the nivolumab and the nivolumab + ipilimumab treatment arms in subjects with previously 
treated SCLC regardless of PD-L1 expression (Hellman et al 2017). 
Nivolumab has been approved as monotherapy in the United States for the treatment of patients 
with unresectable or metastatic melanoma, metastatic non–small cell lung cancer (NSCLC), 
advanced renal cell carcinoma (RCC), recurrent or metastatic squamous cell carcinoma of the 
head and neck, and classical Hodgkin lymphoma.  Nivolumab is also approved in combination 
with ipilimumab in patients with unresectable or metastatic melanoma (Opdivo PI 2017).  


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Nivolumab is approved in the European Union as monotherapy or in combination with 
ipilimumab for advanced (unresectable or metastatic) melanoma, as monotherapy for locally 
advanced or metastatic NSCLC after prior chemotherapy, for advanced RCC after prior therapy, 
and for Hodgkin lymphoma following autologous stem cell transplant and treatment with 
brentuximab vedotin (Opdivo SPC 2015). 
1.4. 
Study Rationale 
Cancer has several common characteristic that can be observed across numerous tumor types.  
One common characteristic is the uncontrolled growth and survival of cells and their ability to 
become invasive throughout the body.  LSD1 contributes to tumor development by altering 
epigenetic marks on histones and nonhistone proteins.  Accumulating data have validated that 
either genetic depletion or pharmacological inhibition of LSD1 normalizes oncogenic and cancer 
stem cell−like patterns of gene expression, thereby inducing differentiation programs, decreasing 
cell proliferation, and promoting apoptosis in cancer cells (Harris et al 2012, Schenk et al 2012).  
Therefore, LSD1 inhibitors have the potential to be effective treatments for human cancers with 
aberrant LSD1 activation. 
1.5. 
Justification of Route, Dose Regimen, and Treatment Period 
The starting dose of 2 mg INCB059872 administered QOD orally is proposed for this clinical 
study based on the assessment in GLP toxicology studies. 
INCB059872 will be administered orally QOD or QD over a 28-day cycle.  Part 1 will be a 
dose-escalating design in order to determine the recommended dose(s) of INCB059872 for 
dose-expansion (Part 2). 
The proposed starting dose and schedule of INCB059872 for combination therapy is based on 
preclinical data and emerging clinical data from Part 1 of this study.  To ensure safety of 
INCB059872 in combination with ATRA or azacitidine, the starting dose will be defined as 
2 dose levels below the RP2D from Part 1 (monotherapy dose escalation).  In Part 3, Treatment 
Group (TG) C, INCB059872 will be combined with ATRA (tretinoin) based on recent evidence 
to support synergism between ATRA and LSD1 inhibitors in AML (Schenk et al 2012).  
INCB059872 will be administered at a starting dose of 2 mg QD (2 dose levels below the RP2D) 
in combination with ATRA administered to subjects according to the commercial label 
(Vesanoid 2010), a starting dose of 45 mg/m2 per day administered as 2 evenly divided doses.  
Treatment Group D will combine INCB059872 at a starting dose of 2 mg QD with azacitidine.  
The azacitidine regimen selected for use in this study (dose of 75 mg/m2 SC or IV for 7 days 
during the first 9-day or less period [ie, a 2-day break allowed on weekend, if needed] of each 
28-day treatment cycle) is appropriate to the patient population.  The tolerability and activity of 
this regimen have been established (Lyons et al 2009, García-Delgado et al 2014) as an 
acceptable alternative to the recommended dosing schedule of Days 1 to 7 of each 28-day 
treatment cycle.  If tolerated, TG C and TG D will escalate independently and in parallel until the 
maximum tolerated dose (MTD) or optimal dose(s) of the combination is identified.  If the 
starting dose is not tolerated in any of the combination treatment groups, a lower dose of 
INCB059872 may be explored; otherwise, higher doses found to be safe and tolerable in Part 1 
may be explored. 


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Treatment Group E will combine INCB059872 at the RP2D for solid tumors, 3 mg QOD, in 
combination with nivolumab administered at a dose of 3 mg/kg administered as an IV infusion 
over 60 minutes every 2 weeks.  If the starting dose is not tolerated in any of the combination 
treatment groups, a lower dose of INCB059872 may be explored.  
1.6. 
Potential Risks and Benefits of the Treatment Regimen 
1.6.1. 
Potential Risks of INCB059872 Based on Preclinical Safety 
The nonclinical safety program to support this IND was designed in accordance with ICH S9 for 
advanced cancer.  In pivotal 1-month studies, INCB059872 was administered on a QOD 
regimen.  The doses and dosing regimen for the pivotal GLP studies were selected based on the 
results of previous range-finding studies, where findings in the bone marrow (most prominent: 
abnormal megakaryocytes, decreased megakaryocytes) leading to marked thrombocytopenia 
resulted in subsequent internal and external hemorrhages in rats given ≥ 3 mg/kg (human 
equivalent dose 28.8 mg) QD and in dogs given ≥ 1 mg/kg (human equivalent dose 32.4 mg) 
QD.  These observations suggested that QOD dosing may provide the best option for 
maximizing efficacy (which was similar after QD and QOD dosing regimens in nonclinical 
pharmacology studies) while minimizing toxicity (thrombocytopenia). 
The primary INCB059872 toxicity findings included abnormal megakaryocyte morphology in 
bone marrow, thrombocytopenia, lower red blood parameters and higher reticulocytes, decreased 
mature granulocytes in the bone marrow and neutropenia, and increased monocyte count, and 
were attributed to the pharmacological activity of INCB059872.  These findings were all 
partially or fully reversible after a 4-week recovery period.  The toxicities produced by 
INCB059872 are similar to those described for a conditional LSD1 knockdown model in mice as 
described in literature (Sprüssel et al 2012), where LSD1 deficiency suppressed terminal 
granulopoiesis, erythropoiesis, and platelet production, with the exception of monopoiesis, which 
was promoted.  Sprüssel et al (2012) also showed that peripheral blood granulocytopenia, 
monocytosis, anemia, and thrombocytopenia were reversible after restoration of LSD1 activity. 
During the recovery period, a dose-dependent increase of platelet counts was observed.  The 
maximum increase was about 3-fold compared to baseline values, and the peak time was 
approximately 14 days.  The platelet counts returned to baseline values approximately 28 days 
after INCB059872 treatment cessation. 
One dog administered 1 mg/kg QOD (the highest dose tested) in the 1-month study was 
euthanized; the cause of debilitation was an acute stomach ulcer.  Although similar 
gastrointestinal findings were not observed in other animals, the relationship of this finding to 
INCB059872 could not be excluded. 
There were no off-target toxicities identified in rats.  INCB059872 was negative in the Ames 
mutagenicity assay. 
The starting dose for this study was determined based on pharmacology-driven changes in bone 
marrow and peripheral blood (thrombocytopenia) in rats and dogs.  In the 1-month GLP rat 
study, the severely toxic dose in 10% (STD10) of rodents was above the highest tested dose of 
2.1 mg/kg QOD (12.6 mg/m2 per day).  In the 1-month dog study, because a relationship of the 
acute stomach ulcer to INCB059872 in the animal euthanized in extremis at 1 mg/kg could not 


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be excluded, the highest non−severely toxic dose (HNSTD) was considered to be 0.4 mg/kg 
(8 mg/m2 per day).  The human equivalent dose associated with these doses are 20.2 mg (rat) and 
13 mg (dog); applying a 10-fold safety factor for the rat and 6-fold safety factor in the dog results 
in doses of 2.02 mg and 2.17 mg, respectively.  Thus, a starting dose of 2 mg INCB059872 QOD 
was selected for this study; it is projected to provide exposures above the whole blood EC50 for 
LSD1 inhibition for approximately 2 hours, and thus expected to be pharmacologically active.  
The total AUC0-48 at this dose is projected to be 0.2 µM∙h, which is approximately 2.5-fold lower 
(female dogs) and approximately 18-fold lower (male rats) than the unbound AUC0-24 values for 
the HNSTD in dogs and STD10 in rats, as determined in the 1-month GLP studies. 
Taking into consideration that INCB059872 is a covalent inhibitor of LSD1, Cmax-based safety 
margins should also be considered: at 2 mg QOD, the human steady-state plasma Cmax is 
projected to be approximately 0.05 µM (approximately 0.037 µM, unbound), which is 
approximately 5.8-fold lower (female dog) and approximately 30-fold lower (male rats) than the 
unbound Cmax values for the HNSTD (dogs) and STD10 (rats), as determined in the 1-month GLP 
studies. 
In summary, the starting dose of 2 mg INCB059872 administered QOD is considered to be safe 
for subjects based on the following: 
• This dose was selected based on the overall toxicology assessment, including 
hematologic effects observed at the dog HNSTD and rat STD10, and applying 
appropriate safety factors.  These findings were not associated with evidence of 
extensive hemorrhage. 
• There are adequate exposure-based safety margins projected for both the AUC and 
the Cmax for the starting dose (2 mg). 
• The main toxicities (eg, thrombocytopenia, neutropenia, and anemia) are manageable 
in the clinic. 
• There is evidence for reversibility of all toxicities (eg, hematology and bone marrow 
effects). 
• There is a plan for comprehensive evaluation of safety before each dose escalation. 
1.6.2. 
Clinical Experience With INCB059872 
Part 1 (dose escalation), which determines the starting dose(s) of INCB059872 for dose 
expansion and combination therapy based on the MTD has been open and enrolling since 
MAY 2016.  Both QOD and QD schedules have been explored to collect safety, PK, and PD data 
to establish the optimal dose and schedule for patients with solid tumor and hematological 
malignancies.  The safety was closely monitored by assessments as described in throughout this 
Protocol as well as the frequency, duration, and severity of adverse events (AEs).  Patient status 
was discussed with the treating physicians during regular safety meetings.   
In Part 1, the initial 2 mg QOD dose was well-tolerated by subjects in both treatment groups, 
TG A (AML/MDS) and TGB (solid tumors).  As AML/MDS is a rapidly proliferating disease, it 
was decided in discussion with the participating investigators to use a daily dose (QD) schedule 
for TG A.  A total of 17 subjects have been treated in 4 different cohorts (3 at 2 mg QOD, 6 at 
2 mg QD, 5 at 3 mg QD, and 3 at 4 mg QD) in TG A.  The treatment was generally 


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well-tolerated without any dose-limiting toxicities (DLTs).  The monotherapy recommended 
Phase 2 dose for AML/MDS subjects was determined to be 4 mg QD.  
In TG B, a total of 22 subjects have been treated in 6 different cohorts.  The QOD schedules included 
16 of those patients (3 at 2 mg QOD, 6 at 3 mg QOD, and 7 at 4 mg QOD) in 3 different cohorts.  
The QOD schedule was generally well-tolerated.  There was 1 DLT of Grade 4 thrombocytopenia at 
4 mg QOD.  Further dose escalation was stopped, and the next lower dose cohort of 3 mg QOD was 
expanded to treat a total of 6 patients.  No DLTs or Grade 3/4 thrombocytopenia were reported at 
3 mg QOD, and this dose is the recommended Phase 2 dose for solid tumors.  Dose escalation of the 
QD schedule in TG B has been halted due to 2 DLTs in the 3 mg QD cohort and 1 DLT in the 
2 mg QD cohort; however, a lower dose of 1 mg QD is currently ongoing.  Table 1 summarizes 
the number of subjects who enrolled in Study INCB 59872-101 by treatment cohort, as of the 
data cutoff date. 
Table 1: 
Number of Subjects Who Enrolled in Study INCB 59872-101 (as of 
10 JUL 2017) 
Treatment 
Number of Subjects 
Total number of subjects exposed to INCB059872 
39 
TG A:  AML 
17 
2 mg QOD 
3 
2 mg QD 
6 
3 mg QD 
5 
4 mg QD 
3 
TG B:  SCLC (and other solid tumors with medical monitor approval) 
22 
2 mg QOD 
3 
3 mg QOD 
6 
3 mg QD 
3 
4 mg QOD 
7 
2 mg QD 
1 
1 mg QD 
2 
Preliminary unaudited data, as of 10 JUL 2017, are presented here for 39 subjects who have been 
treated with INCB059872 doses of 1 mg QD, 2 mg (QOD or QD), 3 mg (QOD or QD), and 4 mg 
(QOD or QD).  Eight subjects were receiving treatment as of the data cutoff date.  Of the 
39 subjects, 12 subjects have received INCB059872 for > 20 days, 14 subjects have received 
INCB059872 for > 30 days, and 6 subjects have received INCB059872 for > 90 days. 
Table 2 and Table 3 summarize TEAEs in descending order that occur in at least 3 subjects total 
for each treatment group.  The most frequent TEAEs among all dose cohorts in TG A were 
fatigue and nausea (6 subjects each).  The most frequent TEAEs among all dose cohorts in TG B 
were thrombocytopenia and dysgeusia (9 subjects each). 
Based on preclinical data generated to date, there is reason to believe that subjects may develop 
some level of thrombocytopenia.  As of the data cutoff date, 6 DLTs of ≥ Grade 3 
thrombocytopenia or platelet count decrease have been reported in the 2 mg QD, 3 mg QD, and 


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4 mg QOD cohorts in TG B (1, 2, and 3 respectively).  Treatment interruption occurred in the 
subjects with DLTs and resumed following recovery; 4 of these subjects resumed study 
treatment at a reduced dose (3 mg QOD). 
Four treatment-emergent serious adverse events (SAEs) resulted in discontinuation of study 
treatment:  thrombocytopenia, bile duct obstruction, epistaxis, and hypotension.  With the 
exception of thrombocytopenia, none of these TEAEs leading to INCB59872 discontinuation 
were considered related to study treatment.  Five treatment-emergent SAEs have resulted in 
death, none of which were considered related to study treatment by the investigators:  
leukocytosis, sepsis, pulmonary alveolar hemorrhage, respiratory failure, and gastrointestinal 
hemorrhage.  
Table 2: 
Treatment Group A:  Summary of Treatment-Emergent Adverse Events 
Occurring in at Least 3 Subjects in Decreasing Order of Frequency by 
Subject Total, Any Grade (Preliminary Data From Study INCB 59872-101) 
MedDRA Preferred Term 
2 mg QD 
2 mg QOD 
3 mg QD 
4 mg QD 
Total 
Number of subjects enrolled 
as of the data cutoff date 
6 
3 
5 
3 
17 
Number of subjects who had 
at least 1 TEAE 
6 
3 
5 
3 
17 
Fatigue 
0 
3 
2 
1 
6 
Nausea 
1 
2 
2 
1 
6 
Decreased appetite 
2 
1 
1 
1 
5 
Febrile neutropenia 
1 
1 
1 
2 
5 
Anaemia 
0 
0 
2 
2 
4 
Dysgeusia 
1 
0 
2 
1 
4 
Hypophosphatemia 
1 
0 
1 
2 
4 
Vomiting 
2 
1 
0 
1 
4 
Cough 
1 
1 
1 
0 
3 
Diarrhoea 
0 
1 
2 
0 
3 
Hypotension 
1 
1 
1 
0 
3 
Platelet count decreased 
0 
0 
1 
2 
3 
Weight decreased 
2 
0 
1 
0 
3 


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Table 3: 
Treatment Group B:  Summary of Treatment-Emergent Adverse Events 
Occurring in at Least 3 Subjects in Decreasing Order of Frequency by 
Subject Total, Any Grade (Preliminary Data From Study INCB 59872-101) 
MedDRA Preferred Term 
1 mg 
QDa 
2 mg 
QD 
2 mg 
QOD 
3 mg 
QDb 
3 mg 
QOD 
4 mg 
QOD 
Total 
Number of subjects enrolled 
as of the data cutoff date 
2 
1 
3 
3 
6 
7 
21 
Number of subjects who 
had at least 1 TEAE 
1 
1 
3 
3 
6 
7 
20 
Thrombocytopenia 
0 
1 
0 
2 
2 
4 
9 
Dysgeusia 
0 
0 
3 
2 
1 
3 
9 
Fatigue 
0 
0 
2 
2 
1 
3 
8 
Nausea 
0 
0 
2 
0 
4 
1 
7 
Constipation 
0 
0 
0 
1 
3 
1 
5 
Platelet count decreased 
0 
0 
1 
1 
1 
2 
5 
Diarrhoea 
1 
0 
3 
0 
0 
1 
5 
Decreased appetite 
0 
0 
1 
1 
2 
0 
4 
Neutropenia 
0 
0 
0 
2 
0 
2 
4 
Abdominal pain 
0 
0 
1 
0 
2 
0 
3 
Stomatitis 
0 
0 
0 
0 
2 
1 
3 
Vomiting 
0 
0 
1 
0 
2 
0 
3 
AST increased 
0 
0 
0 
1 
1 
1 
3 
a AE data not complete for this cohort. 
b All subjects had a dose interruption and dose reduction to 3mg QOD in the first cycle. 
1.6.3. 
Potential Risks of All-Trans Retinoic Acid 
Boxed warnings for ATRA include retinoic acid−APL syndrome characterized by fever, 
dyspnea, acute respiratory distress, weight gain, radiographic pulmonary infiltrates, pleural and 
pericardial effusions, edema, and hepatic, renal, and multiorgan failure; rapidly evolving 
leukocytosis; and teratogenicity.  Evaluation and management should be performed as described 
in the package insert (Vesanoid 2010). 
Additional risks and precautions according to the package insert include headache, fever, dry 
skin, dry mucous membranes, bone pain, nausea and vomiting, rash, mouth sores, itching, 
sweating, eyesight changes, flu-like symptoms, coagulation disorder, infections, swelling of feet 
or ankles, bone/joint pain, and abdominal pain.  A complete discussion of risks associated with 
ATRA can be found at http://dailymed.nlm.nih.gov/. 


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1.6.4. 
Potential Risks of Azacitidine 
The primary DLT observed with azacitidine therapy is myelosuppression, typically manifesting 
as leukopenia, anemia, thrombocytopenia, and/or neutropenia.  Hematologic toxicities are 
reversible and are managed through dose interruptions and/or reductions.  Subjects will have 
blood counts monitored weekly during the first cycle of treatment and before starting each course 
of therapy thereafter, at a minimum.  Azacitidine has also been associated with severe adverse 
reactions, including hepatic coma and renal failure.  Subjects with significant baseline hepatic or 
renal impairment are excluded from this clinical study.  Additional adverse reactions associated 
with the use of azacitidine (≥ 20%) include nausea, vomiting, constipation, diarrhea, fever, 
dyspnea, petechiae, and ecchymosis.  A complete discussion of risks associated with azacitidine 
can be found at http://dailymed.nlm.nih.gov/. 
1.6.5. 
Potential Risks Associated With Nivolumab 
Due to the mechanism of action of nivolumab, immune-mediated adverse reactions have been 
seen when used as monotherapy and in combination with ipilimumab.  Guidance is provided in 
the package insert for the management of immune-mediated pneumonitis, immune-mediated 
colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated 
nephritis and renal dysfunction, immune-mediated skin adverse reactions, and immune-mediated 
encephalitis.  Infusion reactions are also possible following administration of nivolumab.  The 
most common adverse reactions seen in ≥ 20% of patients receiving nivolumab monotherapy 
were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenic conditions, cough, 
dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, 
and pyrexia.  The most common adverse reactions seen in ≥ 20% of subjects receiving 
nivolumab in combination with ipilimumab were fatigue, rash, diarrhea, nausea, pyrexia, 
vomiting, and dyspnea (Opdivo PI 2017).  Refer to the nivolumab prescribing information and 
EU summary of product characteristics for updated information regarding safety and risks. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• Part 1:  To evaluate the safety and tolerability and determine the recommended 
dose(s) of INCB059872 for further study in advanced malignancies. 
• Part 2:  To further evaluate the safety and tolerability of INCB059872 for further 
study in advanced malignancies. 
• Part 3:  To evaluate the safety and tolerability and determine the recommended dose 
of INCB059872 in combination with other therapies for further study in advanced 
malignancies. 
• Part 4:  To further evaluate the safety and tolerability of INCB059872 in 
combination with other therapies in advanced malignancies. 
2.1.2. 
Secondary Objectives 
• Parts 1 and 2:  To assess preliminary antitumor activity of INCB059872 as a 
monotherapy in subjects with advanced malignancies. 
• Parts 3 and 4:  To assess preliminary antitumor activity of INCB059872 in 
combination with other therapies in subjects with advanced malignancies 
• To evaluate the PK of INCB059872 and assess the effect of food (TG B1 only) on the 
PK of INCB059872. 
 
 


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2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
• Parts 1 and 2:  Safety and tolerability as assessed by monitoring frequency, duration, 
and severity of adverse events (AEs) through physical examinations, by evaluating 
changes in vital signs and electrocardiograms (ECGs), and through clinical laboratory 
blood and urine sample evaluations. 
• Parts 3 and 4:  Safety and tolerability as assessed by monitoring frequency, duration, 
and severity of AEs through physical examinations, by evaluating changes in vital 
signs and ECGs, and through clinical laboratory blood and urine sample evaluations 
in combinations therapies. 
2.2.2. 
Secondary Endpoints 
• Parts 1 and 2:  Tumor response rates in those subjects with measurable disease or 
spleen volume changes as determined by investigator assessment of response per 
disease-specific guidelines. 
− Solid tumors:  Objective response rate (ORR), defined as the percentage of 
subjects having complete response (CR) or partial response (PR) will be 
determined by the investigator assessment of radiographic disease assessments 
per RECIST v1.1. 
− Acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS):  ORR, 
defined as the proportion of subjects who achieve CR or complete remission with 
incomplete hematologic recovery (CRi) per the International Working Group 
Response Criteria for Acute Myeloid Leukemia or the International Working 
Group Response Criteria for MDS, as applicable. 
− MF:  Change and percentage change in spleen volume reduction (SVR) as 
measured by magnetic resonance imaging (MRI; computed tomography [CT] 
scan in subjects who are not a candidate for MRI or when MRI is not readily 
available) at Week 12 when compared with baseline. 
• Parts 3 and 4:  Tumor response rates in those subjects with measurable disease as 
determined by investigator assessment of response per disease-specific guidelines. 
− Small cell lung cancer (SCLC):  ORR, defined as the percentage of subjects 
having CR or PR will be determined by the investigator assessment of 
radiographic disease assessments per RECIST v1.1. 
− AML/MDS:  ORR, defined as the proportion of subjects who achieve CR or CRi 
per the International Working Group Response Criteria for Acute Myeloid 
Leukemia or the International Working Group Response Criteria for MDS, as 
applicable. 
• PK parameters of INCB059872 in plasma:  Cmax, Tmax, Cmin, AUC0-t, t½, and Cl/F. 


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3. 
SUBJECT ELIGIBILITY 
Potential subjects include those with advanced or metastatic malignancies who are ineligible for 
all therapeutic options that are standard of care or known to confer clinical benefit, or who refuse 
these treatments. 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Male or female subjects, age 18 years or older. 
2. Presence of measurable disease that has been confirmed by histology or cytology.  
Myelofibrosis subjects must have palpable spleen of ≥ 5 cm below the left subcostal 
margin on physical examination at the screening visit. 
3. The following malignancy types will be included in each of the treatment groups: 
 
Treatment 
Group 
Malignancy Histology 
Part 1 
(Dose Escalation) 
A 
AML or MDS  
B 
SCLC (other solid tumors, eg, endocrine tumors, are 
allowed with medical monitor approval) 
Part 2 
(Dose Expansion) 
A1 
Relapsed/refractory AML or MDS 
A2 
MF (PMF, PPV-MF, and PET-MF) 
B1 
SCLC 
B2 
Ewing's sarcoma and poorly differentiated 
neuroendocrine tumors 
Parts 3 and 4 
(Combination Dose 
Escalation/Expansion) 
C/C1 
Relapsed/refractory AML 
D/D1 
Newly diagnosed, treatment-naive AML, or MDS who 
are unfit to tolerate standard intensive chemotherapy at 
study entry and who are eligible to receive azacitidine 
as first-line therapy for the disease under study. 
E/E1 
SCLC previously progressed on platinum-based 
treatment 
4. Subjects must meet specific disease and treatment criteria as follows: 
• TG A/A1/A2, TG B/B1/B2, TG C/C1, and TG E/E1:  The subject must not be a 
candidate for potentially curative therapy or standard-of-care approved therapy.  
• TG A2:  The subjects must have confirmed diagnosis of primary MF (PMF), post–
polycythemia vera MF (PPV-MF), or post–essential thrombocythemia MF (PET-MF) 
according to revised WHO 2016 criteria. 


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• TG D/D1: 
Subjects with newly diagnosed, treatment-naive AML who are unfit to tolerate 
standard intensive chemotherapy at study entry based on at least 1 of the following 
criteria (Ferrara et al 2013): 
− Age ≥ 75 years old. 
− History of congestive heart failure or documented ejection fraction ≤ 50%. 
− Pulmonary disease with diffusing capacity of the lungs for carbon monoxide 
≤ 65% or FEVI ≤ 65%, or dyspnea at rest or requiring oxygen. 
− Any other comorbidity that the physician judges to be incompatible with intensive 
chemotherapy. 
OR 
Subjects with newly diagnosed, treatment-naïve, IPSS-R intermediate or higher risk 
disease MDS who have at least 5% bone marrow blasts, who are unfit to tolerate 
standard intensive chemotherapy at study entry, and who are eligible to receive 
azacitidine as first-line therapy for the disease under study. 
− The following treatments for prior lower risk MDS are acceptable:  Revlimid®, 
low-dose cytarabine, and growth factors. 
• TG E/E1:  The subjects in TG E must have previously received platinum-based 
therapy, but additional lines of therapies are allowed.  The subjects in TG E1 must not 
have received more than 1 previous line of therapy for locally advanced or metastatic 
SCLC.  The previous line of therapy must be a platinum-based therapy, and the 
subjects must have progressed on or after this treatment.  
5. Willingness to undergo a pretreatment bone marrow biopsy or aspirate (AML/MDS/MF) 
during screening (may be waived with medical monitor approval).  Subjects with solid 
malignancies must have baseline archival tumor specimen available:  a tumor block or 
approximately 15 slides from biopsy or resection of primary tumor or metastasis that are 
< 2 years old (specimens > 2 years old may be accepted with medical monitor approval). 
6. ECOG performance status 0 to 2 (see Appendix E). 
7. Willingness to avoid pregnancy or fathering children based on the following criteria: 
a. Woman of non-childbearing potential (ie, surgically sterile with a hysterectomy 
and/or bilateral oophorectomy, ≥ 12 months of amenorrhea.) 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 and who agrees to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
safety follow-up.  Permitted methods that are at least 99% effective in preventing 
pregnancy (see Appendix A) should be communicated to the subjects and their 
understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through safety follow-up.  Permitted methods that 
are at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the subjects and their understanding confirmed. 


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3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Receipt of anticancer medications, anticancer therapies, or investigational drugs within 
the following interval before the first administration of study drug (requirement may be 
waived with medical monitor approval): 
a. < 5 half-lives or 14 days, whichever is longer, for any investigational agent 
b. < 5 half-lives for all other anticancer medications 
c. < 6 weeks for mitomycin-C or nitrosoureas 
2. Any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable 
chronic toxicities (≤ Grade 2) not expected to resolve. 
3. All treatment groups:  prior receipt of an LSD1 inhibitor therapy.  Parts 3 and 4 
TG E/E1:  prior receipt of anti–PD-1, anti–PD-L1, or anti–PD-L2 antibody. 
4. Any of the following laboratory results at screening without transfusions and 
hematopoietic growth factor support in solid tumors (no lower limits in AML and MDS, 
or in MF with medical monitor approval): 
Laboratory Parameter 
Value 
Absolute neutrophil count (× 109/L) 
< 1.5 
Hemoglobin (g/dL) 
< 9.0 
Platelet count (× 109/L) 
< 100 
5. Laboratory and medical history parameters outside Protocol-defined range unless 
associated with primary malignancy or metastatic disease and with medical monitor 
approval: 
a. Total bilirubin > 1.5 × institutional upper limit of normal (ULN) if no liver metastases 
or > 3 × ULN in the presence of liver metastases or presence of documented Gilbert 
syndrome (unconjugated hyperbilirubinemia). 
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
> 2.0 × institutional ULN. 
c. Creatinine clearance < 60 mL/min based on the institutional formula. 
6. History or evidence of bleeding disorder requiring treatment. 
7. History or presence of an abnormal ECG that in the investigator's opinion is clinically 
meaningful.  A screening QTc interval > 470 milliseconds, as corrected by Fridericia, is 
excluded.  For subjects with an intraventricular conduction delay (QRS interval 
120 milliseconds), the JTc interval may be used in place of the QTc with sponsor 
approval.  Subjects with left bundle branch block are excluded. 
8. Prior radiotherapy within 2 weeks of study treatment.  Subjects must have recovered from 
all radiation-related toxicities, including radiation pneumonitis, and not require 
corticosteroids.  Evidence of fibrosis within a radiation field from prior radiotherapy is 
permitted with medical monitor approval.  A 1-week washout period is permitted for 
palliative radiation to non−central nervous system (CNS) disease with medical monitor 
approval. 


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9. Unless approved by the medical monitor, allogeneic hematopoietic stem cell transplant 
within 6 months before treatment, or active graft-versus-host-disease after allogeneic 
transplant, or receipt of immunosuppressive therapy following allogeneic transplant 
within 2 weeks of Cycle 1 Day 1 (prednisone ≤ 10 mg/day is allowed). 
10. Unless approved by the medical monitor, autologous hematopoietic stem cell transplant 
within 3 months before treatment. 
11. History of human immunodeficiency virus infection. 
12. Untreated brain or CNS metastases or brain/CNS metastases that have progressed (eg, 
evidence of new or enlarging brain metastasis or new neurological symptoms attributable 
to brain/CNS metastases).  Subjects with previously treated and clinically stable 
brain/CNS metastases and who are off all corticosteroids for ≥ 4 weeks are eligible. 
13. History of clinically significant or uncontrolled cardiac disease, including recent history 
(within 6 months) of unstable angina, acute myocardial infarction, New York Heart 
Association Class III or IV congestive heart failure, or arrhythmia requiring therapy. 
14. Pregnant or nursing women or subjects expecting to conceive or father children within 
the projected duration of the study, starting with the screening visit through completion of 
safety follow-up visit. 
15. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy. 
16. Chronic or current active infectious disease requiring systemic antibiotics or antifungal or 
antiviral treatment, unless approved by sponsor medical monitor. 
17. Current use of prohibited medication as described in Section 5.6.2. 
18. Inability or unlikeliness to comply with the dose schedule and study evaluations, in the 
opinion of the investigator. 
19. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
20. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the subject; or interfere with interpretation of study data. 
21. Inability to comprehend or unwilling to sign the informed consent form (ICF). 
22. Inability to swallow and retain oral medication. 
23. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 
24. TG E/E1:  Active, known, or suspected autoimmune disease.  Subjects are permitted to 
enroll with vitiligo, diabetes mellitus, resolved childhood asthma/atopy, residual 
hypothyroidism due to an autoimmune immune condition only requiring thyroid hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger. 
25. TG C/C1:  known allergy or reaction to any component of ATRA. 
26. TG D/D1:  known allergy or reaction to any component of azacitidine.   
27. TG E/E1:  known allergy or reaction to any component of nivolumab. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an open-label, dose-escalation/dose-expansion study of the LSD1 inhibitor INCB059872 
as a monotherapy and combination therapy in subjects with advanced malignancies.  Subjects 
will receive INCB059872 doses QOD on a 28-day continuous therapy schedule; if QOD is 
well-tolerated, the next dose may be administered at a different dosing regimen (ie, QD) but will 
not exceed the 100% dose escalation for a total daily dose.  As illustrated in Figure 1, the study 
will be conducted in 4 parts:  Parts 1 and 2 will evaluate INCB059872 as monotherapy, with 
Part 1 for dose escalation and Part 2 for dose expansion, and Parts 3 and 4 will evaluate 
INCB059872 in combination with select therapies, with Part 3 for combination dose escalation 
and Part 4 for combination dose expansion.  Part 1 (monotherapy dose escalation) will determine 
the starting dose(s) of INCB059872 for dose expansion, based on MTD.  The recommended 
dose(s) will be taken forward into Part 2 (monotherapy dose expansion).  The initiation of Part 2 
will be based on further review of the ongoing clinical study and preclinical data of INCB059872 
and information from literature.  Part 3 (dose escalation of INCB059872 in combination therapy) 
will be initiated after the MTD in Part 1 is determined.  Part 4 (dose expansion of INCB059872 
in combination therapy) will explore the dose(s) confirmed in Part 3 and may be different based 
on combination therapy and/or tumor type. 
4.1.1. 
Monotherapy Dose Escalation (Part 1) 
Approximately 24 subjects will be enrolled into each dose-escalation treatment group. 
Treatment Group A will enroll subjects with AML or MDS.  The enrollment in TG B is 
prioritized for SCLC.  Enrollment of subjects with other solid malignancies (eg, endocrine 
tumors) is allowed with the sponsor medical monitor approval. 
Dose escalation for TG A and TG B in Part 1 will proceed independently, with each treatment 
group following a 3 + 3 design.  The starting dose of INCB059872 for TG A and TG B will be 
2 mg QOD.  A minimum of 3 subjects will initially be enrolled in each treatment group in Part 1, 
and each subject will be observed for a DLT observation period of 1 cycle (28 days) before the 
next dose cohort begins enrollment.  Subjects must have taken at least 75% of the cohort-specific 
dose (at least 11 doses for QOD schedule or at least 21 doses for QD schedule) in the first 
28 days of study treatment or have had a DLT to be considered evaluable.  Subjects who are not 
evaluable will be replaced.  The dose will be escalated by up to 100% if none (0) of the first 
3 evaluable subjects enrolled has a DLT.  Dose escalation should proceed in smaller increments 
(ie, by no more than 50%) if a DLT is observed, or if 2 or more subjects at a given dose level 
experience Grade 2 or higher AEs (unless they are clearly and incontrovertibly due to an 
alternative cause). 
If 1 of the first 3 evaluable subjects enrolled has a DLT, the cohort will be expanded to include 
3 additional evaluable subjects, and if no DLT occurs in the additional 3 subjects, then the dose 
will be escalated by up to 100%.  Otherwise, if 2 subjects in a cohort of 3 or 6 subjects 
experience DLTs, the MTD will be deemed to be exceeded.  An interim lower dose level may be 
explored if the dose increment has been 100%.  The MTD will be defined as 1 dose level below 


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the dose level at which one-third or more subjects experience DLTs.  Upon the aggregate review 
of overall safety, PK, 
and efficacy, a recommended dose (per tumor type) will be determined 
to maximize the clinical benefit/risk margin. 
4.1.2. 
Monotherapy Dose Expansion (Part 2)  
Upon identification of the recommended dose(s), up to 4 expansion cohorts per tumor type of 
approximately 15 subjects each may begin enrollment to further determine safety, tolerability, 
efficacy, PK, 
 of the selected dose(s).  Treatment Group A1 will enroll subjects with 
AML or MDS (based on emerging data, the sponsor may decide to enroll specific subtypes of 
AML).  Subjects in this A1 will have an opportunity to switch their treatment to a combination 
dose that is tested and found safe.  Only subjects who have stable disease or better response for 
≥ 3 months on monotherapy will be allowed to do so.  Treatment Group A2 will enroll subjects 
with MF (PMF, PPV-MF, and PET-MF).  Treatment Group B1 will enroll subjects with SCLC.  
Treatment Group B2 will enroll subjects with Ewing's sarcoma and poorly differentiated 
neuroendocrine tumors. 
The selected doses for each treatment group are as follows:  
• TG A1 dose will be 4 mg QD based on the safety and tolerability assessment in TG A 
(Part 1). 
• TG A2, TG B1, and TG B2 doses will be 3 mg QOD based on the safety and 
tolerability assessment in TG B (Part 1). 
A study of the effect of food on the PK of INCB059872 will be conducted in Part 2, TG B1 only. 
If ≥ 5 subjects in the first 15 subjects of any cohort cumulatively (or more than 33% of subjects 
in cohorts larger than 15 subjects) experience DLTs during Cycle 1, then further enrollment to 
the cohort will be stopped, and a lower dose level may be explored. 
Individual dose titration will be permitted according to Protocol-defined safety parameters.  
Subjects will continue to receive INCB059872 in 28-day cycles until a withdrawal criterion is 
met. 
4.1.3. 
Combination Dose-Finding (Part 3) 
Part 3 enrollment will be initiated after the MTD has been determined in Part 1 and will include 
dose-finding to evaluate safety and tolerability of the combinations.  Enrollment of Part 3 will 
occur in parallel with Part 2.  Dose-finding will use a 3 + 3 design to evaluate different doses of 
INCB059872 in combination with other therapies in the following treatment groups:  
• Combination TG C:  INCB059872 in combination with ATRA in subjects with 
relapsed/refractory AML.  The starting dose for INCB059872 in this cohort will be 
2 mg QD (2 dose levels below the recommended dose for monotherapy expansion in 
TG A1). 
• Combination TG D:  INCB059872 in combination with azacitidine in subjects with 
newly diagnosed, treatment-naive AML or MDS with at least 5% bone marrow blasts 
and IPSS-R intermediate or higher risk disease who are unfit to tolerate standard 
intensive chemotherapy at study entry and who are eligible to receive azacitidine as 
first-line therapy for the disease under study.  The starting dose for INCB059872 in 


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this cohort will be 2 mg QD (2 dose levels below the recommended dose for 
monotherapy expansion in TG A1). 
• Combination TG E:  INCB059872 in combination with nivolumab in subjects with 
advanced SCLC who previously progressed on platinum-based treatment.  The 
starting dose for INCB059872 in this cohort will be 3 mg QOD (the recommended 
dose for monotherapy expansion in TG B1). 
The starting dose of INCB059872 in the combination treatment groups was based upon the 
tolerability of INCB059872 monotherapy identified in Part 1 of this study.  Doses of the 
combination agents will be selected from conventional dose regimens and will remain the same 
for all dose-finding and dose-expansion cohorts.  INCB059872 doses will not exceed the 
monotherapy MTD identified in Part 1.  A minimum of 3 subjects will initially be enrolled in 
each treatment group in Part 3, and each subject will be observed for a DLT observation period 
of 1 cycle (28 days) before the next dose cohort or expansion to Part 4 begins enrollment.  
Subjects must have taken at least 75% of the cohort-specific dose (at least 11 doses for QOD 
schedule or at least 21 doses for QD schedule) in the first 28 days of study treatment or have had 
a DLT to be considered evaluable.  Subjects who are not evaluable will be replaced.  
If tolerated, the combination treatment groups will escalate independently and in parallel until 
the MTD or optimal doses of the combinations are identified and will be followed by 
independent expansion cohorts at the selected dose(s).  If the starting dose is not tolerated in any 
of the combination treatment groups, a lower dose of INCB059872 may be explored; otherwise, 
higher doses found to be safe and tolerable in Part 1 may be explored.  The sponsor, in 
consultation with participating investigators, may elect to expand a dose cohort(s) deemed 
tolerable, to up to 12 subjects, in order to obtain supplemental PK, 
, and safety data. 
4.1.4. 
Combination Dose Expansion (Part 4) 
Upon identification of the recommended dose(s) for each treatment combination in Part 3, 
expansion cohorts of approximately 30 subjects in each treatment group may begin enrollment to 
further determine safety, tolerability, efficacy, PK, 
 of the selected dose(s). 
• Combination TG C1:  INCB059872 in combination with ATRA using the regimen 
identified in Part 3 in subjects with relapsed/refractory AML. 
• Combination TG D1:  INCB059872 in combination with azacitidine using the 
regimen identified in Part 3 in subjects with newly diagnosed, treatment-naive AML 
or MDS with at least 5% bone marrow blasts and IPSS-R intermediate or higher risk 
disease who are unfit to tolerate standard intensive chemotherapy at study entry and 
who are eligible to receive azacitidine as first-line therapy for the disease under study. 
• Combination TG E1:  INCB059872 in combination with nivolumab using the 
regimen identified in Part 3 in subjects with advanced SCLC who previously 
progressed on platinum based treatment. 
In Part 4, a stopping rule for futility is planned for each combination dose expansion treatment 
group.  The futility analyses for combination TGs will be conducted when 15 subjects for each 
disease type have been treated and evaluated for response or have permanently discontinued 
study treatment because of disease progression, withdrawal of consent, or death.  The futility 


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analyses for TG D1 will be conducted when the first 15 subjects with AML or when the first 
15 subjects with MDS have been treated. 
Figure 1: 
Study Design 
 
4.2. 
Measures Taken to Avoid Bias 
This is an open-label study; no comparisons will be made between subjects or against historical 
controls.  Measurements of safety and efficacy are objective measurements, and only 
comparisons to pretreatment conditions will be made. 


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4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Approximately 215 subjects will be enrolled in this study as follows:  
• Part 1 will enroll approximately 24 subjects into each dose-escalation treatment 
group.  This may vary due to the number of cohorts required to determine the target 
dose(s).  
• Part 2, approximately 15 subjects will be enrolled in each of the 4 treatment groups.  
• Part 3 will enroll approximately 15 subjects total for all three treatment groups.  This 
number may vary due to the number of cohorts required to determine the optimal 
combination dose.  The sponsor, in consultation with participating investigators, may 
elect to expand a dose cohort(s) deemed tolerable, to up to 12 subjects, in order to 
obtain supplemental PK, 
, and safety data.  
• Part 4 will enroll approximately 30 subjects in TG C1, TG D1, and TG E1.  
4.3.2. 
Replacement of Subjects 
In Parts 1 and 3, if a subject is not evaluable (ie, did not receive at least 75% of cohort-specific 
dose within the first 28 days of study treatment), another subject will be enrolled at this dose 
level.  Subjects who report DLTs will be considered evaluable for the purpose of determining the 
safety and tolerability of the dose.  
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, screening assessments may be completed over a period of up to 28 days.  
Each subject enrolled in the study may continue to receive study treatment in continuous 28-day 
cycles.  If the subject discontinues INCB059872, the treatment period will end and the subject 
will enter the follow-up period (see Section 6.4).  Study participation is expected to average 
approximately 6 months per individual subject. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the informed consent form.  The end of the study 
will occur when all subjects have discontinued study drug and have completed applicable 
follow-up assessments. 
If there have been ≤ 2 subjects on study for more than 6 months, a database lock of the study 
may occur to allow the analysis of the study data.  Any remaining subjects may continue to 
receive study treatment and be seen by the investigator per usual standard of care for this 
population.  The investigator will be expected to monitor for and report any SAEs, AEs of 
special interest, and pregnancies, as detailed in Section 8.  The remaining subjects are considered 
to be on study until a discontinuation criterion is met and written notification is provided to the 
sponsor. 


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4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
5. 
TREATMENT 
INCB059872 will be self-administered orally QOD or QD on a 28-day cycle.  In each cycle of 
the QOD dosing schedule, subjects should receive 14 doses of INCB059872.  In each cycle of 
the QD dosing schedule, subjects should receive 28 doses of INCB059872.  Tablets will be 
available in 1 mg strength.  The initial starting dose for Part 1 will be 2 mg QOD.  The initial 
starting dose for other parts of the study will be based on the aggregate data review of Part 1. 
For QOD administration, if a dose is missed by more than 24 hours, the subject should skip the 
dose and take the next scheduled dose at the usual time.  For QD administration, if a dose is 
missed by more than 4 hours, the subject should skip the dose and take the next scheduled dose 
at the usual time.  INCB059872 tablets should be taken on an empty stomach if possible (refrain 
from food consumption during the period 2 hours before and 1 hour after taking INCB059872).  
For subjects participating in the food-effect portion of the study in Part 2, TG B1, a high-fat, 
high-calorie meal will be consumed within 30 minutes before taking INCB059872 on Cycle 2 
Day 1. 
Alternative dosing regimens (ie, QD) may be explored based on emerging PK/
 and safety 
data. 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Study sites will enter subject demographic and baseline data into the Interactive Response 
Technology (IRT) in order to receive a subject number at the time of the subject enrollment.  
Sites will have to update the IRT system at each visit in order to receive the treatment allocation.  
All subject numbers will be 6 digits; the first 3 digits will be the site number, and the last 3 digits 
will be the subject's number.  This subject number will be maintained throughout the study and 
will not be reassigned.  Subjects who withdraw consent or discontinue from the study after being 
assigned a subject number will retain their initial number. 
This is a nonrandomized study; subjects will be assigned the same dose and treatment regimen in 
a particular treatment group.  The investigator or designee will pull the correct number of bottles 
of study drug from their stock and dispense the study drug to the subject.  All subsequent 
dispensing of study drug should follow this process.  Refer to the IRT manual for detailed 
information. 


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For subjects who signed an ICF but are not allocated and for subjects who are allocated but were 
not treated, refer to the eCRF Completion Guidelines for instruction on which eCRFs to 
complete. 
5.1.2. 
Randomization and Blinding 
Not applicable. 
5.2. 
Study Drug Materials and Management 
5.2.1. 
INCB059872 
5.2.1.1. 
Supply, Packaging, and Labeling 
Study drug will be supplied as 1 mg tablets of INCB059872.  All tablet excipients comply with 
the requirements of the applicable compendial monographs (Ph Eur, USP/NF; refer to the IB). 
INCB059872 will be provided as 1 mg tablets packaged in high-density polyethylene bottles.  
No preparation is required. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country and will state "Caution: New Drug--Limited by Federal (or 
United States) law to investigational use." 
5.2.1.2. 
Storage 
Bottles of tablets should be stored in a refrigerator and maintained at a temperature between 2°C 
and 8°C (36°F to 46°F). 
5.2.1.3. 
Instruction to Subjects for Handling Study Drug (INCB059872) 
The subject must be instructed in the handling of study drug as follows: 
• To store the study drug in the refrigerator. 
• To only remove from the study drug bottle/kit the number of tablets needed at the 
time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses on schedule. 
• To report any missed doses. 
• To take study drug immediately upon awakening or 2 hours after completing a meal 
with a glass of water. 
• If the subject vomits after taking study drug, the subject should not take another dose. 
• To keep study drug in a safe place and out of reach of children. 
• To bring all used and unused study drug kits to the site at each visit. 
• Subjects who do not take their dose in the morning as instructed should plan to take 
the dose in the evening, with the same fasting parameters applied. 


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• If a dose is missed by more than 24 hours on a QOD schedule, that dose should be 
skipped, and the next scheduled dose should be administered at the usual time. 
• If a dose is missed by more than 4 hours on a QD schedule, that dose should be 
skipped, and the next scheduled dose should be administered at the usual time. 
5.2.2. 
Conventional Care Drugs 
Every effort should be made by the sites to procure the commercially available and packaged 
product.  However, Incyte will provide certain reference therapy or therapies, such as tretinoin 
capsules or azacitidine or nivolumab where required by applicable law or regulation or under 
other limited circumstances when a subject may not otherwise have access to the therapy or 
therapies. 
5.2.2.1. 
Tretinoin Capsules 
In Parts 3 and 4 TG C and TG C1, Tretinoin (ATRA) capsules will be administered as an 
open-label commercial product in accordance with local prescribing information at a dose of 
45 mg/m2 per day.  The daily dose should be administered as 2 evenly divided doses.  Drug is 
available in 10 mg capsules and should be stored in accordance with the package insert.  Toxicity 
associated with tretinoin capsules will be managed per instruction in the package insert. 
5.2.2.2. 
Azacitidine 
In the Parts 3 and 4 TG D and TG D1, azacitidine will be administered in accordance with local 
prescribing information as an open-label commercial product at a starting dose of 75 mg/m2 SC 
or IV for 7 days during the first 9-day or less period (ie a 2-day break allowed on weekend, if 
needed) of each 28-day treatment cycle.  Toxicity associated with azacitidine dosing will be 
managed per instructions in the package insert (Vidaza PI 2014). 
Investigative sites must provide subjects with administration and storage instructions, as per 
package insert or institution standard, for azacitidine SC syringes dispensed to subjects for 
administration away from investigative site. 
5.2.2.3. 
Nivolumab 
Nivolumab will be administered at a dose of 3 mg/kg as an IV infusion over 60 minutes every 
2 weeks (Q2W).  Toxicity associated with immune reactions or infusion reactions will be 
managed following guidance in Sections 5.4.8 and 5.4.9. 
Nivolumab must be used in accordance with the storage conditions and shelf life in the 
manufacturer's approved label. 
5.3. 
Treatment Compliance 
5.3.1. 
Treatment Compliance With INCB059872 
Compliance with all study-related treatments should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with INCB059872 will be calculated by the sponsor based on the drug 
accountability documented by the site staff and monitored by the sponsor/designee (tablet 


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counts).  Subjects will be instructed to bring all study drugs with them to the study visits in order 
for site personnel to conduct tablet counts to assess study drug accountability.  The drug 
accountability documentation will be used by the sponsor to calculate treatment compliance. 
5.3.2. 
Treatment Compliance With ATRA, Azacitidine, and Nivolumab 
Compliance with ATRA will be calculated by the sponsor based on the drug accountability 
documented by the site staff and monitored by the sponsor/designee (tablet counts).  Subjects 
will be instructed to bring all study drugs with them to the study visits in order for site personnel 
to conduct tablet counts to assess study drug accountability.  The drug accountability 
documentation will be used by the sponsor to calculate treatment compliance. 
Azacitidine and nivolumab may be administered as an IV infusion by site personnel.  Receipt of 
infusions will be documented by the site staff and monitored by the sponsor/designee.  
Azacitidine may also be administered SC away from the investigative site and should be 
documented to ensure drug accountability. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications of INCB059872 
Selections and modifications to the study drug regimen are planned for dose-escalation cohorts.  
Dose interruptions and modifications also may occur for individual study subjects.  The 
identification of DLTs will define the doses used in planned cohorts.  Further, the occurrence of 
DLTs and other toxicities (related or unrelated to study drug) will guide decisions for treatment 
interruptions and discontinuation for individual subjects. 
Subjects enrolled in the dose-escalation portion of the study will have the option of escalating to 
a dose found to be tolerated in a subsequent cohort either within the same or alternative regimen. 
Subjects enrolled in TG C and TG D who have a bone marrow blast response (at least MFLS for 
AML, and CR or Marrow CR for MDS) may be able to explore different and less intensive 
dosing regimens to allow for hematologic recovery, especially platelet recovery, as approved by 
the medical monitor, such as switching from QD dosing to QOD dosing.  If the subject shows 
signs of losing the response and if deemed safe by the investigator, then the subject is allowed to 
revert to the prior dose and dosing schedule, but a more intensive dosing regimen than the 
starting dose is not allowed. 
Dosing modifications due to response only is not allowed during the DLT evaluation period.  In 
addition to dose interruption and reduction, dosing schedule modification (eg, switching from 
QD to QOD dosing) is also allowed for toxicity management per medical monitor approval. 
5.4.2. 
Dose Modifications of Conventional Care Agents 
Decisions regarding dose reduction of conventional care agents (ATRA, azacitidine, nivolumab) 
should be made following the guidelines in Table 5 and in consultation with the sponsor's 
medical monitor, taking into account relatedness of the AE to the study drug and the subject's 
underlying condition as well as in accordance with local prescribing information. 




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5.4.4. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the sponsor (whenever possible), necessary to optimally treat the subject. 
5.4.5. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 2 weeks.  During follow-up, subjects should be seen as often as medically indicated 
to assure safety. 
5.4.6. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, to agree on dose escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
5.4.7. 
Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB059872 
Study treatment may be delayed up to 2 weeks (14 days) to allow for resolution of toxicity with 
the exception of irAEs in subjects enrolled in TG E/E1 (see Table 6 for the management of 
irAEs).  Subjects may resume treatment if no medical condition or other circumstance exists that, 
in the opinion of the investigator, would make the subject unsuitable for further participation in 
the study.  The treating investigator should contact the sponsor to discuss the case of any subject 
whose treatment has been delayed for more than 14 days before restarting study treatment. 
Because subjects may enter the study with extensive pretreatment and/or severe bone marrow 
infiltration by the primary disease, these dose reduction rules are provided as guidelines (see 
Table 5).  Individual decisions regarding dose reduction should be made using clinical judgment 
and in consultation with the sponsor's medical monitor, taking into account relatedness of the AE 
to the study drug and the subject's underlying condition.  Adverse events that have a clear 
alternative explanation or transient (≤ 72 hours) abnormal laboratory values without associated 
clinically significant signs or symptoms may be exempt from dose-reduction rules. 






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Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of drug-related 
AEs with potential immunologic etiology are outlined in Table 6.  Detailed supportive care 
guidelines for specific irAEs can be in found in Appendix H.  Nivolumab may have specific 
irAE management guidelines within the package insert; the treating investigator may use labeled 
guidance or institutional guidelines for the management of irAEs if preferred.  For each AE, 
attempts should be made to rule out other causes, including but not limited to metastatic disease 
or bacterial or viral infection, which might require specific supportive care.   
Table 6: 
General Approach to Handling Immune-Related Adverse Events 
irAE 
Withhold/Discontinue 
Nivolumab and INCB059872 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1  
No action. 
Not applicable. 
Provide symptomatic treatment. 
Grade 2  
Withhold nivolumab.  May 
withhold INCB059872 per 
investigator's discretion.  
Discontinue if unable to 
reduce corticosteroid dose to 
< 10 mg/day of prednisone or 
equivalent within 6 weeks of 
toxicity. 
May return to treatment if 
improves to Grade 1 or 
resolves within 6 weeks. 
If AE resolves within 
4 weeks, subject may restart 
at the same dose and 
schedule for both nivolumab 
and INCB059872. 
For an AE that does not 
resolve within 4 weeks, 
nivolumab should be 
reduced 1 dose level but 
INCB059872 may be 
restarted at the same dose 
and schedule.  
If AE does not resolve 
within 6 weeks, study 
treatment with both study 
drugs should be 
discontinued or discussed 
with medical monitor. 
Consider systemic corticosteroids in 
addition to appropriate symptomatic 
treatment. 
Grades 3  
Withhold or discontinue 
nivolumab and INCB059872.  
Discontinue if unable to 
reduce corticosteroid dose to 
< 10 mg/day of prednisone or 
equivalent within 6 weeks of 
toxicity. 
Any restart of study 
treatment must be discussed 
with medical monitor before 
restarting treatment. 
Systemic corticosteroids are indicated 
in addition to appropriate symptomatic 
treatment.  May use 1 to 2 mg/kg of 
prednisone or equivalent per day. 
Steroid taper should be considered 
once symptoms improve to ≤ Grade 1 
and tapered over at least 4 weeks in 
most cases. 
Grade 4  
Discontinue nivolumab and 
INCB059872. 
Not applicable.  Any 
exceptions require medical 
monitor approval. 
Systemic corticosteroids are indicated 
in addition to appropriate symptomatic 
treatment.  May use 1 to 2 mg/kg 
prednisone or equivalent per day.  
Steroid taper should be considered 
once symptoms improve to ≤ Grade 1 
and tapered over at least 4 weeks in 
most cases. 


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5.4.9. 
Management of Infusion Reactions 
Subjects in TG E/E1 may experience an infusion reaction associated with administration of study 
treatment.  Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  Nivolumab infusion 
reactions should be managed according to guidance within the package insert; the treating 
investigator may use labeled guidance or institutional guidelines for the management of infusion 
reactions if preferred. 
5.4.10. 
Criteria for Permanent Discontinuation of INCB059872 
The occurrence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study drug treatment and will require that the study drug be 
permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
subject's ability to continue study-specific procedures or is considered to not be in the 
subject's best interest. 
• An AE requiring more than 2 dose reductions. 
• Persistent AE requiring a delay of therapy for more than 2 weeks (14 days) unless a 
greater delay has been approved by the sponsor. 
5.4.11. 
Criteria and Procedures for Dose Increases of INCB059872 
Intrasubject dose escalation will be permitted with sponsor preapproval in the following 
circumstances: 
• The Protocol eligibility criteria are met at the time of escalation. 
• The subject has received ≥ 4 cycles of study drug without drug-related toxicity 
≥ Grade 2. 
• The next higher dose level has been determined to be safe based on the MTD criteria. 
• The subject is willing to submit to the PK sampling and safety monitoring schedules 
as in Cycle 1 Day 15. 
• In the opinion of the investigator, the subject does not have any concurrent condition 
or circumstance that would complicate the dose escalation or PK sampling, or pose 
increased risk to the subject. 


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5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study drug for the following reasons: 
• The subject becomes pregnant. 
• Consent is withdrawn.  Note:  Consent withdrawn means that the subject can no 
longer be followed.  Subjects may choose to discontinue study treatment and remain 
in the study to be followed for disease progression. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
• Unacceptable toxicity has occurred. 
• Disease progression has occurred, except in the circumstance where, in the setting of 
otherwise stable disease, a medical procedure or radiation therapy is required to a 
single lesion, with medical monitor approval. 
A subject may be discontinued from study treatment as follows: 
• If, during the course of the study, a subject is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, the sponsor should be consulted for instruction on handling the 
subject. 
5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the last date of 
the last dose of study drug and the reason for subject withdrawal will be recorded in the eCRF.  
In addition, the following steps should be followed (Note:  These visits are described in 
Section 6): 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the IRT. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, are deemed irreversible, or 
initiation of a new anticancer treatment, whichever occurs first. 


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If the subject discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, subjects will have the option of withdrawing consent for study treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments. 
5.6. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 28 days before the first dose of study treatment and 30 days after the 
last dose of study treatment, or until the subject begins a new anticancer therapy, whichever 
occurs first, will be recorded in the eCRF. 
5.6.1. 
Restricted Medications 
• If concomitant administration of an anticoagulant/antiplatelet medication is indicated, 
caution and enhanced monitoring are required. 
− History of thrombocytopenia and any concurrent INCB059872-related 
thrombocytopenia should be a factor in the choice of anticoagulant and dose. 
• Hydroxyurea is restricted during the treatment periods of the study; however, it may 
be used to treat hyperleukocytosis per medical monitor approval. 
5.6.2. 
Prohibited Medications 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
periods of this study: 
• Use of any anticancer drugs during study. 
• Hydroxyurea is prohibited within 48 hours before initiation of study treatment during 
the screening period and within 24 hours before collection of 
 
. 
• Aspirin in doses exceeding 81 mg/day. 
• Use of potent inhibitors of CYP2D6 or potent inhibitors or inducers of CYP3A4 
(Appendix B). 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments (Table 7), 
and all laboratory assessments will be performed as indicated in Table 8.  Table 9 presents a 
summary of clinical laboratory analytes to be assessed.  The order of assessments is suggested by 
the order of mention within the schedule.  See Section 7 for instructions on each assessment.  
Further details of study procedures and assessments can be found in the study reference manual. 


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Table 7: 
Schedule of Assessments 
Procedure 
Protocol 
Section 
Screening 
Treatment 
EOT 
Follow-Up 
 
Cycle 1 
Cycles 2+ 
Safety 
Disease 
Status 
Notes 
Days 
-28 to -1 
Day 1 
Day 8 
(± 2 Days) 
Day 15 
(± 2 Days) 
Day 22 
(±2 Days) 
Day 1 
(± 2 Day) 
Day 15 
(± 2 Days) 
30 Days 
(+5 Days) 
Every 
8-9 Wks 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
Review inclusion 
and exclusion 
criteria 
3 
X 
X 
 
 
 
 
 
 
 
 
 
Demography and 
medical history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical 
examination/ 
body weight, 
height 
7.5.2 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
 
* Comprehensive 
examination at 
screening, targeted 
physical examination 
thereafter.  Height at 
screening only. 
Vital signs 
7.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
7.5.4 
X 
X* 
X** 
X* 
 
 
 
X 
X 
 
* Timed triplicate ECG 
(separated by 2-5 min); 
predose and 1, 2, and 
6 hours postdose. 
** Triplicate ECG 
(separated by 2-5 min) 
at 1 timepoint 
approximately 24 hours 
after last dose. 
ECOG status 
N/A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CT or MRI for 
solid tumors 
7.6, 
6.4.2  
X 
 
 
 
 
X* 
 
X 
 
X 
* Every 8 weeks 
(± 7 days) from Cycle 1 
Day 1. 


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Table 7: 
Schedule of Assessments (Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment 
EOT 
Follow-Up 
 
Cycle 1 
Cycles 2+ 
Safety 
Disease 
Status 
Notes 
Days 
-28 to -1 
Day 1 
Day 8 
(± 2 Days) 
Day 15 
(± 2 Days) 
Day 22 
(±2 Days) 
Day 1 
(± 2 Day) 
Day 15 
(± 2 Days) 
30 Days 
(+5 Days) 
Every 
8-9 Wks 
AML/MDS 
disease 
assessments  
7.6, 
6.4.2 
X 
 
 
 
 
X* 
 
X 
 
X 
* Every 4 weeks from 
baseline; can be peripheral 
blood or bone marrow 
aspirate or biopsy. 
MF disease 
assessments 
(spleen palpation) 
7.6, 
6.4.2 
X 
X 
 
 
 
X* 
 
X 
 
X 
* Every 4 weeks from Week 
4 through Week 24 and 
every 12 weeks after Week 
24. 
MF disease 
assessments (bone 
marrow 
assessment) 
7.6 
X 
 
 
 
 
X* 
 
 
 
 
* Every 24 weeks. 
MF subjects:  
MRI of the upper 
and lower  
abdomen and 
pelvis 
7.6 
X 
 
 
 
 
X* 
 
 
 
 
* Every 12 weeks from 
baseline; CT scan may be 
substituted if MRI is 
contraindicated. 
Review AEs 
8.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug 
dispensing 
N/A 
 
X 
 
 
 
X* 
 
 
 
 
* Drug dispensed on Day 1 
of each cycle. 


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Table 7: 
Schedule of Assessments (Continued) 
Procedure 
Protocol 
Section 
Screening 
Treatment 
EOT 
Follow-Up 
 
Cycle 1 
Cycles 2+ 
Safety 
Disease 
Status 
Notes 
Days 
-28 to -1 
Day 1 
Day 8 
(± 2 Days) 
Day 15 
(± 2 Days) 
Day 22 
(±2 Days) 
Day 1 
(± 2 Day) 
Day 15 
(± 2 Days) 
30 Days 
(+5 Days) 
Every 
8-9 Wks 
Administer 
INCB059872 at 
site 
N/A 
 
X 
X* 
X* 
X* 
X** 
 
 
 
 
* Subjects should not take 
drug at home but must 
bring medication; they will 
take their dose after initial 
PK blood draw.  NOTE:  
Drug is not given on Day 8, 
but if on a dosing day, 
subject should follow rules 
above. 
** TG B1 subjects for 
food-effect study. 
Assess 
compliance 
5.3 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Administer 
ATRA at site 
 
 
X* 
X* 
X* 
X* 
 
 
 
 
 
* 45 mg/m2 per day 
administered as 2 evenly 
divided doses; AM dose 
only in the clinic. 
Administer 
azacitidine at site 
 
 
X* 
X* 
X* 
X* 
X* 
 
 
 
 
* 75 mg/m2 SC or IV 
for7 days during the first 
9-day or less period (ie, a 2-
day break allowed on 
weekend, if needed) of each 
28-day treatment cycle.   
Administer 
nivolumab at site 
 
 
X* 
 
X* 
 
X* 
X* 
 
 
 
* 3 mg/kg Q2W. 
Distribute 
reminders 
7.10.1 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
CT = computed tomography; 
; MRI = magnetic resonance imaging; 
 
 


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Table 8: 
Schedule of Laboratory Assessments 
Local Laboratory 
Tests 
Protocol 
Section 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Cycles 2+ 
Day 1 
Day 8 
(± 2 Days) 
Day 15 
(± 2 Days) 
Day 22 
(±2 Days) 
Day 1 
(± 2 Day) 
Day 15 
(± 2 Days) 
30 Days 
(+5 Days) 
Serum chemistries 
Table 9  
X 
X* 
X 
X 
X 
X 
X 
X 
X 
* May be performed 3 days before 
the first dose. 
Hematology* 
Table 9 
X 
X** 
X 
X 
X 
X 
X 
X*** 
X 
* Must be drawn twice a week for 
the first 2 weeks of study 
treatment.  In addition to Cycle 1 
Day 1 and Cycle 1 Day 8, 
hematology samples should be 
drawn at Cycle 1 Day 4 ± 1 day 
and Cycle 1 Day 11 ± 1 day.  
** May be performed 3 days 
before the first dose. 
*** Must be drawn twice a week 
for 2 weeks after last dose. 
Lipid panel 
Table 9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation panel 
Table 9 
X 
 
 
 
 
X* 
 
X 
 
* Cycle 2 Day 1 and then every 
3 cycles thereafter. 
Hepatitis screening 
Table 9 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
Table 9 
X 
 
 
 
 
X* 
 
 
 
* Cycle 2 Day 1 and then every 
3 cycles thereafter  
Pregnancy test  
Table 9 
X* 
X** 
 
 
 
 
 
X** 
 
All female subjects of 
childbearing potential. 
* Serum 
** Urine 
PK plasma 
(predose) 
7.8.1 
 
X 
X 
X 
X 
X* 
 
 
 
Collect before morning dose of 
study drug. 
* Cycle 2 Day 1, only for 
food-effect testing in Part 2. 
PK plasma TIMED 
(postdose) 
7.8.1.1 
 
X* 
 
X* 
 
X** 
 
 
 
* Collect at 0.5, 1, 2, 4, and 
6 hours after INCB059872 dose.  
Excess sample will be used for 
 analysis. 
** Cycle 2 Day 1 only for 
food-effect study. 


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Table 8: 
Schedule of Laboratory Assessments (Continued) 
Local Laboratory 
Tests 
Protocol 
Section 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Notes 
Cycle 1 
Cycles 2+ 
Day 1 
Day 8 
(± 2 Days) 
Day 15 
(± 2 Days) 
Day 22 
(±2 Days) 
Day 1 
(± 2 Day) 
Day 15 
(± 2 Days) 
30 Days 
(+5 Days) 
Urine PK 
7.8.2 
 
 
 
X 
 
 
 
 
 
Obtain a predose sample and store 
separately.  Provide a complete 
urine output collection from 
Hour 0 (starting after morning 
dose) through 6 hours. 


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Table 9: 
Local Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis with Microscopic 
Examination 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST  
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Complete blood count, 
including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
• Blast (for hematologic  
tumor types as 
applicable) 
 
Differential count, including: 
• 
Basophils 
• 
Eosinophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Neutrophils 
 
Absolute values must be 
provided for:  
• 
WBC differential 
laboratory results 
• 
Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Hepatitis B surface antigen 
Hepatitis B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
Prothrombin 
time/international 
normalized ratio 
Partial thromboplastin 
time 
Lipid Panel 
Subjects With AML/MDS 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
Low-density lipoprotein 
High-density lipoprotein 
Immunophenotyping  
Cytogenetics 
Female subjects of 
childbearing potential 
require a serum test at 
screening and a urine 
pregnancy test before the 
first dose on Cycle 1 
Day 1 and at EOT. 
Pregnancy tests (serum or 
urine) should be repeated 
if required by local 
regulations. 
Subjects With MF 
JAK-2 mutation status 
Cytogenetics 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
 


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6.1. 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(Cycle 1 Day 1).  Screening may not exceed 28 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 28 days of Cycle 1 Day 1).  All information 
associated with eligibility requirements must be entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
treatment assignment will be used to determine subject eligibility.  Treatment should start as 
soon as possible, but within 3 days after the date of enrollment.  Additionally, a subject who fails 
screening may repeat the screening process 1 time if the investigator believes there has been a 
change in eligibility status (eg, after recovery from an infection).  (Note:  For subjects who fail 
screening but are rescreened, a new subject number will be assigned.) 
6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study drug (Cycle 1 
Day 1) through the point at which the investigator determines the subject will be permanently 
discontinued from study drug.  Cycle 1 Day 1 must be no more than 28 days after the subject has 
signed the ICF and no more than 3 days after the date of registration.  Dates for subsequent study 
visits will be determined based on this day and should occur within the specified visit windows 
noted in Table 7 and Table 8 of the scheduled date unless delayed for safety reasons.  At Cycle 1 
Day 1, results from screening visit evaluations should be reviewed to determine whether the 
subject continues to meet the eligibility requirements, as specified in Section 3. 
Note:  Day 15 visits beyond Cycle 4 may be optional (except for subjects in TG E/E1) per 
subject overall status and approval by the sponsor medical monitor. 
6.3. 
End of Treatment 
When the subject permanently discontinues study drug, the EOT visit should be conducted.  If 
the EOT visit coincides with a regular study visit, the EOT evaluations will supersede those of 
that scheduled visit, and the data should be entered in the EOT visit in the eCRF.  The subject 
should be encouraged to return for the follow-up visit. 


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6.4. 
Follow-Up 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 to 35 days after the EOT visit (or after the last dose of study drug if 
the EOT visit was not performed).  Note that subjects will be required to submit to twice weekly 
blood draws in the 2 weeks after the last dose of study drug. 
Adverse events and SAEs must be reported up until at least 30 days after the last dose of study 
drug, the date of the follow-up visit, or until toxicities resolve, return to baseline, are deemed 
irreversible, or the subject initiates a new anticancer treatment, whichever occurs first.  
Reasonable efforts should be made to have the subject return for the follow-up visit and report 
any AEs that may occur during this period.   
If a subject is scheduled to begin a new anticancer therapy before the end of the 30-day safety 
follow-up period, the safety follow-up visit should be performed before new anticancer therapy 
is started. 
6.4.2. 
Disease Status Follow-Up 
Subjects who discontinue study treatment for a reason other than disease progression will move 
into the disease status follow-up period and should be assessed every 8 to 9 weeks by radiologic 
imaging (SCLC/solid tumors) or blood/bone marrow assessment (AML/MDS/MF) to monitor 
disease status.  Every effort should be made to collect information regarding disease status until 
(whichever occurs first): 
• The start of new antineoplastic therapy. 
• Disease progression. 
• Death. 
• The end of the study. 
6.5. 
End of Study 
The end of the study may be designated as the timepoint when all subjects have discontinued the 
study or the sponsor terminates the study. 


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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6, and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology Procedure 
The IRT will be contacted to obtain a subject ID number when a subject enters screening.  Upon 
determining that the subject is eligible for study entry, the IRT will be contacted to enroll the 
subject.  Additionally, the IRT will be contacted at each regular study visit to update the study 
drug supply and cohort management. 
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening. 
7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 30 days before enrollment and up to the end 
of study will be recorded in the eCRF.  The medication record will be maintained after signing 
the ICF to document concomitant medications, including any changes to the dose or regimen.  
Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 
recorded in the eCRF. 
7.5. 
Safety Assessments 
7.5.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 


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nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.5.2. 
Physical Examinations 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or a nurse practitioner, as local law permits. 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
7.5.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination performed at screening will include height and body 
weight, and assessment(s) of the following organ or body systems:  skin; head, eyes, ears, nose, 
and throat; thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; and 
lymph nodes; as well as a brief neurological examination. 
7.5.2.2. 
Targeted Physical Examination 
The targeted physical examination performed at all other visits will be a symptom-directed 
evaluation.  The targeted physical examination will include body weight and assessment(s) of the 
body systems or organs, as indicated by subject symptoms, AEs, or other findings. 
7.5.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Clinically notable abnormalities that are considered 
clinically significant in the judgment of the investigator are to be reported as AEs. 
7.5.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest.  A single ECG is performed at the screening, EOT, and safety follow-up 
visits.  Triplicate ECGs are performed on Cycle 1 Day 1 and Cycle 1 Day 15 at predose and 1, 2, 
and 6 hours postdose.  A triplicate ECG is performed on Cycle 1 Day 8 approximately 24 hours 
after the last dose on Day 7; if a subject is being seen on Day 7 or Day 9 (study drug 
administration days), triplicate ECG should be performed before study drug administration.  
Note that triplicate ECGs should be performed with a 2- to 5-minute break between evaluations.  
Note that the timed schedule may change per emerging PK data. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
subject management; all ECGs will be collected and reviewed by a central ECG vendor.  The 
decision to include or exclude a subject or withdraw a subject from the study based on an ECG 
flagged as "Abnormal, Clinically Significant" is the responsibility of the investigator, in 


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consultation with the sponsor's medical monitor, as appropriate.  Clinically notable abnormalities 
that are considered clinically significant in the judgment of the investigator are to be reported as 
AEs. 
7.5.5. 
Laboratory Assessments 
Sites will use their local laboratories for eligibility and ongoing safety assessments.  Chemistry, 
hematology, coagulation panel, serology, lipid panel, and urinalysis will all be analyzed. 
For MF subjects only:  after 24 weeks, D15 visits of each cycle can be omitted, with medical 
monitor approval.  
7.5.5.1. 
Pregnancy Testing 
A pregnancy test will be required for all women of childbearing potential during screening, on 
Day 1 (before the first dose of study drug) and at the end of treatment visit.  Serum or urine 
pregnancy tests will be conducted as outlined in Table 8, as medically indicated, or per 
country-specific requirement.  Urine pregnancy tests will be done locally.  If a urine pregnancy 
test is positive, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the subject and determine whether it is in the subject's best interest to 
resume study drug and continue participation in the study. 
7.6. 
Efficacy Assessments 
Objective assessment of tumor status is required using appropriate disease-specific techniques, 
and the investigator's assessment will be used to determine responses and will be logged into the 
eCRF.  For SCLC/solid tumors subjects, Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 (Eisenhauer et al 2009) will be used, and the recommended method for 
measuring and following tumor burden will be CT scan or MRI, to include the thorax, abdomen, 
and pelvis; the neck can be included if needed.  Alternative modalities may be substituted for a 
CT scan at the discretion of the investigator, provided that the same modality is used throughout 
the study and the methodology is consist with RECIST v1.1. 
For AML subjects, the International Working Group Response Criteria for Acute Myeloid 
Leukemia (Cheson et al 2003, Appendix D) will be used as the recommended method for 
measuring and following disease status.  For MDS subjects, International Working Group 
Response Criteria for MDS (Cheson et al 2006, Appendix F) will be used as the recommended 
method for measuring and following disease status.  For MF subjects, the proposed Response 
Criteria for MF (Tefferi et al 2013, Appendix G) will be used as the recommended method for 
measuring and following disease status. 
The schedule for disease assessments will be at screening (this will be considered the baseline 
assessment) for all subjects and then once every 8 weeks throughout the study for solid tumor 
and once every 4 weeks for AML/MDS.  The schedule for MF disease assessments will be at 
screening (this will be considered the baseline assessment), once every 4 weeks until Week 24, 
and once every 12 weeks after Week 24.  For subjects who discontinue treatment for reasons 
other than disease progression, every effort should be made to continue monitoring their disease 


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status until the start of new anticancer therapy, documented disease progression, death, or end of 
study, whichever occurs first. 
Bone marrow examination (aspirate and biopsy) is required at screening for subjects with 
diseases that are typically monitored through bone marrow examination, including AML, MDS, 
and MF.  Note:  subjects with a history of allogenic hematopoietic stem cell transplantation 
should have bone marrow collected and analyzed locally for the purposes of determining disease 
status (where applicable); however their sample does not need to be processed for sequencing 
due to chimeric potential. 
Data from the pathology report result from the bone marrow examination will be captured in the 
eCRF.  All bone marrow examinations should include a unilateral aspiration and biopsy with 
FISH and cytogenetic testing, when feasible and indicated.  Subjects may be enrolled based on a 
biopsy only when a "packed marrow" precludes aspiration at the decision of the medical monitor. 
Results of assessments performed under standard of care before the signing of informed consent 
may be used as the baseline disease assessment in lieu of a study-specific procedure if performed 
within 60 days of the first dose of study drug (Cycle 1 Day 1) and if adequate archive material is 
available and there has been no anticancer therapy in the interim. 
For disease assessment timepoints in AML, MDS, and MF that do not correspond to a bone 
marrow examination, peripheral blood myeloid blast percentage will be evaluated by 
microscopic evaluation or other appropriate methodology and will be used as appropriate in 
conjunction with other parameters (eg, cytopenias) in determining disease status. 
For AML and MDS subjects, a bone marrow disease assessment is strongly encouraged during 
Cycle 2, preferably at Cycle 2 Day 1 for subjects who have a significant circulating blast count 
reduction (as determined by the investigator), including subjects who are not completely cleared 
of circulating blasts; a bone marrow biopsy and/or aspirates for response is to be performed at 
Cycle 4 Day 1 or earlier as clinically indicated, followed by every other month as clinically 
indicated, or upon circulating blood cell recovery to assess antileukemic activity (cytogenetic 
testing is not required if CR is not presented).  Bone marrow examination schedule can be 
modified with approval from the medical monitor. 
For MF subjects, bone marrow biopsy must be completed at screening or baseline visit, unless 
biopsy and data from previous 2 months are available.  Additional biopsies will be performed at 
Week 24, Week 48, and every 24 weeks.  If a biopsy is not possible or contraindicated, or the 
tissue requirement cannot be satisfied, this requirement may be waived with approval from the 
medical monitor.  
For MF subject disease assessment with spleen palpation:  spleen length will be assessed by 
manual palpation at every study visit (laboratory-only visits not included) and will be used for 
routine subject management.  Investigators should use a soft centimeter ruler so that palpable 
spleen length is measured in centimeters and not in finger breadths.  The edge of the spleen shall 
be determined by palpation and measured in centimeters, using a soft ruler, from the costal 
margin to the point of greatest splenic protrusion.  Spleen length must be recorded on the CRF. 


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7.8. 
Pharmacokinetic Assessments 
7.8.1. 
Blood Sample Collection 
Pharmacokinetic samples will be obtained at the visits indicated in the Schedule of Laboratory 
Assessments (Table 8) to evaluate plasma PK parameters as described in Appendix C.  For PK 
sample collection, the following will be recorded:  
• The exact date and time of the blood sample.  
• The date and time of the last dose of study drug before blood collection (if 
applicable).  
• The time of the most recent meal.  
Subjects will receive reminder cards in advance of the study visit providing instructions to 
prepare for the visit (see Section 7.10.1).  Instructions for plasma preparation and sample 
shipping will be provided in the Laboratory Manual. 
7.8.1.1. 
Timed Pharmacokinetic Testing 
Timed PK testing will be performed using the timepoints shown in Table 10.  The timing of PK 
sample collection may be coordinated with other timed tests (
 ECG).  On these 
study dates, the subject should arrive at the research unit in the morning.  If study drug has been 
previously dispensed, the reminder card (see Section 7.10.1) will remind the subject to refrain 
from taking the study drug at home that day.  Subjects will also be reminded about fasting 
requirements, as applicable (see Table 10).  A trough (predose) PK sample will be collected early 
in the study visit, followed by administration of the study drug and subsequent timed blood 
samples.  The study drug will be administered with approximately 240 mL of water.  Subjects 
should remain fasting from food or water for at least 1 hour postdose, after which a meal or 
snack may be consumed. 






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their morning dose of study drug on Days 1, 8, 15, or 22 of Cycle 1 and then Days 1 and 15 for 
all other cycles, as they will take it after blood draws for safety evaluation have been completed.  
The reminder cards will have an area on which the date and time of the last dose taken (from the 
previous evening) and the time of their last meal before the visit should be recorded. 
8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an AE is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related, that occurs 
after a subject provides informed consent.  Abnormal laboratory values or test results occurring 
after informed consent constitute AEs only if they induce clinical signs or symptoms, are 
considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 30 days after the last dose of study drug.  Adverse 
events (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE 
(eg, resulted in hospitalization, a life-threatening event, or death), the specific events(s) should 
be reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 4.  The CTCAE 
v4.03 severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly 
using Grades 1 through 4 and have the outcome noted as fatal.  If an event is not classified by 
CTCAE the severity of the AE will be graded according to the scale below to estimate the grade 
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Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious AE (SAE) definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 


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8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE does not automatically indicate an SAE unless it meets the definition 
of serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may 
be required (see Section 5.4) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied  tumor type not associated with 
any deterioration in condition (ie, bone marrow biopsy for AML subjects) 
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the tumor type under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above. 


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8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 30 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor it its designee only if the investigator suspects a causal 
relationship to the study drug.   
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment. 
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 


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8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.4.7 for the maximum permitted duration of study drug interruption). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochure (IB).  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications (INs).  Any important new safety information should be discussed with the subject 
during the study, as necessary.  If new significant risks are identified, they will be added to the 
ICF. 
8.7. 
Data Monitoring Committee 
No independent Data Monitoring Committee is planned for this study.  Decisions to continue the 
enrollment in subsequent dose level cohort, dose level to be tested, as well as number of subjects 
to be evaluated, will be made after the appropriate data are collected and reviewed by sponsor 
representatives (eg, medical monitor) and investigators or designees.  The group of sponsor 
representatives and investigators or designees will convene regularly (eg, once weekly) or ad hoc 
for specific discussions.  Meeting minutes will be documented. 
An internal Data Safety Monitoring Board (iDSMB) will review safety data at regular intervals 
throughout the study.  The frequency of meetings will be contingent upon enrollment and 
availability of safety data for analysis and review.  Details regarding membership, roles, and 
responsibilities of the committee are specified in the iDSMB charter. 


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8.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9. 
STATISTICS 
9.1. 
Study Populations 
The populations to be analyzed include the following: 
• The full analysis set/safety population consists of subjects enrolled in the study who 
received at least 1 dose of study drug. 
• The PK/
 population consists of all enrolled subjects who had PK/
 data. 
9.2. 
Selection of Sample Size 
Part 1 and Part 3 of the study will use a standard 3 + 3 dose-escalation design, and the sample 
size will depend on the frequency of DLTs and the number of dose-escalation cohorts before 
reaching the MTD.  Approximately 3 to 6 subjects will be enrolled in each dose level.  Using this 
design, the probability of dose escalation for various DLT rates is given in Table 11. 
Table 11: 
Probability of Dose Escalation by DLT Rate 
True DLT Rate 
Probability of Dose Escalation 
10% 
90.6% 
20% 
70.9% 
30% 
49.4% 
40% 
30.9% 
50% 
17.2% 
60% 
8.2% 
For Part 2, approximately 15 subjects will be enrolled for each expansion cohort.  The evaluation 
of 15 subjects will provide a ≥ 90% chance of observing at least 1 toxicity with a true event rate 
of ≥ 15%. 




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9.4.3.2. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value will be produced using 
CTCAE grade. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.3.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 12), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 12: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24/min 
< 8/min 
9.4.3.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (Table 13).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 


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Table 13: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 470 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
QTcF = Fridericia correction. 
9.4.3.5. 
Adverse Events of Special Interest 
Based on preclinical data generated to date, there is reason to believe that subjects will develop 
some level of thrombocytopenia.  No human data have been generated yet to support this.  
Additionally, there is a chance for a "rebound" effect on platelets (potentially thrombocytosis) 
once the drug is discontinued, but human data have not been generated to support this effect.  
Subjects will be monitored closely and based on CTCAE grading of thrombosis will be reported 
as AEs as appropriate. 
9.4.4. 
Pharmacokinetic Analysis 
The PK parameters of Cmax, Tmax, Cmin, AUC0-t, t½, and Cl/F (INCB059872) will be calculated 
from the blood plasma concentrations of INCB059872 using standard noncompartmental 
(model-independent) PK methods.  Pharmacokinetic calculations will be performed, if 
appropriate, using commercial software such as WinNonlin®.  Nominal times will be used in all 
cases, except when the difference between the actual time and nominal time is greater than 
15 minutes for samples collected up to 4 hours after administration and greater than 30 minutes 
for samples collected more than 4 hours after administration; in these cases, actual time will be 
used for PK analysis.  Refer to Appendix C for a detailed list and description of the PK 
parameters. 
If there is a sufficient amount of plasma concentration data from this study, the data will be 
analyzed by standard population PK methods using appropriate software (eg, NONMEM). 
 
 
 
9.5. 
Analyses for the Data Monitoring Committee 
Preplanned analyses of safety will be provided to the iDSMB at regular intervals throughout the 
study as specified in the iDSMB charter. 
9.6. 
Interim Analysis 
In Part 4, a stopping rule for futility is planned for each combination dose expansion treatment 
group.  The futility analyses for combination TGs will be conducted when 15 subjects for each 
disease type have been treated and evaluated for response or have permanently discontinued 
study treatment because of disease progression, withdrawal of consent, or death.  The futility 


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analyses for TG D1 will be conducted when the first 15 subjects with AML or when the first 
15 subjects with MDS have been treated.  Combination TG C1 will be terminated for futility if 
≤ 1 of the 15 subjects responded (ie, CR, CRi, MLFS) based on assessments provided by 
investigator.  Combination TG D1 will terminate enrollment for subjects with AML if ≤ 2 of the 
first 15 AML subjects responded (ie, CR, CRi, MLFS) or will terminate enrollment for subjects 
with MDS if ≤ 2 of the first 15 MDS subjects responded (ie, CR or marrow CR), based on 
assessments provided by investigator.  Combination TG E1 will be terminated for futility if 
≤ 1 of the 15 subjects responded (ie, CR or PR) based on assessments provided by investigator. 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 


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− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 
• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities.  
The investigator or designee must maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 


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• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
study drug.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 


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Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research subjects, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 




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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 


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APPENDIX B. POTENT CYP2D6 INHIBITORS AND POTENT CYP3A4 
INHIBITORS AND INDUCERS 
In Vivo CYP2D6 Potent Inhibitor 
Inhibitor 
Therapeutic Class 
Quinidine 
antiarrhythmic 
Fluoxetine 
Antidepressants 
Dacomitinib 
Kinase inhibitors 
Ecstasy 
Recreational drug 
Paroxetine 
Antidepressant 
Bupropion 
Antidepressant 
In Vivo CYP3A4 Potent Inhibitors 
Inhibitor 
Therapeutic Class 
Indinavir/RIT) 
Protease inhibitor 
Tipranavir/RIT 
Protease inhibitor 
Ritonavir 
Protease inhibitor 
Cobicistat (GS-9350) 
None 
Indinavir 
Protease inhibitor 
Ketoconazole 
Antifungal 
Troleandomycin 
Antibiotics 
Telaprevir 
Antivirals 
Danoprevir/RIT 
Antivirals 
Elvitegravir/RIT 
Treatments of AIDS 
Saquinavir/RIT 
Protease inhibitors 
Lopinavir/RIT 
Protease inhibitors 
Itraconazole 
Antifungals 
Voriconazole 
Antifungals 
Mibefradil 
Calcium channel blocker 
LCL161 
Cancer treatment 


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In Vivo CYP3A4 Potent Inhibitors (Continued) 
Inhibitor 
Therapeutic Class 
Clarithromycin 
Antibiotics 
Posaconazole 
Antifungals 
Telithromycin 
Antibiotics 
Grapefruit juice DS 
Food products 
Conivaptan 
Diuretics 
Nefazodone 
Antidepressants 
Nelfinavir 
Protease inhibitors 
Saquinavir 
Protease inhibitors 
Idelalisib 
Kinase inhibitors 
Boceprevir 
Antivirals 
In Vivo CYP3A4 Potent Inducers 
Inducers 
Therapeutic Class 
Rifampin 
Antibiotics 
Mitotane 
Other antineoplastics 
Avasimibe 
Other antilipemics 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St John’s Wort 
Herbal medications 
Rifabutin 
Antibiotics 
Phenobarbital 
Anticonvulsants 
 
Source:  University of Washington School of Pharmaceutics: Drug Interaction Database Program. 2002. 
http://www.druginteractioninfo.org. 


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APPENDIX C. PHARMACOKINETIC ANALYTICAL PARAMETERS 
Cave 
Average steady-state plasma concentration (AUC0-12h/12h or 
AUC0-24h/24h) 
Cmax 
Maximum observed plasma concentration 
Cmin 
Minimum observed plasma concentration during the dosing interval 
Tmax 
Time to maximum plasma concentration 
AUC0-t 
Area under the single-dose plasma concentration-time curve from Hour 0 
to the last quantifiable measurable plasma concentration, calculated by the 
linear trapezoidal rule for increasing concentrations and the log 
trapezoidal rule for decreasing concentrations 
AUC0-τ (ie, 
AUC0-12h or 
AUC0-24h) 
Area under the steady-state plasma concentration-time curve over 
1 dosing interval calculated by the linear trapezoidal rule for increasing 
concentrations and the log trapezoidal rule for decreasing concentrations 
λz 
Apparent terminal phase disposition rate constant, where λz is the 
magnitude of the slope of the linear regression of the log concentration 
versus time profile during the terminal phase 
t½ 
Apparent plasma terminal phase disposition half-life (whenever possible), 
where t½ = (ln2) / λz 
Cl/F 
Oral dose clearance 
Vz/F 
Apparent oral dose volume of distribution 
Fluctuation 
Steady-state fluctuation ([Cmax – Cmin]/Cave) 
In addition, the following PK parameters may be calculated, whenever possible, for each subject 
based on the urine INCB059872 concentrations: 
Ae 
Amount of drug excreted in the urine over sampling interval 
Clr 
Renal clearance, where Clr = Ae/AUC 
% Excreted or fe 
percent excreted in the urine, where % Excreted = 100 (Ae/dose) 
Pharmacokinetic calculations will be performed, if appropriate, using commercial software such 
as WinNonlin®.  Additional details of analyses will be described in the statistical analysis plan. 


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APPENDIX D. INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR ACUTE MYELOID LEUKEMIA 
Response Category 
Response Definition 
Complete remission (CR)1 
Bone marrow blasts < 5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; absolute neutrophil count 
> 1.0 × 109/L (1000/μL); platelet count > 100 × 109/L (100,000/μL); 
independence of red cell transfusions 
CR with incomplete recovery 
(CRi) 
All CR criteria except for residual neutropenia (< 1.0 × 109/L [1000/μL]) 
or thrombocytopenia (< 100 × 109/L [100,000/µL]) 
Morphologic leukemia-free 
state 
Bone marrow blasts < 5 percent; absence of blasts with Auer rods; 
absence of extramedullary disease; no hematologic recovery required 
Partial remission (PR) 
All hematologic criteria of CR; decrease of bone marrow blast 
percentage to 5 to 25 percent; and decrease of pretreatment bone marrow 
blast percentage by at least 50 percent 
Cytogenetic CR (CRC) 
Reversion to a normal karyotype at the time of morphologic CR (or CRi) 
in cases with an abnormal karyotype at the time of diagnosis; based on 
the evaluation of 20 metaphase cells from bone marrow 
Molecular CR (CRm) 
No standard definition; depends on molecular target 
Treatment failure 
Resistant disease (RD) 
Failure to achieve CR or Cri or PR (Phase 1 trials); only includes patients 
surviving ≥ 7 days following completion of initial treatment, with 
evidence of persistent leukemia by blood and/or bone marrow 
examination 
Death in aplasia 
Deaths occurring ≥ 7 days following completion of initial treatment 
while cytopenic; with an aplastic or hypoplastic bone marrow obtained 
within 7 days of death, without evidence of persistent leukemia 
Death from indeterminate 
cause 
Deaths occurring before completion of therapy, or < 7 days following its 
completion; or deaths occurring ≥ 7 days following completion of initial 
therapy with no blasts in the blood, but no bone marrow examination 
available 
Relapse2 
Bone marrow blasts ≥ 5 percent; or reappearance of blasts in the blood; 
or development of extramedullary disease 
1 All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate 
with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation may help to 
distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy should be performed 
in cases of dry tap, or if no spicules are obtained; no minimum duration of response required. 
2 In cases with low blast percentages (5 to 10 percent), a repeat marrow should be performed to confirm relapse.  
Appearance of new dysplastic changes should be closely monitored for emerging relapse.  In a patient who has 
been recently treated, dysplasia or a transient increase in blasts may reflect a chemotherapy effect and recovery of 
hematopoiesis. Cytogenetics should be tested to distinguish true relapse from therapy-related MDS/AML. 
Source:  Cheson et al 2003. 


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APPENDIX E. EASTERN COOPERATIVE GROUP PERFORMANCE 
STATUS SCORING 
Grade ECOG Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Source:  Oken et al 1982. 




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APPENDIX G. REVISED RESPONSE CRITERIA FOR MYELOFIBROSIS 
Response 
Category 
Required Criteria 
(for all categories, benefit must last for ≥ 12 weeks to qualify as a response) 
Complete 
response 
• Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤ Grade 1 MF† 
• Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and < UNL; 
• Platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cells‡ 
• Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH 
Partial response 
• Hemoglobin ≥100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and < UNL; platelet count 
≥ 100 × 109/L and < UNL; < 2% immature myeloid cells‡ 
• Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH 
• Bone marrow:* Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 MF†, and 
peripheral blood:  Hemoglobin ≥ 85 but < 100 g/L and < UNL; neutrophil count 
≥ 1 × 109/L and < UNL; platelet count ≥ 50, but < 100 × 109/L and < UNL; < 2% immature 
myeloid cells‡ 
• Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH 
Clinical 
improvement 
• The achievement of anemia, spleen or symptoms response without progressive disease or 
increase in severity of anemia, thrombocytopenia, or neutropenia§ 
Anemia response  
• Transfusion-independent patients:  a ≥ 20 g/L increase in hemoglobin level|| 
• Transfusion-dependent patients:  becoming transfusion-independent¶ 
Spleen response 
• Baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpable** or 
• Baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥ 50%** 
- 
Baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for 
spleen response 
- 
Spleen response requires confirmation by MRI or computed tomography showing 
≥ 35% spleen volume reduction. 
Progressive 
disease‡‡ 
• Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
• ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm 
or 
• 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or 
• Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or 
• Peripheral blood blast content of ≥ 20% associated with an absolute blast count of 
≥ 1 × 109/L that lasts for at least 2 weeks 
Stable disease 
• Belonging to none of the above listed response categories. 
Relapse 
• No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
• Loss of anemia response persisting for at least 1 month, or 
• Loss of spleen response persisting for at least 1 month. 
See above for definitions of anemia response, spleen response, and progressive disease.  Increase in severity of anemia 
constitutes the occurrence of new transfusion dependency or a ≥ 20 g/L decrease in hemoglobin level from pretreatment 
baseline that lasts for at least 12 weeks.  Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade 
decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0.  In addition, assignment to CI requires a minimum platelet count of 
≥ 25,000 × 109/L and absolute neutrophil count of ≥ 0.5 × 109/L. 


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|| Applicable only to patients with baseline hemoglobin of < 100 g/L.  In patients not meeting the strict criteria for transfusion 
dependency at the time of study enrollment (see as follows), but who have received transfusions within the previous month, the 
pretransfusion hemoglobin level should be used as the baseline. 
¶ Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood cells (PRBC), 
in the 12 weeks before study enrollment, for a hemoglobin level of < 85 g/L, in the absence of bleeding or treatment-induced 
anemia.  In addition, the most recent transfusion episode must have occurred in the 28 days before study enrollment.  Response 
in transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive "rolling" 12-week interval 
during the treatment phase, capped by a hemoglobin level of ≥ 85 g/L. 
# In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
** Spleen or liver responses must be confirmed by imaging studies where a ≥ 35% reduction in spleen volume, as assessed by 
MRI or CT, is required.  Furthermore, a ≥ 35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response 
regardless of what is reported with physical examination. 
‡‡ Progressive disease assignment for splenomegaly requires confirmation by MRI or computed tomography showing a ≥ 25% 
increase in spleen volume from baseline.  Baseline values for both physical examination and imaging studies refer to 
pretreatment baseline and not to posttreatment measurements. 
Source:  Tefferi et al 2013. 


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APPENDIX H. PROCEDURES AND SUPPORTIVE CARE GUIDELINES 
FOR SUBJECTS EXHIBITING IMMUNE-RELATED 
ADVERSE EVENTS 
Note:  Use as guidance in conjunction with institutional practice, the nivolumab package insert, 
and consultation with the medical monitor. 
irAE 
Supportive Care 
Pneumonitis 
For Grade 2 (mild to moderate new symptoms): 
• 
Monitor symptoms daily and consider hospitalization.  
• 
Promptly start systemic steroids per institutional standard of care. 
• 
Consider adding prophylactic antibiotics for opportunistic infections in the 
case of prolonged steroid administration. 
• 
Reimaging as clinically indicated. 
• 
If no improvement within 3 to 5 days, additional work-up should be considered 
and prompt treatment with IV methylprednisolone should be started. 
• 
If still no improvement within 3 to 5 days despite IV methylprednisone, 
consider starting immunosuppressive therapy (eg, infliximab), after discussing 
with the medical monitor. 
Caution:  Important to rule out sepsis and refer to infliximab label for general 
guidance before using infliximab.  
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungal, or anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections 
(Category 2B recommendation).  
• 
Consider pulmonary and infectious disease consult.  
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening): 
• 
Promptly initiate empiric IV methylprednisolone or equivalent.  
• 
Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.  Consider obtaining pulmonary and infectious 
disease consult.  
• 
If no improvement within 3-5 days, additional work-up should be considered 
and prompt treatment with additional immunosuppressive therapy 
(eg, infliximab), after discussing with the medical monitor. 
Caution: Rule out sepsis and refer to infliximab label for general guidance 
before using infliximab.  
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and in particular, anti-PCP treatment 
(refer to current NCCN Guidelines for treatment of cancer-related infections 
(Category 2B recommendation).  


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irAE 
Supportive Care 
Diarrhea/Colitis 
Note:  Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus). 
For Grade 2 (mild to moderate new symptoms): 
• 
Consider symptomatic treatment, including hydration, electrolyte replacement, 
dietary changes (eg, American Dietetic Association colitis diet), and 
loperamide and/or budesonide. 
• 
Promptly start systemic steroids per institutional standard of care. 
• 
If event is not responsive within 3 to 5 days or worsens, gastrointestinal (GI) 
consult should be obtained for consideration of further work-up, and prompt 
treatment with IV methylprednisolone started. 
• 
If still no improvement within 3 to 5 days, consider starting 
immunosuppressives (eg, infliximab) after discussing with the medical 
monitor. 
Caution:  Important to rule out bowel perforation and refer to infliximab label 
for general guidance before using infliximab. 
• 
Consult medical monitor if no resolution to ≤ Grade 1 in 3 to 4 days. 
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening diarrhea, 
life-threatening): 
• 
Treatment with systemic corticosteroids should be initiated per institutional 
standard of care. 
• 
Manage symptoms and consider GI consult for further work-up as appropriate. 
• 
If still no improvement within 3 to 5 days, consider starting 
immunosuppressives (eg, infliximab), after discussing with the medical 
monitor. 
Caution:  Ensure GI consult to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 


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irAE 
Supportive Care 
Hepatitis 
For Grade 2 (mild to moderate new symptoms): 
• 
Observe subject with regular and frequent checking of liver chemistries until 
improving or resolved. 
• 
Rule out non-irAE etiologies. 
• 
If event is persistent (> 3-5 days) or worsens, consider starting systemic 
steroids per institutional standard of care. 
• 
If still no improvement within 3 to 5 days, consider additional work-up and 
prompt treatment with IV methylprednisolone. 
• 
If still no improvement within 3 to 5 days, consider starting 
immunosuppressives (eg, mycophenolate mofetil), after discussing with the 
medical monitor. 
• 
Infliximab should NOT be used. 
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening hepatitis, 
life-threatening): 
• 
Promptly initiate empiric IV methylprednisolone or equivalent. 
• 
If still no improvement within 3 to 5 days, consider starting treatment with 
immunosuppressive therapy (eg, mycophenolate mofetil), after discussing with 
the medical monitor. 
• 
Infliximab should NOT be used. 
• 
Consider hepatology consult for additional work-up, as appropriate. 
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 


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irAE 
Supportive Care 
Dermatitis 
Note:  Monitor subjects 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.  If there is any bullous 
formation, the medical monitor should be contacted, and study treatment should be 
discontinued. 
For Grade 2 (mild to moderate new symptoms): 
• 
Consider dermatology consult. 
• 
Consider symptomatic treatment per institutional standard of care. 
• 
Consider moderate-strength topical steroid. 
• 
If no improvement of rash/skin lesions occurs within 3 to 5 days or is 
worsening despite symptomatic treatment and/or use of moderate strength 
topical steroid, discuss with medical monitor and promptly start systemic 
steroids. 
For Grade 3 or 4 (severe or new symptoms, new/worsening dermatitis, 
life-threatening): 
• 
Consider dermatology consult. 
• 
Promptly initiate empiric IV methylprednisolone or equivalent. 
• 
Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.   
• 
Consider hospitalization. 
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
• 
Discuss with medical monitor. 
Renal Failure or 
Nephritis 
Note:  Subjects should be monitored for signs and symptoms that may be related to 
changes in renal function.  Subjects should be thoroughly evaluated to rule out any 
alternative etiology.  Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2) in order to prevent 
potential progression to higher grade event. 
For Grades 2 to 4:  
• 
Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.  Consider consult with nephrologist, if 
clinically indicated.   
• 
If event is persistent (> 3-5 days) or worsens, promptly start systemic steroids 
per institutional standard of care. 
• 
If event is not responsive within 3-5 days or worsens despite steroids, 
additional work-up should be considered, and prompt treatment with IV 
methylprednisolone started. 
• 
Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 


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irAE 
Supportive Care 
Endocrinopathies 
Note:  Subjects should be monitored for clinical signs and symptoms of 
hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or 
hypothyroidism.  Subjects may present with fatigue, headache, mental status 
changes, 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. 
For Grade 2 (mild to moderate new symptoms):  
• 
In hypophysitis, treat with systemic corticosteroids, per institutional standard 
of care.  When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
Note: These suggested supportive care measures also apply to Grade 3 
hypophysitis  
• 
In hyperthyroidism, nonselective beta-blockers (eg, propranolol) are suggested 
as initial therapy. 
• 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyronine, is indicated per standard of care. 
Note: Isolated hypothyroidism may be treated with replacement therapy 
without treatment interruption and without corticosteroids. 
• 
Evaluate endocrine function and, as clinically indicated, consider pituitary 
scan. 
• 
For subjects with abnormal endocrine work-up, except for those with isolated 
hypothyroidism, consider short-term, high-dose corticosteroids (eg, 
methylprednisolone or IV equivalent) and initiate appropriate hormone 
replacement therapy. 
• 
For subjects with normal endocrine work-up (labs or MRI), repeat labs/MRI as 
clinically indicated. 
For Grade 3 or 4 (severe or new symptoms, new/worsening endocrinopathies, 
life-threatening): 
• 
Hypothyroidism may be treated with replacement therapy without treatment 
interruption and without corticosteroids. 
• 
In hyperthyroidism, treat with an initial dose of IV corticosteroid followed by 
oral corticosteroids.  Consider initiation of systemic corticosteroids at a dose of 
1-2 mg/kg per day of prednisone or equivalent, and initiate appropriate 
hormone replacement therapy.  Once improving, gradually taper 
immunosuppressive steroids over ≥ 4 weeks. 
• 
In hypophysitis, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.  Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• 
For adrenal crisis, severe dehydration, hypotension, or shock:  immediately 
initiate intravenous corticosteroids with mineralocorticoid activity. 
• 
Consult endocrinologist. 
• 
Consult medical monitor. 


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irAE 
Supportive Care 
Neuropathies 
Note:  Monitor subjects for symptoms of motor or sensory neuropathy such as 
unilateral or bilateral weakness, sensory alterations, or paresthesia. 
For Grade 2 (mild to moderate new symptoms):  
• 
Consider systemic corticosteroids per institutional standard of care in addition 
to appropriate symptomatic treatment. 
• 
If no improvement within 3-5 days, consider additional work-up and consider 
treating with additional immunosuppressive therapy (eg, IV IgG), after 
discussing with the medical monitor. 
For Grade 3 or 4 (severe or new symptoms, new/worsening neuropathies, 
life-threatening): 
• 
Consider initiation of systemic corticosteroids (IV administration should be 
strongly considered) for severe neuropathies. 
• 
Institute medical intervention as appropriate for management of severe 
neuropathy. 
• 
If no improvement within 3-5 days despite IV corticosteroids, consider 
additional workup and consider treating with additional immunosuppressants 
(eg, IV IgG) after discussing with the medical monitor. 
• 
Once stable, gradually taper steroids over ≥ 4 weeks. 


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Amendment 7 (13 JUN 2019) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to include 
additional safety monitoring and modify the inclusion criteria for MDS patients in Treatment 
Group D for Parts 3 and 4 of the Protocol. 
1. Synopsis; Section 3.1, Subject Inclusion Criteria; Section 4.1.3, Combination Dose-
Finding (Part 3); Section 4.1.4, Combination Dose Expansion (Part 4) (including 
Figure 1: Study Design) 
Description of change:  All applicable sections have been updated to modify the 
inclusion criteria for MDS subjects in Treatment Group D for Parts 3 and 4 of the 
Protocol. 
Rationale for change:  Per FDA request. 
2. Synopsis; Section 6, Study Assessments (Table 8: Schedule of Laboratory 
Assessments) 
Description of change:  Two additional collections for hematology were added in the 
first 2 weeks of study treatment, one at Cycle 1 Day 4 and another at Cycle 1 Day 11. 
Rationale for change:  To include additional hematology monitoring to the study in 
response to platelet changes with INCB059872. 
3. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 6 (16 APR 2019) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update Treatment Group D to include MDS 
subjects, update dose interruption and modification guidance, update inclusion criteria, and 
update the schedule of assessments for MF subjects.  This amendment includes the changes to 
Protocol INCB 59872-101 Amendment 5 (30 JUL 2018) summarized below.  A redline version 
of the amendment depicting the updated and previous text is also provided. 
1. Synopsis; Section 2.2.2, Secondary Endpoints; 
; 
Section 3.1, Subject Inclusion Criteria; Section 4.1.3, Combination Dose-Finding 
(Part 3); Section 4.1.4, Combination Dose-Expansion (Figure 1, Study Design); 
Section 9.6, Interim Analysis 
Description of change:  All applicable sections have been updated to include MDS 
subjects eligible to receive azacitidine as first-line therapy in Treatment Group D for 
Parts 3 and 4 of the Protocol. 
Rationale for change:  The scientific rationale that was applicable to AML is also 
applicable for MDS patients. 
2. Synopsis; Section 4.1.4, Combination Dose Expansion (Part 4); Section 9.6, Interim 
Analysis 
Description of change:  Futility analysis was updated to include MLFS in the AML 
interim analysis. 
Rationale for change:  Revised to include subjects who are having a response in the 
absence of platelet recovery due to on-target activity of LSD1 inhibition. 
3. Synopsis; Section 3.2, Subject Exclusion Criteria 
Description of change:  Exclusion Criterion #7 was updated to allow subjects to enroll 
in the study with a QTc interval of up to 470 milliseconds. 
Rationale for change:  Updated as a more appropriate criterion in this patient 
population. 
4. Section 5.4.1, Dose Modification of INCB059872 
Description of change:  Updated dose modification guidance for INCB059872 to permit 
subjects in Treatment Groups C and D having a bone marrow blast response to explore a 
less intensive dosing regimen. 
Rationale for change:  Updated to allow for platelet recovery in subjects demonstrating 
a bone marrow blast response that may not otherwise occur on the recommended dosing 
regimen due to the activity of INCB059872. 
5. Section 5.4.7, Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB059872 (Table 5:  Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  Table 5 was updated to provide additional guidance and 
clarification regarding the guidance for interruption and restarting INCB059872 for 
thrombocytopenia in AML/MDS/MF. 




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Amendment 5 (30 JUL 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update and add treatment modification guidance for 
SAEs with suspected causal relationship to study drug.  This amendment includes the changes to 
Protocol INCB 59872-101 Amendment 4 (06 NOV 2017) summarized below.  A redline version 
of the amendment depicting the updated and previous text is also provided. 
1. Section 5.4.7, Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB059872 (Table 5: Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  Table 5 was updated to include additional guidance for 
treatment modification or discontinuation with decreases in platelets or leukocytosis. 
Rationale for change:  To provide additional guidance for dose modifications and 
ensure patient safety, to the extent possible, in this difficult population. 
2. Synopsis; Section 8.7, Data Monitoring Committee; Section 9.5, Analyses for the 
Data Monitoring Committee 
Description of change:  All relevant sections were updated to iDSMB from SMC. 
Rationale for change:  To provide consistency with the internal name given to the safety 
monitoring board implemented in this study. 
3. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 4 (06 NOV 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the selected doses for monotherapy 
expansion in Part 2, update the starting doses of INCB059872 in Part 3, clarify DLT evaluability 
criteria, add early stopping rules for futility in Part 4, adjust the endpoints, revise the eligibility 
criteria for Cohorts D and D1, add an internal safety committee, and remove references to a 
pharmacologically active dose.  This amendment includes the changes to Protocol 
INCB 59872-101 Amendment 3 (22 SEP 2017) summarized below.  A redline version of the 
amendment depicting the updated and previous text is also provided. 
1. Synopsis; Section 4.1.2, Monotherapy Dose Expansion (Part 2); Section 4.1.3, 
Combination Dose-Finding (Part 3) 
Description of change:  The selected doses for monotherapy expansion in Part 2 were 
included to specify that expansion cohort TG A1 would be at INCB059872 4 mg QD and 
monotherapy dose expansion cohorts TG A2, TG B1, and TG B2 would be at 
INCB059872 3 mg QOD.  The selected starting does for combination dose-finding 
(Part 3) were included to specify that Combination TG C and TG D would start at 
INCB059872 2 mg QD in combination with either ATRA or azacitidine and that TG E 
would start at INCB059872 3 mg QOD in combination with nivolumab.  All relevant 
Protocol sections were revised accordingly. 
Rationale for change:  Per FDA recommendation. 
2. Synopsis; Section 4.1.1, Monotherapy Dose Escalation (Part 1); Section 4.1.3, 
Combination Dose-Finding (Part 3); Section 4.3.2, Replacement of Subjects 
Description of change:  Revised to clarify that if a subject does not complete the 
minimum number of doses and still has a DLT, the DLT will be counted in the numerator 
for the purposes of dose escalation decisions.  All relevant Protocol sections were revised 
accordingly. 
Rationale for change:  Per FDA recommendation. 
3. Synopsis;  Section 4.1.4, Combination Dose Expansion (Part 4); Section 9.6, Interim 
Analysis 
Description of change:  Revised to include interim futility analysis for each of the 
treatment groups in Part 4. 
Rationale for change:  Per FDA recommendation. 
4. Synopsis; Section 2, Study Objectives and Endpoints 
Description of change:  Objectives were revised to include determination of recommend 
dose for further study in Part 3.  For Parts 2 (monotherapy dose expansion) and 4 
(combination dose expansion), the primary objective was revised to assess safety and 
tolerability, the objective of preliminary antitumor activity was changed to a secondary 
objective, 
.  All 
corresponding endpoints and relevant Protocol sections were revised accordingly. 






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Rationale for change:  To provide additional clarification of the population requiring 
medical monitor approval for values below the lower limits in select laboratory values 
and to provide appropriate requirements for subjects with liver metastases. 
5. Synopsis; Section 5, Treatment 
Description of change:  Addition of text to specify the number of doses and guidance 
missed doses within a cycle using the once daily (QD) schedule. 
Rationale for change:  To provide clarification for dosing in the QD schedule. 
6. Section 1.6.2, Clinical Experience With INCB059872 
Description of change:  This section was updated to include a preliminary, unaudited 
summary of safety data from the INCB 59872-101 study inclusive of the monotherapy 
dose cohorts initial evaluation period for the proposed INCB59872 starting doses in the 
added combination cohorts. 
Rationale:  To provide an updated summary of the adverse event data observed in this 
study. 
7. Section 5.1.1, Subject Numbering and Treatment Assignment 
Description of change:  Addition of text to include that sites will have to contact the 
Interactive Response Technology (IRT) at the time of subject enrollment to receive a 
subject number and to update the IRT system at each visit to receive the treatment 
allocation. 
Rationale:  To provide clarification of IRT procedures. 
8. Section 5.6, Concomitant Medications 
Description of change:  This section was updated to include additional information for 
recording concomitant medications in the electronic case report form. 
Rationale:  To provide clarification for recording concomitant medications. 
9. Synopsis; Table 7, Schedule of Assessments 
Description of change:  This section was updated to include a timeframe for computed 
tomography or magnetic resonance imaging assessments for solid tumors and to adjust 
the timeframe for Cycle 2 Day 1 assessments. 
Rationale:  To provide clarification and flexibility for efficacy assessments in solid 
tumors and to provide consistency for the time window for scheduled visits. 
10. Synopsis; Section 8.7, Data Monitoring Committee 
Description of change:  This section was updated to provide details for the safety and 
data meetings occurring throughout the study. 
Rationale:  To provide clarification of the attendees and meetings, which will occur 
throughout the study, regarding dose escalation, safety, etc. 
11. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 2 (28 JUL 2016) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to update the language in the inclusion and exclusion 
criteria to provide more clarity, to provide additional language regarding different regimens to be 
explored in this study, and to update Tables 1 through 5.   
The changes made to the Protocol INCB 59872-101 Amendment 1 (19 JAN 2016) are 
summarized below.  A redline version of the amendment depicting the updated and previous text 
is also provided. 
1. Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  In inclusion criterion #5, the number of slides from biopsy has 
been changed from 25 unstained slides (with a minimum of 15) to approximately 
15 slides. 
Rationale for change:  This will allow more flexibility in what sites will be able to 
provide. 
2. Synopsis; Section 3.2, Subject Exclusion Criteria 
a. Description of changes:  Language added at the end of exclusion criterion #5:   
"Laboratory and medical history parameters outside Protocol-defined range unless 
associated with primary malignancy or metastatic disease and with medical monitor 
approval." 
Rationale for change:  To not exclude subjects with laboratory abnormalities due to 
malignancy. 
b. Description of change:  Exclusion criterion #8 was revised to indicate that subjects 
must have recovered from all radiation-related toxicities, including radiation 
pneumonitis (instead of requiring that subjects have not had radiation pneumonitis). 
Rationale for change:  The exclusion criterion was reworded to be clear that the 
radiation pneumonitis was associated with the last radiation therapy. 
c. Description of change:  Exclusion criterion #11 has been split into 2 criteria:  #11 is 
now "History of human immunodeficiency virus infection" and #23 is "Evidence of 
active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection." 
Rationale for change:  To provide clarity to the different issues that need to be 
regarded for exclusion; to provide a simple definition for hepatitis B and hepatitis C 
exclusion criteria. 
d. Description of change:  A temporal condition has been added to exclusion criterion 
#13:  "History of clinically significant or uncontrolled cardiac disease, including 
recent history (within 6 months) of unstable angina, acute myocardial infarction, New 
York Heart Association Class III or IV congestive heart failure, or arrhythmia 
requiring therapy." 
Rationale for change:  To ensure that subjects are not entering study with an 
unstable cardiac condition. 


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3. Section 4.1, Overall Study Design 
Description of change:  Language has been added to clarify the option to explore a 
different dosing regimen and how the dose will be selected:  "Subjects will receive 
INCB059872 doses once QOD on a 28-day continuous therapy schedule; if QOD is well 
tolerated, the next dose may be administered at a different dosing regimen (ie, QD) but 
will not exceed the 100% dose escalation for a total daily dose." 
Rationale for change:  To provide more clarity to steps for dose increase/regimen 
adjustment. 
4. Section 5.4.2, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose of INCB059872 (Table 1:  Definition of Dose Limiting Toxicity) 
Description of change:  Conditions for febrile neutropenia were changed from "all 
tumor types" to "for solid tumors only." 
Rationale for change:  Febrile neutropenia is not a relevant dose-limiting toxicity for 
hematologic malignancies. 
5. Section 5.4.6, Criteria and Procedures for Dose Interruptions and Adjustments of 
INCB059872 (Table 2:  Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  Parameters for ALT and AST have been changed to allow up to 
20 × the upper limit of normal before discontinuation.  
Rationale for change:  More flexibility is required based on tumor types and disease 
process. 
6. Synopsis 
Description of change:  Under Study Schedule/Procedures, the following sentence was 
deleted from the "Laboratory tests for safety" section:  "Subjects with AML/MDS/MF 
will have bone marrow aspirate/biopsy evaluations and laboratory assessments as part of 
the disease response assessment performed."  In the "Clinical assessments" section, the 
list of examples for assessment of disease status at screening was revised to include bone 
marrow biopsy/aspirate and peripheral blood. 
Rationale for change:  Tables 3 and 4 were modified to provide more clarity to the 
procedures required and the tissue required for the analysis at the different timepoints. 
7. Section 5.8.4, Criteria and Procedures for Dose Increases of INCB059872 
Description of change:  The fourth bullet was revised to indicate "The subject is willing 
to submit to the PK sampling and safety monitoring schedules as in Cycle 1 Day 15." 
Rationale for change:  This language was added to ensure it was clear that subjects 
whose dose of study is increase must allow additional pharmacokinetic and safety 
monitoring that is outlined in Cycle 1 Day 15. 


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8. Section 6, Study Assessments (Table 3: Schedule of Assessments; Table 4: Schedule 
of Laboratory Assessments; Table 5: Local Laboratory Tests: Required Analytes) 
Description of change:  Modifications were made to Tables 3 through 5 to clarify 
clinical and laboratory assessment schedules and ensure correlation with the body text of 
the Protocol. 
Rationale for change:  The tables were updated for clarity and better instruction for the 
clinical sites. 
9. Section 7.5.4, Electrocardiograms 
Description of change:  More detail added regarding the timing for single 
electrocardiograms (ECGs) and triplicate ECGs. 
Rationale for change:  To clarify the ECG procedures and make the text consistent with 
the Schedule of Assessments (Table 4). 
10. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment, including changes noted in Protocol Administrative Change 1 (dated 
08 MAR 2016):  deleting the safety laboratory line item and adding the survival 
follow-up visit in Table 3; adding lipid panel to Table 4; and adding blood urea nitrogen 
to Table 5. 


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Amendment 1 (19 JAN 2016) 
Overall Rationale for the Amendment: 
The primary purpose of Amendment 1 is to delete combination therapy from the study design, 
refine exclusion criteria, add to the prohibited medication list, increase dose-limiting toxicity 
language, improve language for restarting study drug and at what increments, and add stopping 
rules.   
The changes made to the Protocol INCB 59872-101 (15 DEC 2015) are summarized below.  A 
redline version of the amendment depicting the updated and previous text is also provided. 
1. Synopsis; Section 1, Introduction; Section 2, Study Objectives and Endpoints; 
Section 3, Subject Eligibility; Section 4, Investigational Plan; Section 5, Treatment; 
Section 6, Study Assessments; Section 7.7.4, Food-Effect PK Testing; Section 8.3.2, 
Reporting; Section 9.2, Selection of Sample Size; Section 11, References 
Description of change:   All references to combination treatment have been removed.  The 
study design has changed to include only Part 1 (dose escalation) and Part 2 (dose 
expansion).  The additional treatment groups and parts associated with combination therapy 
have been removed.  The number of subjects has been updated accordingly (total number of 
subjects is now 108 instead of 230).  Additionally, the background, risk, and dosing 
information on the 3 combination therapies have been removed.  In Section 11, references 
supporting the combination and product inserts for the combination products have been 
deleted.  Figure 1 (Study Design) has been updated, and Table 3 (Schedule of Assessments) 
has been updated to delete the administration of the combination products.   
Rationale for change:  Per FDA request. 
2. Synopsis; Section 3, Study Population 
Description of change:  The study population language has been refined to read, "Subjects 
with advanced or metastatic malignancies who are ineligible for all therapeutic options that 
are standard of care or known to confer benefit, or who refuse these treatments." 
Rationale for change:  Per FDA request.  Language was provided by Agency. 
3. Synopsis; Section 4.1, Overall Study Design 
Description of change:  The following language was added:  "Dose escalation should 
proceed in smaller increments (ie, by no more than 50%) if a DLT is observed, or if 2 or 
more subjects at a given dose level experience Grade 2 or higher AEs (unless they are clearly 
and incontrovertibly due to an alternative cause)." 
Rationale for change:  Per FDA request.  Language was provided by Agency. 
4. Table 1:  Definition of Dose-Limiting Toxicity 
Description of change:  Delete "Other events considered no clinical significant in the 
judgment of the investigator" from nonhematologic toxicity. 
Rationale for change:  Per FDA request. 





SAP_001.pdf: 
Official Title:
NCT Number:
Document Date:
A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, 
Safety and Tolerability Study of INCB059872 in Subjects With 
Advanced Malignancies
NCT02712905
Statistical Analysis Plan Version 1: 01-October-2018


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INCB 59872-101 Statistical Analysis Plan 
01 OCT 2018 
STATISTICAL ANALYSIS PLAN 
INCB 59872-101 
A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety 
and Tolerability Study of INCB059872 in Subjects With Advanced 
Malignancies 
IND Number: 
EudraCT Number 
2017-001710-28 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment (Version) 5 dated 30 JUL 2018 
CRF Approval Date: 
23 APR 2018 
SAP Version: 
Original 
SAP Author: 
, PhD 
 Biostatistics 
Date of Plan: 
01 OCT 2018 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 
CONFIDENTIAL 


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INCB 59872-101 Statistical Analysis Plan 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1.
INTRODUCTION ........................................................................................................8 
2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Study Objectives ...........................................................................................................9 
2.2.1. 
Primary Objectives .......................................................................................................9 
2.2.2. 
Secondary Objectives ...................................................................................................9 
 
 .................................................................................................9 
2.3. 
Study Endpoints ..........................................................................................................10 
2.3.1. 
Primary Endpoints ......................................................................................................10 
2.3.2. 
Secondary Endpoints ..................................................................................................10 
 
 ................................................................................................10 
3.
STUDY DESIGN .......................................................................................................11 
3.1. 
Randomization ............................................................................................................13 
3.2. 
Control of Type I Error ...............................................................................................13 
3.3. 
Sample Size Considerations .......................................................................................14 
3.4. 
Schedule of Assessments ............................................................................................14 
4.
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................15 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................15 
4.1.1. 
Day 1 ...........................................................................................................................15 
4.1.2. 
Study Day ...................................................................................................................15 
4.1.3. 
Baseline Value ............................................................................................................15 
4.1.4. 
Handling of Missing and Incomplete Data .................................................................16 
4.1.5. 
Cycle Length and Duration .........................................................................................16 
4.2. 
Variable Definitions ....................................................................................................16 
4.2.1. 
Body Mass Index ........................................................................................................16 
4.2.2. 
Body Surface Area ......................................................................................................17 
4.2.3. 
Prior and Concomitant Medication .............................................................................17 
5.
STATISTICAL METHODOLOGY ...........................................................................18 
5.1. 
General Methodology .................................................................................................18 
5.2. 
Treatment Groups .......................................................................................................18 
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5.3. 
Analysis Populations ..................................................................................................19 
5.3.1. 
Full Analysis Set .........................................................................................................19 
5.3.2. 
Safety Population ........................................................................................................19 
5.3.3. 
Pharmacokinetic Evaluable Population ......................................................................19 
6.
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND
ANALYSES ...............................................................................................................20 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............20 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................20 
6.1.2. 
Disease History ...........................................................................................................20 
6.1.3. 
Prior Cancer Therapy ..................................................................................................21 
6.1.4. 
Medical History ..........................................................................................................21 
6.2. 
Disposition of Subjects ...............................................................................................21 
6.3. 
Protocol Deviations ....................................................................................................21 
6.4. 
Exposure .....................................................................................................................21 
6.4.1. 
Exposure for INCB059872 .........................................................................................21 
6.4.2. 
Exposure for All-Trans Retinoic Acid ........................................................................22 
6.4.3. 
Exposure for Azacitidine ............................................................................................22 
6.4.4. 
Exposure for Nivolumab .............................................................................................22 
6.5. 
Study Drug Compliance .............................................................................................23 
6.6. 
Prior and Concomitant Medication .............................................................................23 
7.
EFFICACY .................................................................................................................24 
7.1. 
General Considerations ...............................................................................................24 
7.2. 
Efficacy Hypotheses ...................................................................................................24 
7.3. 
Analysis of the Efficacy Parameters ...........................................................................24 
7.3.1. 
Solid Tumors ..............................................................................................................24 
7.3.1.1. 
Response Assessment .................................................................................................24 
7.3.1.2. 
Best Overall Response and Objective Response Rate ................................................24 
 
 ..........................................................................................................25 
 
 ..........................................................................................25 
 
 .................................................................................................26 
7.3.1.6. 
Best Change in Target Lesion Size .............................................................................26 
7.3.2. 
Acute Myeloid Leukemia ...........................................................................................26 
7.3.2.1. 
Response Assessment .................................................................................................26 
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7.3.2.2. 
Best Overall Response and Objective Response Rate ................................................27 
 
 ..........................................................................................................27 
 
 ..........................................................................................28 
 
 .................................................................................................28 
7.3.3. 
Myelodysplastic Syndrome ........................................................................................28 
7.3.3.1. 
Response Assessment .................................................................................................28 
7.3.3.2. 
Best Overall Response and Objective Response Rate ................................................29 
 
 ..........................................................................................................30 
 
 ..........................................................................................30 
 
 .................................................................................................30 
7.3.4. 
Myelofibrosis ..............................................................................................................30 
7.3.4.1. 
Spleen Volume Reduction ..........................................................................................30 
 
 .......................................31 
 
 .........................................................................31 
7.4. 
Analysis of Other Efficacy Variables .........................................................................31 
7.4.1. 
Eastern Cooperative Oncology Group Performance Status ........................................31 
8.
PHARMACOKINETIC ANALYSES ........................................................................32 
9.
SAFETY AND TOLERABILITY ..............................................................................32 
9.1. 
General Considerations ...............................................................................................32 
9.2. 
Adverse Events ...........................................................................................................32 
9.2.1. 
Adverse Event Definitions ..........................................................................................32 
9.2.2. 
Dose-Limiting Toxicities ............................................................................................33 
9.2.3. 
Immune-Related Adverse Events ...............................................................................33 
9.2.4. 
Adverse Event Summaries ..........................................................................................33 
9.3. 
Clinical Laboratory Tests ...........................................................................................34 
9.3.1. 
Laboratory Value Definitions .....................................................................................34 
9.3.2. 
Laboratory Value Summaries .....................................................................................35 
9.4. 
Vital Signs ..................................................................................................................35 
9.5. 
Electrocardiograms .....................................................................................................35 
10.
INTERIM ANALYSES ..............................................................................................37 
10.1. 
Overview of Interim Analyses ....................................................................................37 
10.2. 
Derivations and Calculations for Interim Analyses ....................................................37 
11.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................38 
CONFIDENTIAL 


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11.1. 
Changes to Protocol-Defined Analyses ......................................................................38 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................38 
12.
REFERENCES ...........................................................................................................39 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................40 
LIST OF TABLES 
Table 1: 
Probability of Dose Escalation by DLT Rate .............................................................14 
 
 ............................................25 
Table 3: 
Confirmation of Complete Remission, Partial Remission, and Marrow 
Complete Remission for Myelodysplastic Syndrome ................................................29 
Table 4: 
Normal Ranges for Vital Sign Values ........................................................................35 
Table 5: 
Normal Ranges for Electrocardiogram Values ...........................................................36 
Table 6: 
Statistical Analysis Plan Versions ..............................................................................38 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................13 
CONFIDENTIAL 


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01 OCT 2018 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AML 
acute myeloid leukemia 
ATRA 
all-trans retinoic acid 
BMI 
body mass index 
BOR 
best overall response 
bpm 
beats per minute 
BSA 
body surface area 
CCyR 
complete cytogenetic response 
CI 
confidence interval 
CMR 
complete molecular response 
CR 
complete remission/complete response 
CRF 
case report form 
CRi 
Complete remission with incomplete hematologic recovery 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration (US) 
HI-E 
hematologic improvement-erythroid response 
HI-N 
hematologic improvement-neutrophil response 
HI-P 
hematologic improvement-platelet response 
IPSS-R 
International Prognostic Scoring System Risk 
irAE 
immune-related adverse event 
IWG 
International Working Group 
LSD1 
lysine-specific demethylase 1 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MLFS 
morphologic leukemia-free state 
CONFIDENTIAL 


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INCB 59872-101 Statistical Analysis Plan 
01 OCT 2018 
Abbreviation 
Definition 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NA 
not applicable 
NE 
not evaluable 
ORR 
objective response rate 
PCyR 
partial cytogenetic response 
PD 
progressive disease 
PK 
pharmacokinetic 
PR 
partial remission/partial response 
PT 
preferred term 
QD 
once daily 
QOD 
every other day 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TG 
treatment group 
TSS 
total symptom score 
WHO 
World Health Organization 
CONFIDENTIAL 




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2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS
2.1. 
Protocol and Case Report Form Version
This SAP is based on INCB 59872-101 Protocol Amendment 5 dated 30 JUL 2018 and CRFs 
approved 23 APR 2018.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and CRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
•
Part 1:  To evaluate the safety and tolerability and determine the recommended
dose(s) of INCB059872 for further study in advanced malignancies.
•
Part 2:  To further evaluate the safety and tolerability of INCB059872 for further
study in advanced malignancies.
•
Part 3:  To evaluate the safety and tolerability and determine the recommended dose
of INCB059872 in combination with other therapies for further study in advanced
malignancies.
•
Part 4:  To further evaluate the safety and tolerability of INCB059872 in
combination with other therapies in advanced malignancies.
2.2.2. 
Secondary Objectives
•
Parts 1 and 2:  To assess preliminary antitumor activity of INCB059872 as a
monotherapy in subjects with advanced malignancies.
•
Parts 3 and 4:  To assess preliminary antitumor activity of INCB059872 in
combination with other therapies in subjects with advanced malignancies.
•
To evaluate the PK of INCB059872 and assess the effect of food (TG B1 only) on the
PK of INCB059872.
 
CONFIDENTIAL 


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2.3. 
Study Endpoints 
2.3.1. 
Primary Endpoints 
•
Parts 1 and 2:  Safety and tolerability as assessed by monitoring frequency, duration,
and severity of AEs, through physical examinations, by evaluating changes in vital
signs and ECGs, and through clinical laboratory blood and urine sample evaluations.
•
Parts 3 and 4:  Safety and tolerability as assessed by monitoring frequency, duration,
and severity of AEs, through physical examinations, by evaluating changes in vital
signs and ECGs, and through clinical laboratory blood and urine sample evaluations
in combinations therapies.
2.3.2. 
Secondary Endpoints
•
Parts 1 and 2:  Tumor response rates in those subjects with measurable disease or
spleen volume changes as determined by investigator assessment of response per
disease-specific guidelines.
−
Solid tumors:  ORR, defined as the percentage of subjects having CR or PR will
be determined by the investigator assessment of radiographic disease assessments
per RECIST v1.1.
−
AML/MDS:  ORR, defined as the proportion of subjects who achieve CR or CRi
per the IWG Response Criteria for AML or the IWG Response Criteria for MDS,
as applicable.
−
MF:  Change and percentage change in spleen volume as measured by MRI
(CT scan in subjects who are not a candidate for MRI or when MRI is not readily
available) at Week 12 when compared with baseline.
•
Parts 3 and 4:  Tumor response rates in those subjects with measurable disease as
determined by investigator assessment of response per disease-specific guidelines.
−
SCLC:  ORR, defined as the percentage of subjects having CR or PR will be
determined by the investigator assessment of radiographic disease assessments
per RECIST v1.1.
−
AML:  ORR, defined as the proportion of subjects who achieve CR or CRi per the
IWG Response Criteria for AML.
•
PK parameters of INCB059872 in plasma:  Cmax, Tmax, Cmin, AUC0-t, t½, and Cl/F.
 
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3. 
STUDY DESIGN 
This is an open-label, dose-escalation/dose-expansion study of the LSD1 inhibitor INCB059872 
as a monotherapy and combination therapy in subjects with advanced malignancies.  As 
illustrated in Figure 1, the study will be conducted in 4 parts:  Parts 1 and 2 will evaluate 
INCB059872 as a monotherapy, with Part 1 for dose escalation and Part 2 for dose expansion, 
and Parts 3 and 4 will evaluate INCB059872 in combination with select therapies, with Part 3 for 
combination dose escalation and Part 4 for combination dose expansion.  Part 1 (monotherapy 
dose escalation) will determine the dose(s) of INCB059872 for dose expansion, based on the 
MTD.  The recommended dose(s) will be taken forward into Part 2 (monotherapy dose 
expansion).  The initiation of Part 2 will be based on further review of the ongoing clinical study 
and preclinical data of INCB059872 and information from literature.  Part 3 (dose escalation of 
INCB059872 in combination therapy) will be initiated after the MTD in Part 1 is determined.  
Part 4 (dose expansion of INCB059872 in combination therapy) will explore the dose(s) 
confirmed in Part 3 and may be different based on combination therapy and/or tumor type. 
In Part 1, TG A will enroll subjects with AML or MDS.  The enrollment in TG B is prioritized 
for SCLC.  Enrollment of subjects with other solid malignancies (eg, endocrine tumors) is 
allowed with sponsor medical monitor approval.  Dose escalation for TG A and TG B in Part 1 
will proceed independently, with each treatment group following a 3 + 3 design.  The starting 
dose of INCB059872 for TG A and TG B will be 2 mg QOD.  If QOD is well-tolerated, the next 
dose may be administered at a different dosing regimen (ie, once daily) but will not exceed the 
100% dose escalation for a total daily dose.  Upon identification of the recommended dose(s), up 
to 4 expansion cohorts per tumor type of approximately 15 subjects each may begin enrollment 
in Part 2 to further determine the safety, tolerability, efficacy, PK, and pharmacodynamics of the 
selected dose(s). 
In Part 2, TG A1 will enroll subjects with AML or MDS and subjects in this cohort will have an 
opportunity to switch their treatment to a combination dose that is tested and found safe.  
Treatment Group A2 will enroll subjects with primary myelofibrosis or secondary MF 
(post–polycythemia vera myelofibrosis or post–essential thrombocythemia myelofibrosis).  
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Treatment Group B1 will enroll subjects with SCLC.  Treatment Group B2 will enroll subjects 
with Ewing's sarcoma and poorly differentiated neuroendocrine tumors. 
Part 3 enrollment will be initiated after the MTD has been determined in Part 1 and will include 
dose-finding to evaluate safety and tolerability of the combinations.  Dose-finding will use a 
3 + 3 design to evaluate different doses of INCB059872 in combination with other therapies in 
the following treatment groups: 
• Combination TG C will evaluate INCB059872 in combination with ATRA in 
subjects with relapsed/refractory AML.  The starting dose for INCB059872 in this 
cohort will be 2 mg QD (2 dose levels below the recommended dose for monotherapy 
expansion in TG A1). 
• Combination TG D will evaluate INCB059872 in combination with azacitidine in 
subjects with newly diagnosed, treatment-naive AML who are unfit to tolerate 
standard intensive chemotherapy at study entry.  The starting dose for INCB059872 
in this cohort will be 2 mg QD (2 dose levels below the recommended dose for 
monotherapy expansion in TG A1). 
• Combination TG E will evaluate INCB059872 in combination with nivolumab in 
subjects with advanced SCLC previously progressed on platinum-based treatment.  
The starting dose for INCB059872 in this cohort will be 3 mg QOD (the 
recommended dose for monotherapy expansion in TG B1). 
Upon identification of the recommended dose(s) for each treatment combination in Part 3, 
expansion cohorts of approximately 30 subjects in each treatment group may begin enrollment in 
Part 4 to further determine the safety, tolerability, efficacy, PK, and pharmacodynamics of the 
selected dose(s).  In Part 4, combination TG C1 will evaluate INCB059872 in combination with 
ATRA using the regimen identified in Part 3 in subjects with relapsed/refractory AML.  
Combination TG D1 will evaluate INCB059872 in combination with azacitidine using the 
regimen identified in Part 3 in subjects with newly diagnosed, treatment-naive AML who are 
unfit to tolerate standard intensive chemotherapy at study entry.  Combination TG E1 will 
evaluate INCB059872 in combination with nivolumab using the regimen identified in Part 3 in 
subjects with advanced SCLC who previously progressed on platinum based treatment. 
In Part 4, a stopping rule for futility is planned for each combination dose expansion treatment 
group when 15 subjects have been treated and evaluated for response or have permanently 
discontinued study treatment because of disease progression, withdrawal of consent, or death.  
Combination TG C1 will be terminated for futility if ≤ 1 of the 15 subjects responded (ie, CR or 
CRi) based on assessments provided by investigator.  Combination TG D1 will be terminated for 
futility if ≤ 2 of the 15 subjects responded (ie, CR or CRi) based on assessments provided by 
investigator.  Combination TG E1 will be terminated for futility if ≤ 1 of the 15 subjects 
responded (ie, CR or PR) based on assessments provided by investigator. 
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Figure 1: 
Study Design 
 
3.1. 
Randomization 
Not applicable. 
3.2. 
Control of Type I Error 
All statistical analyses are exploratory in nature.  Unless otherwise specified, all CIs provided 
will be at the 95% CI. 
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3.3. 
Sample Size Considerations 
Parts 1 and 3 of the study will use a standard 3 + 3 dose-escalation design, and the sample size 
will depend on the frequency of DLTs and the number of dose-escalation cohorts studied before 
reaching the MTD.  Approximately 3 to 6 subjects will be enrolled in each dose level.  Using this 
design, the probability of dose escalation for various DLT rates is given in Table 1. 
Table 1: 
Probability of Dose Escalation by DLT Rate 
True DLT Rate 
Probability of Dose Escalation 
10% 
90.6% 
20% 
70.9% 
30% 
49.4% 
40% 
30.9% 
50% 
17.2% 
60% 
8.2% 
For Part 2, approximately 15 subjects will be enrolled for each expansion cohort.  The evaluation 
of 15 subjects will provide a ≥ 90% chance of observing at least 1 toxicity with a true event rate 
of ≥ 15%. 
For Part 4, for each of the combination cohorts (TGs C1, D1, and E1), up to approximately 
30 subjects will be enrolled.  The evaluation of 30 subjects will provide approximately 90% 
chance of observing at least 1 toxicity with a true event rate of ≥ 7%. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 5 dated 30 JUL 2018 for a full description of all study procedures 
and assessment schedules for this study. 
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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
For monotherapy (Parts 1 and 2), Day 1 is the date that the first dose of INCB059872 is 
administered to the subjects. 
For combination therapy (Parts 3 and 4), Day 1 is the date that the first dose of study treatment 
(INCB059872, ATRA, azacitidine, or nivolumab) is administered to the subjects.  
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
For monotherapy (Parts 1 and 2), baseline is the last nonmissing measurement obtained before 
the first administration of INCB059872, unless otherwise defined. 
For combination therapy (Parts 3 and 4), baseline is the last nonmissing measurement obtained 
before the first administration of INCB059872 and ATRA (TGs C and C1), INCB059872 and 
azacitidine (TGs D and D1), or INCB059872 and nivolumab (TGs E and E1), unless otherwise 
defined. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
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4.1.4. 
Handling of Missing and Incomplete Data  
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 
When calculating time since diagnosis of cancer, partial cancer diagnosis date will be handled as 
follows: 
• If only the day is missing, then the imputed day will be the first of the month. 
• If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
• No imputation will be done if the date is completely missing. 
Missing or partial date of last dose will be handled as follows: 
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the last day of the month or the date that the subject discontinued treatment. 
• Otherwise, the date that the subject discontinued treatment will be used as the date of 
the last dose. 
For relevant efficacy endpoints, partial date of death will be imputed as follows: 
• If mmyyyy for the last known alive date = mmyyyy for the death date, then the death 
date will be set to the day after the last known alive date. 
• If mmyyyy for the last known alive date < mmyyyy for the death date, then the death 
date will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 
4.1.5. 
Cycle Length and Duration 
Azacitidine will be administered as an open-label commercial product at a starting dose of 
75 mg/m2 subcutaneously or intravenously for 7 days during the first 9-day or less period 
(ie, a 2-day break allowed on weekend, if needed) of each 28-day treatment cycle.  Nivolumab 
will be administered at a dose of 3 mg/kg as an intravenous infusion over 60 minutes every 
2 weeks (Day 1 and Day 15 of each 28-day treatment cycle). 
For combination therapy (Parts 3 and 4), Cycle 1 Day 1 is the day that the first dose of 
INCB059872, ATRA, azacitidine, or nivolumab is administered.  Actual Day 1 of subsequent 
cycles will correspond with the first day of administration of azacitidine or nivolumab in that 
cycle; thus, treatment cycles may become out of sync with the originally planned schedule and 
cycle length may be different from 28 days.  The date of Day 1 of subsequent cycles recorded on 
the eCRF will be used as Day 1 of the subsequent cycles. 
4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
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4.2.2. 
Body Surface Area 
For subjects in TGs C and C1 and TGs D and D1 (Parts 3 and 4), the BSA will be calculated 
based on the Mosteller (1987) formula as follows: 
BSA (m2) = {[weight (kg) × height (cm)] / 3600}½. 
4.2.3. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
INCB059872 (Parts 1 and 2), INCB059872 and ATRA (TGs C and C1), INCB059872 and 
azacitidine (TGs D and D1), or INCB059872 and nivolumab (TGs E and E1). 
Concomitant medication is defined as any nonstudy medication that is started accordingly:  
• Before the date of first administration of INCB059872 (Parts 1 and 2), INCB059872 
and ATRA (TGs C and C1), INCB059872 and azacitidine (TGs D and D1), or 
INCB059872 and nivolumab (TGs E and E1) and is ongoing throughout the study or 
ends on/after the date of first study treatment administration. 
• On/after the date of first administration of INCB059872, ATRA, azacitidine, or 
nivolumab and is ongoing or ends during the course of study treatment 
administration. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCB059872, ATRA, azacitidine, or nivolumab.  In the listing, it 
will be indicated whether a medication is prior-only, concomitant-only, or both prior and 
concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; Version 9.4 or later) will 
be used for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries 
for continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
Interim analyses are planned for this study as defined in Section 10. 
5.2. 
Treatment Groups 
This is an open-label, dose-escalation/dose-expansion study of the LSD1 inhibitor INCB059872 
as a monotherapy and combination therapy in subjects with advanced malignancies.  The study 
will be conducted in 4 parts:  Parts 1 and 2 will evaluate INCB059872 as monotherapy, with 
Part 1 for dose escalation and Part 2 for dose expansion, and Parts 3 and 4 will evaluate 
INCB059872 in combination with select therapies, with Part 3 for combination dose escalation 
and Part 4 for combination dose expansion. 
For monotherapy, Parts 1 and 2 will be combined for summary purposes.  Disease history and 
efficacy endpoints will be summarized by tumor types (AML, MF, MDS, SCLC, Ewing's 
sarcoma, poorly differentiated neuroendocrine, and other solid tumors).  Within each tumor type, 
data will be summarized overall and by dose levels based on the dose regimen initially assigned.  
Summary tables for some tumor types may be replaced with listings when appropriate.  For 
instance, an efficacy summary table for a cancer type may be replaced with a listing if this cancer 
type only contains a few subjects.  All other data, including demographics, baseline disease 
characteristics, disposition, and safety, will be summarized separately for hematologic 
malignancies (TG A/A1/A2 combined as Group A) and solid tumor malignancies (TG B/B1/B2 
combined as Group B).  Within each group, data will be summarized overall and by dose levels 
based on the dose regimen initially assigned. 
For combination therapy (Parts 3 and 4), all data in dose escalation and dose expansion will be 
combined and summarized by the following defined groups:  
• Group C = TG C + TG C1; 
• Group D = TG D + TG D1; 
• Group E = TG E + TG E1. 
Within each group, data will be summarized overall and by dose levels based on the dose 
regimen initially assigned. 
In the event that several dose regimens tested are deemed substantially below the MTD, these 
doses may be combined for summary purposes. 
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5.3. 
Analysis Populations 
5.3.1. 
Full Analysis Set 
The FAS includes all subjects enrolled in the study who received at least 1 dose of INCB059872, 
ATRA, azacitidine, or nivolumab. 
The FAS will be used for the summary of demographics, baseline characteristics, subject 
disposition, and analyses of all efficacy data. 
5.3.2. 
Safety Population 
The safety population includes all enrolled subjects who received at least 1 dose of 
INCB059872, ATRA, azacitidine, or nivolumab. 
All safety analyses will be conducted using the safety population. 
5.3.3. 
Pharmacokinetic Evaluable Population 
The PK-evaluable population includes all subjects who received at least 1 dose of study 
treatment and provided at least 1 postdose sample (1 PK measurement).  The study 
pharmacokineticist will review data listings of study drug administration and sample records to 
identify subjects to be excluded from analyses of PK data. 
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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics will be summarized for the FAS:  age, sex, race, ethnicity, weight, 
height, BMI, and BSA (TGs C/C1 and TGs D/D1).  Size of spleen and liver by manual palpation 
(for subjects with MF as applicable), and ECOG performance status at baseline will be 
summarized and listed for the FAS. 
6.1.2. 
Disease History 
For AML subjects in the FAS, time since initial diagnosis, AML disease category, current WHO 
classification, French-American-British classification, European LeukemiaNET risk 
classification, presence of extramedullary disease, FLT3 status, IDH1 status, and IDH2 status 
will be summarized and listed. 
For MDS subjects in the FAS, time since initial diagnosis, current WHO classification, current 
IPSS-R group for MDS, and current IPSS-R prognostic variable for cytogenetics will be 
summarized and listed. 
For MF subjects in the FAS, time since initial diagnosis, current MF disease category, 
availability of bone marrow biopsy result, prior medications for MF, prior splenic irradiation, 
transfusion dependence per protocol definition, prognostic factors, IWG risk level, and 
JAK2 status will be summarized and listed. 
For SCLC subjects in the FAS, time since initial diagnosis, stage at initial diagnosis, current 
stage of disease, current sites of disease, MYC rearrangement status, and PD-L1 status will be 
summarized and listed.  
For Ewing's sarcoma subjects in the FAS, time since advanced/metastatic diagnosis, stage at 
initial diagnosis, grade at initial diagnosis, sites of disease at initial diagnosis, current stage of 
disease, current sites of disease, cytogenetics status, CDKN2A status, TP53 status, and 
STAG2 status will be summarized and listed. 
For subjects with poorly differentiated neuroendocrine in the FAS, time since initial diagnosis, 
stage at initial diagnosis, current stage of disease, current sites of disease, MYC rearrangement 
status, and PD-L1 status will be summarized and listed. 
For subjects with other solid tumors in the FAS, time since initial diagnosis, stage at initial 
diagnosis, current stage of disease, solid tumor cancer type, current sites of disease, 
MYC rearrangement status, and PD-L1 status will be summarized and listed. 
Time since diagnosis will be calculated as follows: 
Time since diagnosis (years) = (Day 1 date – date of diagnosis + 1) / 365.25. 
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6.1.3. 
Prior Cancer Therapy 
The number of prior systemic cancer therapy regimens will be summarized for all subjects in the 
FAS.  The component drugs of prior systemic therapy regimens will be coded using the WHO 
Drug Dictionary.  The number and percentage of subjects with each drug will be summarized by 
WHO drug class and WHO drug preferred term.  Regimen name, component drugs, start and 
stop dates, purpose of the regimen, best response, reason for discontinuation, and date of 
relapse/progression will be listed. 
The number of subjects who received prior radiation will be summarized for the FAS.  
Radiotherapy type, location of administration, start and stop dates, reason for regimen, total dose, 
and best response will be listed. 
The number of subjects who had prior surgery or surgical procedure for cancer treatment will be 
summarized for the FAS.  Date and description of the surgery/procedure will be listed. 
The number of subjects who had hematopoietic stem cell transplant (for hematologic tumor types 
as applicable) will be summarized for the FAS.  Date of transplant, type of transplant, source 
cell, line of therapy, best response, date of relapse/progression, and the regimen and drug names 
used with the transplant will be listed. 
6.1.4. 
Medical History 
Medical history will be coded to SOC and PT using MedDRA coding dictionary.  For subjects in 
the FAS, medical history will be summarized by SOC and PT and listed.  
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were treated, discontinued study treatment with a 
primary reason for discontinuation, and withdrew from the study with a primary reason for 
withdrawal will be summarized and listed for the FAS. 
The number of subjects enrolled by country and site will also be provided for the full analysis 
set. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be summarized and listed for the full analysis set. 
6.4. 
Exposure 
For subjects in the safety population, exposure to INCB059872, ATRA, azacitidine, and 
nivolumab will be summarized descriptively as the following: 
6.4.1. 
Exposure for INCB059872 
• Duration of treatment (days):  Date of last dose of INCB059872 – date of first dose 
of INCB059872 + 1. 
• Average reported daily dose of INCB059872 (mg/day):  Total reported 
INCB059872 dose (mg) / duration of treatment with INCB059872 (days). 
• Dose modifications for INCB059872: Number of subjects who had INCB059872 
dose reduction and interruption will be summarized. 
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6.4.2. 
Exposure for All-Trans Retinoic Acid 
• Duration of treatment (days):  Date of last dose of ATRA – date of first dose of 
ATRA + 1. 
• Average reported daily dose of ATRA (mg/day): Total reported ATRA dose (mg) / 
duration of treatment with ATRA (days). 
• Dose modifications for ATRA:  Number of subjects who had ATRA dose reduction 
and interruption will be summarized. 
6.4.3. 
Exposure for Azacitidine 
• Number of cycles:  Number of cycles with a nonzero dose of azacitidine. 
• Relative dose intensity of azacitidine (%):  100 × [total actual dose] / [total 
assigned dose]. 
Total actual dose (mg/m2) administered is the sum of the BSA-adjusted cumulative 
dose of azacitidine that has been administered to the subject. 
Total assigned dose (mg/m2) is the total dose expected if the subject had taken all 
doses as initially assigned.  Let S be the study day of the last date that the subject is 
exposed to azacitidine.  Let D be the assigned dose level of 75 in mg/m2.  The total 
assigned dose is defined as 
total assigned dose (mg/m2) = 
, 
where . assigns the largest integer not greater than the argument. 
• Azacitidine dose modifications:  Number of subjects who had azacitidine dose 
reduction and interruption will be summarized. 
6.4.4. 
Exposure for Nivolumab 
• Number of cycles:  Number of cycles with a nonzero dose of nivolumab. 
• Relative dose intensity of nivolumab (%):  100 × [total actual dose] / [total 
assigned dose]. 
Total actual dose (mg/kg) administered is the sum of the weight-adjusted cumulative 
dose of nivolumab that has been administered to the subject. 
Total assigned dose (mg/kg) is the total dose expected if the subject had taken all 
doses as initially assigned.  Let S be the study day of the last date that the subject is 
exposed to nivolumab.  Let D be the assigned dose level of 3 in mg/kg.  The total 
assigned dose is defined as 
total assigned dose (mg/kg) = D × 
, 
where . assigns the smallest integer not less than the argument. 
• Nivolumab dose modifications:  Number of subjects who had nivolumab dose 
reduction and interruption will be summarized. 
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6.5. 
Study Drug Compliance 
For subjects in the safety population, overall compliance (%) for INCB059872 will be calculated 
for all subjects as 
compliance (%) = 100 × [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications. 
The total actual dose taken will be calculated based on information entered on the drug 
accountability eCRF.  If there are dispensed drugs that have not been returned yet, the actual 
dose taken starting from the dispense date of the unreturned drugs will be imputed by the dose 
taken as reported on the dosing eCRF. 
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
Number and percentage of subjects in the FAS with each prior and concomitant medications will 
be summarized by WHO drug class and WHO drug preferred term. 
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7.3.1.6. 
Best Change in Target Lesion Size 
For subjects with measurable lesions at baseline, target lesion sizes will be measured by the sum 
of diameters.  The best percentage change from baseline, defined as the largest decrease in target 
lesion sizes during the study, will be summarized and a waterfall plot of the best percentage 
change will be generated.  Note that for subjects who only have increases in target lesion sizes 
from baseline, the smallest increase will be considered as the best change from baseline. 
Per RECIST criteria, target lesions considered “too small to measure” will be assigned a default 
value of 5 mm for purposes of this analysis.  Likewise, target lesions identified as “not present” 
at postbaseline assessments will be assigned 0 mm for this analysis.  In the event that a target 
lesions is unaccounted for in a particular postbaseline timepoint (ie, the assessment is missing 
or NE), then the overall sum of target lesions will not be evaluable for that post baseline 
timepoint. 
7.3.2. 
Acute Myeloid Leukemia 
7.3.2.1. 
Response Assessment 
Disease assessment for subjects with AML will be performed following the IWG Response 
Criteria for AML (Cheson et al 2003).  The investigator's assessment will be used to determine 
responses and will be logged on the eCRF.  The schedule for disease assessment will be at 
screening, every 4 weeks during the study treatment, at the EOT visit, and every 8 to 9 weeks 
during the disease status follow-up. 
Response status per investigator’s assessment for AML will be recorded in terms of 3 aspects:  
(1) altering the natural history of the disease, (2) cytogenetic response, and (3) molecular 
response.  For altering the natural history of the disease, response status will be recorded at each 
response assessment as CR, CRi, MLFS, PR, peripheral blood blast response, SD, PD, relapse, or 
treatment failure.  For cytogenetic response, response status will be recorded at each response 
assessment visit as CCyR, no response, not assessed, or NA (ie, normal karyotype).  For 
molecular response, response status will be recorded at each response assessment visit as CMR, 
no response, not assessed, or NA (ie, no molecular abnormality identified).  Refer to Appendix D 
in the Protocol for the summarized description of the IWG Response Criteria for AML. 
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7.3.2.2. 
Best Overall Response and Objective Response Rate 
7.3.2.2.1. Altering the Natural History of the Disease 
For AML, BOR based on altering the natural history of the disease is the best response recorded 
before and including the first progression, which consists of treatment failure, relapse, and PD, in 
the order of CR, CRi, MLFS, PR, peripheral blood blast response, SD, and progression.  In the 
case of SD, measurements must meet the SD criterion at least once on or after Day 24. 
A subject is considered a responder if the subject has a BOR of CR or CRi. 
Objective response rate is defined as the proportion of responders based on altering the natural 
history of the disease.  Subjects who do not have sufficient baseline or on-study response 
assessment information to be adequately assessed for response status will be included in the 
denominators in the calculations of ORR. 
Best overall response will be summarized descriptively.  Objective response rate will be 
estimated with its 95% CI.  Confidence intervals will be calculated based on the exact method 
for binomial distributions. 
7.3.2.2.2. Cytogenetic Response  
Cytogenetic response is applicable for subjects with abnormal karyotype at baseline.  Best 
overall response for cytogenetic response is the best response recorded before and including the 
time when the first progression based on altering the natural history of the disease occurs, in the 
order of CCyR, no response, and not assessed. 
Best overall response will be summarized descriptively for subjects with abnormal karyotype at 
baseline. 
7.3.2.2.3. Molecular Response 
Molecular response is applicable for subjects with molecular abnormality at baseline.  Best 
overall response for molecular response is the best response recorded before and including the 
time when the first progression based on altering the natural history of the disease occurs, in the 
order of CMR, no response, and not assessed. 
Best overall response will be summarized descriptively for subjects with molecular abnormality 
at baseline. 
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7.3.3. 
Myelodysplastic Syndrome 
7.3.3.1. 
Response Assessment 
Disease assessment for MDS subjects will be performed following the IWG Response Criteria 
for MDS (Cheson et al 2006).  The investigator's assessment will be used to determine responses 
and will be logged on the eCRF.  The schedule for disease assessment will be at screening, every 
4 weeks during the study treatment, at the EOT visit, and every 8 to 9 weeks during the disease 
status follow-up. 
Response status per investigator’s assessment for MDS will be recorded in terms of 3 aspects:  
(1) altering the natural history of the disease, (2) cytogenetic response, and (3) hematologic 
improvement.  For altering the natural history of the disease, response status will be recorded at 
each response assessment visit as CR, PR, marrow CR, SD, PD, treatment failure, disease 
transformation, or relapse after CR or PR.  For cytogenetic response, response status will be 
recorded at each response assessment visit as CCyR, PCyR, or NA.  For hematologic 
improvement, response status will be recorded at each response assessment visit as HI-E, HI-P, 
HI-N, progression or relapse after hematologic improvement, or NA.  Refer to Appendix F in the 
Protocol for the summarized description of the IWG Response Criteria for MDS. 
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7.3.3.2. 
Best Overall Response and Objective Response Rate 
7.3.3.2.1. Altering the Natural History of the Disease 
For MDS, BOR based on altering the natural history of the disease is the best response recorded 
before and including the first progression, which consists of treatment failure, PD, disease 
transformation, and relapse after CR or PR, in the order of CR, PR, marrow CR, SD, and 
progression.  In the case of SD, measurements must meet the SD criterion at least once on or 
after Day 24.  When analysis requires the confirmation of CR, PR, or marrow CR, responses 
must be at least 4 weeks in duration and the rule in Table 3 should be applied. 
Table 3: 
Confirmation of Complete Remission, Partial Remission, and Marrow 
Complete Remission for Myelodysplastic Syndrome 
First Assessment 
Subsequent Assessment at 4 or 
More Weeks Later 
Confirmed Response 
CR 
CR 
CR 
PR 
PR or CR 
PR 
Marrow CR 
Marrow CR, PR, or CR 
Marrow CR 
A subject is considered a responder if the subject has a best overall response of CR. 
Objective response rate for MDS is defined as the proportion of responders based on altering the 
natural history of the disease.  Subjects who do not have sufficient baseline or on-study response 
assessment information to be adequately assessed for response status will be included in the 
denominators in the calculations of ORR. 
Non-confirmatory BOR will be summarized descriptively, and the ORR will be estimated with 
its 95% CI.  Best confirmed response of CR, PR, and marrow CR will be summarized 
descriptively.  The confirmed ORR will be estimated with its 95% CI.  Confidence intervals will 
be calculated based on the exact method for binomial distributions. 
7.3.3.2.2. Cytogenetic Response  
Cytogenetic response is applicable for subjects with abnormal karyotype at baseline.  Best 
overall response for cytogenetic response is the best response recorded before and including the 
time when the first progression based on altering the natural history of the disease occurs, in the 
order of CCyR or PCyR. 
Best overall response will be summarized descriptively.  Subjects with abnormal karyotype at 
baseline will be used as the denominators in the summary of BOR. 
7.3.3.2.3. Hematologic Improvement 
The number of subjects who had at least one hematologic improvement in post baseline 
assessments along with the corresponding subcategories (ie, HI-E, HI-P, or HI-N) will be 
summarized descriptively. 
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The number of subjects with spleen volume reduction from baseline to Week 12 
 in 
pre-defined categories (eg, < 0% reduction, 0% to < 10% reduction, 10% to < 35% reduction, 
and ≥ 35% reductions) will be summarized by dose levels. 
7.4. 
Analysis of Other Efficacy Variables 
7.4.1. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG status at scheduled assessment times will be summarized categorically by dose levels 
and tumor type. 
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8. 
PHARMACOKINETIC ANALYSES 
The PK parameters of Cmax, Tmax, Cmin, AUC0-t, t½, and Cl/F (INCB059872) will be calculated 
from the blood plasma concentrations of INCB059872 using standard noncompartmental 
(model-independent) PK methods.  Pharmacokinetic calculations will be performed, if 
appropriate, using commercial software such as WinNonlin® (Pharsight Corporation, Mountain 
View, CA).  Nominal times will be used in all cases, except when the difference between the 
actual time and nominal time is greater than 15 minutes for samples collected up to 4 hours after 
administration and greater than 30 minutes for samples collected more than 4 hours after 
administration; in these cases, actual time will be used for PK analysis.  Refer to Appendix C in 
the Protocol for a detailed list and description of the PK parameters. 
9. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays.  Sample data displays are included in a separate 
document. 
9.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique preferred terms reported on 
relatively few subjects. 
9.2. 
Adverse Events 
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study treatment (until 30 days after the last dose of study treatment).  Analysis of 
AEs (as discussed below) will be limited to TEAEs, but data listings will include all AEs 
regardless of their timing in relation to study treatment administration. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE version 4.03.  The CTCAE reporting guidelines and grading details are 
available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study treatment will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study treatment, the AE will be considered to be treatment-related.  The incidence of 
AEs and treatment-related AEs will be tabulated.  In addition, SAEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity.  
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
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9.3.2. 
Laboratory Value Summaries 
All laboratory test results and associated normal ranges from local laboratories will be converted 
to SI units.  When there are multiple laboratory nonmissing values for a subject's particular test 
at a scheduled visit, the laboratory value with the smallest laboratory sequence number will be 
used in by-visit summaries. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, line graphs will be provided for 
hemoglobin, platelet counts, leukocytes, neutrophils, lymphocytes, and blast (for hematologic 
tumor types as applicable). 
Shift tables will be presented showing change in CTCAE grade from baseline to worst grade 
postbaseline.  Separate summaries for abnormally high and abnormally low laboratory values 
will be provided when the laboratory parameter has both high and low grading criteria.  The 
denominator for the percentage calculation will be the number of subjects in the baseline 
category. 
9.4. 
Vital Signs 
Values at each scheduled timepoint, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, temperature, and respiratory 
rate will be summarized descriptively. 
Normal ranges for vital sign values are defined in Table 4.  The abnormal values for subjects 
exhibiting vital sign abnormalities will be listed along with their assigned dose level.  Alert vital 
signs are defined as an absolute value outside the defined normal range and percentage change 
greater than 25%.  The abnormal values for subjects exhibiting alert vital sign abnormalities will 
be listed. 
Table 4: 
Normal Ranges for Vital Sign Values 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38°C 
< 35.5°C 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
9.5. 
Electrocardiograms 
Twelve-lead ECGs including PR, RR, QT, QRS, QTcB, and QTcF intervals will be obtained for 
each subject during the study.  Values at each scheduled timepoint, change, and percentage 
change from baseline will be summarized for each ECG parameter.  Baseline will be determined 
as the average of all nonmissing values before the first administration of INCB059872 (Parts 1 
and 2), INCB059872 and ATRA (TGs C and C1), INCB059872 and azacitidine (TGs D and D1), 
or INCB059872 and nivolumab (TGs E and E1). 
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Normal ranges for ECG values are defined in Table 5.  Electrocardiogram values will also be 
considered abnormal if the absolute percentage change from baseline is more than 25% (30% for 
QRS interval).  Subjects exhibiting ECG abnormalities will be listed with study visit and 
assigned dose level.  Abnormal values for subjects with alert ECG values, defined as both the 
absolute value and the percentage change from baseline being outside normal ranges, will be 
identified and listed.  Outliers of QT, QTcB, and QTcF values, defined as absolute values 
> 450 ms, > 500 ms, or change from baseline > 30 ms, will be summarized. 
Table 5: 
Normal Ranges for Electrocardiogram Values 
Parameter 
High Threshold 
Low Threshold 
PR 
> 220 ms 
< 75 ms 
RR 
> 1330 ms 
< 600 ms 
QT 
> 500 ms 
< 300 ms 
QRS 
> 120 ms 
< 50 ms 
QTcB, QTcF 
> 470 ms 
< 295 ms 
QTcF = Fridericia's correction; QTcB = Bazett's correction.  
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10. 
INTERIM ANALYSES 
10.1. 
Overview of Interim Analyses 
In Part 4, a stopping rule for futility is planned for each combination dose expansion treatment 
group when 15 subjects have been treated and evaluated for response or have permanently 
discontinued study treatment because of disease progression, withdrawal of consent, or death.  
Combination TG C1 will be terminated for futility if ≤ 1 of the 15 subjects responded (ie, CR or 
CRi based on altering the natural history of the disease) based on assessments provided by the 
investigator.  Combination TG D1 will be terminated for futility if ≤ 2 of the 15 subjects 
responded (ie, CR or CRi based on altering the natural history of the disease) based on 
assessments provided by the investigator.  Combination TG E1 will be terminated for futility if 
≤ 1 of the 15 subjects responded (ie, CR or PR) based on assessments provided by the 
investigator.  No formal TFLs were planned for interim analyses. 
An iDSMB will review safety data at regular intervals throughout the study.  Details regarding 
membership, roles, and responsibilities of the committee are specified in the iDSMB charter.  
The process by which the iDSMB will make recommendations and decisions is documented in 
the iDSMB charter. 
10.2. 
Derivations and Calculations for Interim Analyses 
For each combination expansion group, the futility analysis will be conducted for exactly 
15 subjects with the stopping boundary as stated in Section 10.1.  There is no efficacy interim 
analysis planned for the study. 
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11.
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN
All versions of the SAP are listed in Table 6. 
Table 6: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
01 OCT 2018 
11.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
11.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 
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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report.  For Parts 1 and 2 (monotherapy), the disease history and efficacy TFLs will have “.1.1” 
at the end of the numbering for AML, “.1.2” for MDS, “.1.3” for MF, “.1.4” for SCLC, “.1.5” for 
Ewing's sarcoma, “.1.6” for poorly differentiated neuroendocrine, and “.1.7” for other solid 
tumors; all other TFLs will have “.1.1” at the end of numbering for Group A (TG A/A1/A2 
combined) and “.1.2” for Group B (TG B/B1/B2 combined).  For Parts 3 and 4 (combination 
therapy), the TFLs will have “.2.1” at the end of the numbering for Group C (TG C/C1 
combined), “.2.2” for Group D (TG D/D1 combined), and “.2.3” for Group E (TG E/E1 
combined). 
Standard tables will follow the conventions in the Standard Safety Tables initial version.  In-text 
tables are identical in structure and content as appendix tables, but follow a Rich Text Format. 
The list of tables, figures, and listings are to be used as guidelines.  Modifications of the list that 
do not otherwise affect the nature of the analysis will not warrant an amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
1.1.1 
Analysis Populations 
FAS 
1.1.2 
Summary of Subject Disposition 
FAS 
1.1.3 
Summary of Number of Subjects Enrolled by Country and Site 
FAS 
1.1.4 
Summary of Protocol Deviations 
FAS 
1.2.1 
Summary of Demographics and Baseline Disease Characteristics 
FAS 
1.3.1 
Summary of Disease History 
FAS 
1.3.2 
Summary of Prior Cancer Therapy 
FAS 
1.3.3 
Summary of Prior Systematic Cancer Therapy by WHO Drug Class and Preferred 
Term 
FAS 
1.4.1 
Summary of Prior Medications 
FAS 
1.4.2 
Summary of Concomitant Medications 
FAS 
1.5.1 
Summary of General Medical History 
FAS 
2.2.1 
Summary of Best Overall Response and Objective Response Rate 
FAS 
2.2.2 
Summary of Spleen Volume Reduction 
FAS 
2.2.3 
Summary of Response Categories for Spleen Volume Reduction 
FAS 
2.3.4 
Summary of Best Change in Target Lesion Size 
FAS 
2.3.7 
Summary of ECOG Status 
FAS 
3.1 
Summary of Exposure and Compliance 
Safety 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
3.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term 
Safety 
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Table No. 
Title 
Population 
3.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term in 
Decreasing Order of Frequency 
Safety 
3.2.4 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ Class, 
Preferred Term, and Maximum Severity 
Safety 
3.2.5 
Summary of Grade 3 or 4 Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety 
3.2.6 
Summary of Grade 3 or 4 Treatment-Emergent Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency 
Safety 
3.2.7 
Summary of INCB059872 Treatment-Related Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety 
3.2.8 
Summary of INCB059872 Treatment-Related Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency 
Safety 
3.2.9 
Summary of INCB059872 Treatment-Related Adverse Events by MedDRA System 
Organ Class,  Preferred Term, and Maximum Severity 
Safety 
3.2.10 
Summary of Grade 3 or 4 INCB059872 Treatment-Related Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.11 
Summary of ATRA/Azacitidine/Nivolumab Treatment-Related Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.12 
Summary of ATRA/Azacitidine/Nivolumab Treatment-Related Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.13 
Summary of ATRA/Azacitidine/Nivolumab Treatment-Related Adverse Events by 
MedDRA System Organ Class,  Preferred Term, and Maximum Severity 
Safety 
3.2.14 
Summary of Grade 3 or 4 ATRA/Azacitidine/Nivolumab Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.15 
Summary of Treatment-Emergent Adverse Events Leading to Death by MedDRA 
System Organ Class and Preferred Term 
Safety 
3.2.16 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
3.2.17 
Summary of Serious Treatment-Emergent Adverse Events by Preferred Term in 
Decreasing Order of Frequency 
Safety 
3.2.18 
Summary of INCB059872 Treatment-Related Serious Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
3.2.19 
Summary of ATRA/Azacitidine/Nivolumab Treatment-Related Serious Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.20 
Summary of Treatment-Emergent Adverse Events Leading to INCB059872 Dose 
Reduction by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.21 
Summary of Treatment-Emergent Adverse Events Leading to 
ATRA/Azacitidine/Nivolumab Dose Reduction by MedDRA System Organ Class and 
Preferred Term 
Safety 
3.2.22 
Summary of Treatment-Emergent Adverse Events Leading to INCB059872 Dose 
Interruption by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.23 
Summary of Treatment-Emergent Adverse Events Leading to 
ATRA/Azacitidine/Nivolumab Dose Interruption by MedDRA System Organ Class 
and Preferred Term 
Safety 
3.2.24 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
INCB059872 by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.25 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
ATRA/Azacitidine/Nivolumab by MedDRA System Organ Class and Preferred Term 
Safety 
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Table No. 
Title 
Population 
3.2.26 
Summary of Treatment-Emergent Immune-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum Severity 
Safety 
3.3.1 
Summary of Laboratory Values - Hematology 
Safety 
3.3.2 
Shift Summary of Hematology Laboratory Values in CTC Grade - to the Worst 
Abnormal Value 
Safety 
3.3.3 
Summary of Laboratory Values - Chemistry 
Safety 
3.3.4 
Shift Summary of Chemistry Laboratory Values in CTC Grade - to the Worst 
Abnormal Value 
Safety 
3.3.5 
Summary of Laboratory Values - Coagulation 
Safety 
3.3.6 
Shift Summary of Coagulation Laboratory Values in CTC Grade - to the Worst 
Abnormal Value 
Safety 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
3.4.3 
Summary of Pulse 
Safety 
3.4.4 
Summary of Respiration Rate 
Safety 
3.4.5 
Summary of Body Temperature 
Safety 
3.4.6 
Summary of Weight 
Safety 
3.5.1 
Summary of PR Interval (msec) From 12-Lead ECG 
Safety 
3.5.2 
Summary of RR Interval (msec) From 12-Lead ECG 
Safety 
3.5.3 
Summary of QT Interval (msec) From 12-Lead ECG 
Safety 
3.5.4 
Summary of QRS Interval (msec) From 12-Lead ECG 
Safety 
3.5.5 
Summary of QTcB Interval (msec) From 12-Lead ECG 
Safety 
3.5.6 
Summary of QTcF Interval (msec) From 12-Lead ECG 
Safety 
3.5.7 
Summary of Outliers of QT, QTcB, and QTcF Interval Values From 12-Lead ECG 
Safety 
Figures 
Figure No. 
Title 
4.2.1 
Mean Plot for Change in Spleen Volume Reduction From Baseline 
4.2.2 
Mean Plot for Percentage Change in Spleen Volume Reduction From Baseline 
4.3.4 
Waterfall Plot of Best Percent Change in Sum of Target Lesions 
4.6.1 
Line Plot of Mean Values Over Time for Hemoglobin 
4.6.2 
Line Plot of Mean Values Over Time for Platelets 
4.6.3 
Line Plot of Mean Values Over Time for Leukocytes 
4.6.4 
Line Plot of Mean Values Over Time for Neutrophils 
4.6.5 
Line Plot of Mean Values Over Time for Lymphocytes 
4.6.6 
Line Plot of Mean Values Over Time for Blast 
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