A Phase 1/2 Study of INCB053914 in Subjects With Advanced Malignancies
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: Incyte Corporation

 
Official Title: 
A Phase 1/2 Study of INCB053914 in Subjects With Advanced Malignancies 
NCT Number: 
NCT02587598 
 
Document Date: 
 
Clinical Study Protocol Version 8: 18 December 2019 
 
 
 
 
 
 
 
 

 
 
 
 
16.1.1 
PROTOCOL AND PROTOCOL AMENDMENTS 
The documents listed below are enclosed. 
Protocol Amendment 1 – Summary of Changes  
17 JUL 2015 
Protocol Amendment 2 – Summary of Changes 
30 OCT 2015 
Protocol Amendment 3 – Summary of Changes  
13 JUL 2016 
Protocol Amendment 4 – Summary of Changes 
26 AUG 2016 
Protocol Amendment 5 – Summary of Changes  
13 DEC 2016 
Protocol Amendment 6 – Summary of Changes 
15 MAR 2017 
Protocol Amendment 7 – Summary of Changes  
25 FEB 2019 
Protocol Amendment 8 – Summary of Changes 
18 DEC 2019 
Protocol Amendment 8 
18 DEC 2019 
 
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Protocol INCB 53914-101 Am 8 
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Clinical Study Protocol 
INCB 53914-101 / NCT02587598
A Phase 1/2 Study of INCB053914 in Subjects With 
Advanced Malignancies
Product: 
INCB053914 
IND Number: 
126,097 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
03 JUN 2015 
Amendment (Version) 1: 
17 JUL 2015 
Amendment (Version) 2: 
30 OCT 2015 
Amendment (Version) 3: 
13 JUL 2016 
Amendment (Version) 4: 
26 AUG 2016 
Amendment (Version) 5: 
13 DEC 2016 
Amendment (Version) 6: 
15 MAR 2017 
Amendment (Version) 7: 
25 FEB 2019 
Amendment (Version) 8: 
18 DEC 2019 
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 50, 54 56, 312, and Part 11 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 53914-101 Protocol Amendment 8 (Version 8 dated 18 DEC 2019) 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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PAD at the discretion of the sponsor and investigators.  Part 4 (combination dose expansion) further 
evaluate the safety, efficacy, PK, and PD of the selected combination dose regimens identified in Part 3 
in up to 3 expansion cohorts in specific indications relevant to the drug combinations (2 AML; 1 MF).  
A Simon 2-stage design will be implemented in the 2 AML combination expansion cohorts (Part 4). 
Part 1 Monotherapy Dose Escalation 
Between 3 and up to approximately 30 subjects will be enrolled into each of 2 treatment groups.  
Treatment Group A (TGA) will include acute leukemia, high-risk MDS, and MDS/MPNs (including 
atypical chronic myeloid leukemia [aCML], chronic myelomonocytic leukemia [CMML], 
myelodysplastic/myeloproliferative neoplasm unclassifiable [MDS/MPN-U], and refractory anemia with 
ring sideroblasts and thrombocytosis [RARS-T]).  Treatment Group B (TGB) will include MM, 
lymphoma, and other lymphoproliferative neoplasms.  Dose escalation for TGA and TGB will proceed 
independently, with each treatment group following a 3 + 3 design.  At least 3 subjects will be enrolled 
and treated in each cohort.  If no dose-limiting toxicities (DLTs) are observed in the initial 3 subjects, 
the next cohort will begin enrollment at the next higher dose level.  If 1 DLT is observed in the first 
3 subjects, 3 additional subjects will be enrolled in that cohort.  If a DLT occurs in one-third or more of 
the total cohort (ie, ≥ 2 of 6 subjects), then the MTD will be deemed to have been exceeded, and the next 
lower dose level will be deemed to be the MTD.  Thus, the MTD will be defined as 1 dose level below 
that at which one-third or more of subjects in a particular cohort report DLTs.  If the first cohort exceeds 
the MTD, a dose de-escalation will be considered.  The initial dose level in each treatment group will be 
100 mg once daily (QD), with dose increases up to 2-fold until a Grade 2 toxicity that has a reasonable 
possibility of being related to INCB053914 is observed in that treatment group or until a total daily dose 
of 300 mg has been reached in that treatment group, after which dose increases will be limited to ≤ 50%.  
Each subject will be observed for 1 cycle to be evaluable to assess safety and tolerability of the dose.  
The RP2D will be selected based on the totality of the data within each treatment group for further 
investigation in the expansion cohorts, and it is possible that the RP2D could be different among disease 
types.  If there is a distinct discrepancy in tolerability among different disease types in the same 
treatment group, separate disease-specific dose-escalation schedules may be initiated.  If a PAD is 
reached before the MTD, the PAD may be selected as the RP2D based on the clinical data at the 
discretion of the sponsor.  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, PD, 
and safety data. 
Part 2 Monotherapy Dose Expansion 
Upon identification of the RP2D(s), up to 5 expansion cohorts will enroll subjects to further determine 
safety, tolerability, efficacy, PK, and PD of the selected dose(s) as follows: 
• TGA Expansion Cohort 1 (TGA E1):  At least 5 and up to approximately 15 subjects with AML will 
be enrolled and treated at the RP2D identified in Part 1 TGA. 
• TGA Expansion Cohort 2 (TGA E2):  At least 5 and up to approximately 15 subjects with MDS/MPN 
(including aCML, CMML, MDS/MPN-U, and RARS-T) will be enrolled and treated at the RP2D 
identified in Part 1 TGA. 
• TGA Expansion Cohort 3 (TGA E3):  At least 5 and up to approximately 15 subjects with MF will be 
enrolled and treated at the RP2D identified in Part 1 TGA. 
• TGB Expansion Cohort 1 (TGB E1):  At least 5 and up to approximately 15 subjects with MM will be 
enrolled and treated at the RP2D identified in Part 1 TGB. 
• TGB Expansion Cohort 2 (TGB E2):  At least 5 and up to approximately 15 subjects with DLBCL will 
be enrolled and treated at the RP2D identified in Part 1 TGB. 
Individual dose titration will be permitted according to Protocol-defined safety parameters.  Subjects 
will continue to receive INCB053914 in 21-day cycles until withdrawal criteria are met. 
 
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Part 3 Combination Dose-Finding 
Part 3 will include dose-finding to optimize the combination doses.  Dose-finding will use a 3 + 3 design 
to evaluate different doses of INCB053914 in combination with SOC agents in the following treatment 
groups: 
• Combination Treatment Group A (C-TGA):  INCB053914 + I-DAC in subjects with 
relapsed/refractory AML. 
• Combination Treatment Group B (C-TGB):  INCB053914 + azacitidine in subjects with 
relapsed/refractory AML or newly diagnosed AML (de novo or secondary) in subjects ≥ 65 years at 
screening and unfit to receive intensive chemotherapy. 
• Combination Treatment Group C (C-TGC):  INCB053914 + ruxolitinib in subjects with primary or 
secondary MF (PPV-MF or PET-MF) who are currently experiencing a suboptimal response on 
ruxolitinib monotherapy, defined as follows: 
- Palpable spleen of > 10 cm below the left subcostal margin on physical examination  at the 
screening visit OR 
- Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active 
symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 
2 symptom scores ≥ 3 using the Screening Symptom Form.  
The starting dose of INCB053914 in the combination treatment groups will be a PAD and 1 dose level 
below the highest tolerated dose of INCB053914 monotherapy identified in Part 1 of this study.  Starting 
doses of the SOC combination agents will be selected from conventional dose regimens and will remain 
the same for all dose-finding and dose-expansion cohorts.  INCB053914 doses will not exceed the 
monotherapy MTD to be identified in Part 1. 
Combination treatment groups will escalate independently and in parallel until the MTD or optimal 
doses of the combination is identified and will be followed by independent expansion cohorts at the 
selected dose(s).  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, PD, and safety 
data. 
Part 4 Combination Expansion 
Upon identification of the RP2D combination regimens in Part 3, up to 3 expansion cohorts will enroll to 
further determine safety, tolerability, efficacy, PK, and PD in the subject populations as detailed below.  
The 2 AML expansion cohorts will use a Simon 2-stage design to evaluate the efficacy of the 
combination regimens. 
• C-TGA Expansion Cohort 1 (C-TGA E1) will enroll subjects with relapsed/refractory (r/r) AML 
who will be treated with INCB053914 in combination with I-DAC using the regimen identified from 
the Part 3 dose-finding.  The approximate numbers of subjects for Stage 1 and Stage 2 are described in 
the Statistical Methods section of this synopsis.  If an insufficient number of responders are observed 
in the cohort at Stage 1, further enrollment in the cohort will be terminated. 
• C-TGB Expansion Cohort 1 (C-TGB E1) will enroll subjects with newly diagnosed AML (de novo 
or secondary) who are ≥ 65 years at screening and unfit to receive intensive chemotherapy and who 
will be treated with INCB053914 in combination with azacitidine using the regimen identified from 
the Part 3 dose-finding.  The approximate numbers of subjects for Stage 1 and Stage 2 are described 
below in the section of "Statistical Methods."  If an insufficient number of responders are observed in 
the cohort at Stage 1, further enrollment in the cohort will be terminated. 
•  C-TGC Expansion Cohort 1 (C-TGC E1) will enroll up to 16 subjects with PMF or secondary MF 
(PPV-MF or PET-MF) who are currently experiencing a suboptimal response on ruxolitinib 
monotherapy and who will be treated with INCB053914 in combination with ruxolitinib using the 
dose identified from the Part 3 dose-finding. 
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• Optional C-TGA Expansion Cohort 2 (C-TGA E2) 
If the Part 3 C-TGB dose-finding does not yield a tolerable combination of INCB053914 and 
azacitidine, or if the Part 4 C-TGB E1 Simon Stage 1 does not yield favorable efficacy data, then the 
sponsor may elect to evaluate INCB053914 in combination with a low-dose cytarabine (L-DAC) 
regimen in this population.  This option will use an INCB053914 dose deemed tolerable in 
combination with I-DAC and will reference safety and tolerability data obtained from the Part 3 
C-TGA dose-finding.  If the sponsor and investigators believe that the optimal dose regimen of 
INCB053914 in combination with L-DAC will be different from that of INCB053914 in combination 
I-DAC, a separate dose-finding cohort will be initiated to identify the optimal dose regimen of 
INCB053914 in combination with L-DAC. 
Study Population: 
Parts 1 and 2 
Subjects diagnosed with acute leukemia, high-risk MDS, MDS/MPN, MF, MM, or lymphoproliferative 
neoplasms that are unresponsive to currently available therapy and have no SOC options in the opinion 
of the investigator. 
Parts 3 and 4 
Subjects diagnosed with relapsed/refractory AML, subjects with newly diagnosed AML who are 
≥ 65 years of age and unfit for intensive chemotherapy, and subjects with primary or secondary MF who 
are currently experiencing a suboptimal response on ruxolitinib monotherapy. 
Key Inclusion Criteria:  
• Men and women, aged 18 years or older.  Subjects in the C-TGB Expansion Cohort 1 (C-TGB E1) 
with newly diagnosed AML must be ≥ 65 years old. 
• Part 1 monotherapy dose escalation 
- TGA:  Subjects with histologically confirmed diagnosis of acute leukemia, high-risk MDS, or 
MDS/MPN (including aCML, CMML, MDS/MPN-U, and RARS-T). 
- TGB:  Subjects with MM, lymphoma, and other lymphoproliferative neoplasms. 
Part 2 monotherapy dose expansion 
Subjects with histologically confirmed and measureable/evaluable disease: 
- TGA Expansion Cohort 1 (TGA E1):  AML. 
- TGA Expansion Cohort 2 (TGA E2):  MDS/MPN. 
- TGA Expansion Cohort 3 (TGA E3):  MF. 
- TGB Expansion Cohort 1 (TGB E1):  MM. 
- TGB Expansion Cohort 2 (TGB E2):  DLBCL. 
Part 3 combination dose-finding 
Subjects with histologically confirmed and measureable/evaluable disease: 
- Combination Treatment Group A (C-TGA):  relapsed/refractory AML.  Subjects with acute 
promyelocytic leukemia are excluded. 
- Combination Treatment Group B (C-TGB):  relapsed/refractory AML or subjects ≥ 65 years of age 
with newly diagnosed, histologically confirmed and measureable/evaluable AML (de novo or 
secondary) and unfit for intensive chemotherapy.  Subjects with acute promyelocytic leukemia are 
excluded. 
- Combination Treatment Group C (C-TGC):  primary or secondary MF who are currently 
experiencing a suboptimal response on ruxolitinib monotherapy defined as follows: 
 Palpable spleen of > 10 cm below the left subcostal margin on physical examination at the 
screening visit OR 
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 Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active 
symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 
2 symptom scores ≥ 3 using the Screening Symptom Form. 
Part 4 combination expansion 
Subjects with histologically confirmed and measureable/evaluable disease: 
- C-TGA Expansion Cohort 1 (C-TGA E1):  relapsed/refractory AML.  Subjects with acute 
promyelocytic leukemia are excluded. 
- C-TGB Expansion Cohort 1 (C-TGB E1):  newly diagnosed AML (de novo or secondary) who are 
≥ 65 years and unfit to receive intensive chemotherapy.  Subjects with acute promyelocytic 
leukemia are excluded. 
- C-TGC Expansion Cohort 1 (C-TGC E1):  primary or secondary MF who are currently experiencing 
a suboptimal response on ruxolitinib monotherapy defined as follows: 
 Palpable spleen of > 10 cm below the left subcostal margin on physical examination  at the 
screening visit OR 
 Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical exam AND active 
symptoms of MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 
2 symptom scores ≥ 3 using the Screening Symptom Form. 
• Parts 1 and 2 
- Must be unresponsive to currently available therapy and there is no further SOC therapy available in 
the judgment of the investigator. 
- Must not currently be a candidate for curative treatment, including hematopoietic stem cell 
transplant. 
• Parts 3 and 4 
- Subjects with relapsed/refractory AML must have received either induction chemotherapy for AML 
or hypomethylating agents for hematologic disease before AML. 
- Elderly subjects (≥ 65 years) with newly diagnosed AML (de novo or secondary) must be 
treatment-naive and unfit for intensive chemotherapy. 
- Subjects with MF must be receiving ruxolitinib monotherapy at a stable dose for ≥ 8 weeks before 
Study Day 1.  One dose reduction due to toxicities within the 8 weeks before Study Day 1 will be 
permitted.  Acceptable doses are 5 mg twice daily (BID) to 25 mg BID; QD doses are not allowed. 
• Willingness to undergo a pretreatment bone marrow biopsy and/or aspirate (as appropriate to disease), 
or archival sample obtained since completion of most recent therapy (as appropriate to subjects with 
existing bone marrow disease or for whom bone marrow examination is a component of disease status 
assessment).  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. 
• ECOG performance status: 
- Part 1:  0 or 1. 
- Parts 2 through 4:  0, 1, or 2. 
• Life expectancy > 12 weeks or ≥ 24 weeks for Part 3 and Part 4 MF subjects. 
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Key Exclusion Criteria: 
• Inadequate bone marrow function demonstrated by any of the following: 
Laboratory Parameter 
TGB (Part 1) 
TGB (Part 2) 
C-TGC (Parts 3 and 4) 
Hemoglobin (g/dL) 
< 8.0 
< 8.0 
Subjects unwilling to receive red blood 
cell transfusions to treat low hemoglobin 
levels are excluded. 
Platelets (× 109/L) 
< 75 
< 50 
< 50 in 2 weeks before screening or 
platelet transfusions within 4 weeks of 
screening. 
Absolute neutrophils  (× 109/L) 
< 1.0 
< 1.0 
< 0.5 in the 2 weeks before screening. 
Note:  No specific hematologic exclusion criteria apply for TGA (Parts 1 and 2), Part 3 C-TGA and C-TGB, and Part 4 C-TGA 
E1 and C-TGB E1 Cohorts. 
• Inadequate organ function demonstrated by any of the following, unless approved by the medical 
monitor: 
Part 1 and Part 3: 
- Total bilirubin > upper limit of normal (ULN; except total bilirubin > ULN is acceptable if direct 
bilirubin is ≤ 1.2 × ULN.  Subjects with Gilbert's syndrome who have total bilirubin ≤ 2 × ULN may 
be enrolled with medical monitor approval). 
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN. 
- Creatinine clearance < 50 mL/min (< 30 mL/min for MM) based on Cockroft-Gault formula or 
24-hour urine analysis. 
Part 2 and Part  4:  
- Total bilirubin > ULN (except total bilirubin > ULN is acceptable if direct bilirubin is ≤ 1.2 × ULN.  
Subjects with Gilbert's syndrome who have total bilirubin ≤ 2 × ULN may be enrolled with medical 
monitor approval). 
- AST or ALT > 1.5 × ULN. 
- Creatinine clearance < 40 mL/min (< 30 mL/min for MM) based on Cockroft-Gault formula or 
24-hour urine analysis. 
• Receipt of anticancer medications or investigational drugs within the following interval before the 
first administration of study drug (note:  subjects enrolling in C-TGC must continue to receive 
their ruxolitinib throughout the study): 
- < 5 half-lives or 14 days, whichever is longer, for any investigational agent. 
- < 28 days for any antibodies or biological therapies. 
- < 5 half-lives for all other nonbiologic anticancer medications, or sponsor approval. 
- < 6 weeks for mitomycin-C or nitrosoureas. 
- The following are allowed:  hydroxyurea for controlling proliferative disease and low-dose 
corticosteroids (prednisone or equivalent ≤ 10 mg per day).  Hydroxyurea should not be used within 
48 hours before and on the day of PD sample collection or during or 72 hours before or after 
azacitidine administration.  Note:  Concomitant hydroxyurea is prohibited in subjects with MF 
within 8 weeks before enrolling (Day 1) into C-TGC. 
• Unless approved by the medical monitor, may not have received an allogeneic hematopoietic stem cell 
transplant within 6 months before treatment, or have active graft-versus-host disease following 
allogeneic transplant, or have received immunosuppressive therapy (including, but not limited to, 
cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids [> 10 mg/day prednisone 
equivalent]) following allogeneic transplant within 2 weeks of Cycle 1 Day 1. 
• Unless approved by the medical monitor, may not have received autologous hematopoietic stem cell 
transplant within 3 months before treatment. 
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• Has any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable chronic 
toxicities (≤ Grade 2) not expected to resolve, such as stable Grade 2 peripheral neuropathy. 
• Radiotherapy within the 2 weeks before initiation of treatment.  Palliative radiation treatment to 
nonindex or bone lesions performed less than 2 weeks before treatment initiation may be considered 
with medical monitor approval.  In Part 3 and Part 4, MF subjects may not have had splenic irradiation 
within 6 months of the first dose of INCB053914. 
• Part 1 and Part 3 only:  Type 1 diabetes or uncontrolled Type 2 diabetes. 
• Part 1 and Part 3 only:  Hemoglobin A1c (HbA1c) > 8.0% (all subjects will have HbA1c tested at 
screening). 
• Part 1 and Part 3:  Any history of disease involving the central nervous system (CNS). 
Part 2 and Part 4:  Known active disease involving the CNS, for example, brain metastasis or spinal 
cord compression, except primary CNS lymphoma. 
• History of clinically significant or uncontrolled cardiac disease, including recent (within last 6 months) 
unstable angina or acute myocardial infarction, or New York Heart Association Class III or IV 
congestive heart failure, or clinically significant arrhythmias not controlled by medication.  Subjects 
with a pacemaker and well-controlled rhythm for at least 1 month before the first dose of study drug 
will be allowed. 
• Part 1 and Part 3:  Current diagnosis of any chronic or acute respiratory condition or ongoing sequelae 
from any previously diagnosed respiratory condition that is significant in the judgment of the 
investigator or the sponsor's medical monitor.  
Part 2 and Part 4:  Current diagnosis of any severe or uncontrolled obstructive or restrictive respiratory 
condition (eg, Global Initiative for Chronic Obstructive Lung Disease [GOLD] 3 or GOLD 4 chronic 
obstructive pulmonary disease).  
• Gastroesophageal reflux disease not controlled by medication (ie, currently symptomatic) within 
30 days before Cycle 1 Day 1. 
• Prior receipt of a PIM inhibitor. 
• Excessive alcohol use (eg, > 2 drinks per day). 
• Excessive chronic acetaminophen use (> 2 g per day). 
Study Drugs and SOC Medications, Dosages and Modes of Administration:   
Part 1 and Part 2 Monotherapy 
INCB053914 tablets (15 mg and 50 mg strength) will be administered orally in 21-day treatment cycles.  
The initial dose will be 100 mg QD.  Dose escalation during Part 1 of the study will proceed using the 
dose-escalation rules described above.  Dose increases will be accomplished using the following options:  
1) increasing the number of tablets taken at each QD administration, or 2) increasing administration 
frequency to BID, or 3) increasing the number of tablets taken at 1 or more dose administrations and 
increasing the frequency to BID.  The sponsor may implement alternate administration, such as 
intermediate doses, alternate dose regimens, or alternate formulations, depending upon PK, PD, and 
safety results. 
Part 3 and Part 4 Combination Therapy 
Conventional regimens of the SOC combination agents will be used throughout Part 3 and Part 4 of the 
study.  In the Part 3 dose-finding cohorts, the assigned dose of INCB053914 will be dependent upon 
cohort assignment.  In the Part 4 combination expansion cohorts, the dose of INCB053914 will depend 
upon the optimal dose combinations identified in the respective dose-finding cohorts in Part 3. 
INCB053914:  Except as noted in the Protocol, INCB053914 will be self-administered orally BID 
beginning with the Cycle 1 Day 1 morning dose and continuously thereafter in 21- or 28-day cycles 
depending upon the treatment group regimen until treatment withdrawal criteria are met.  All BID doses 
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will be taken in the morning and evening, approximately 12 hours apart and at least 2 hours after a meal.  
The starting dose of INCB053914 in Part 3 will be a PAD and 1 dose level below the highest tolerated 
dose of INCB053914 monotherapy identified in Part 1 of this study.  At the current data cutoff date, the 
highest tolerated dose of INCB053914 monotherapy in Part 1 was 80 mg BID, so the planned starting 
dose for Part 3 will be 65 mg BID.  An alternative starting dose may be selected pending emerging 
safety, PK, and PD data in Part 1. 
Cytarabine:  In the Part 3 C-TGA dose-finding cohorts and Part 4 combination expansion 1 (C-TGA 
E1) cohort, I-DAC will be administered to subjects with relapsed/refractory AML as an open-label 
commercial product at a dose of 1 g/m² per day, 2-hour infusion on Days 1 through 5.  A second 
induction cycle may be started between 15 days and 8 weeks after initiation of Cycle 1, at the discretion 
of the investigator, in subjects with residual leukemia upon bone marrow assessment during initial 
induction, provided all drug-related toxic effects had resolved to ≤ Grade 1.  Up to 2 additional cycles 
may be given as consolidation therapy in subjects who achieved complete remission (CR) or complete 
remission with incomplete platelet recovery, at the discretion of the investigator.  The start of subsequent 
induction or consolidation cycles of I-DAC should be coordinated with the Day 1 of the INCB053914 
21-day visit cycle when feasible. 
If the Part 3 C-TGB dose-finding does not yield a tolerable combination of INCB053914 and 
azacitidine, or if the Part 4 C-TGB E1 Simon Stage 1 does not yield favorable efficacy data, then the 
sponsor may elect to evaluate INCB053914 in combination with a L-DAC regimen to treat elderly 
subjects (≥ 65 years) with newly diagnosed AML (de novo or secondary) who are unfit for intensive 
chemotherapy.  In this event, L-DAC will be administered as an open-label commercial product at a 
dose of 20 mg subcutaneously (SC) on Days 1 through 10 of a 28- to 42-day cycle, depending upon 
hematologic recovery.  Low-dose cytarabine therapy may continue until Protocol withdrawal criteria are 
met, or until subject's condition worsens, per investigator's clinical judgment, and warrants withdrawal. 
Azacitidine:  In the Part 3 C-TGB dose-finding cohorts and Part 4 C-TGB E1 expansion cohort, 
azacitidine will be administered as an open-label commercial product at a dose of 75 mg/m2 SC or 
intravenously (IV) for 7 days during 9-day or less period (ie, a 2-day break allowed on week-end, if 
needed) of each 28-day treatment cycle. 
Ruxolitinib:  In the Part 3 C-TGC dose-finding cohorts and Part 4 C-TGC E1 expansion cohort, 
ruxolitinib will be administered as an open-label commercial BID oral treatment using the dose 
designated as the stable dose at the time of the screening visit for each subject.  Acceptable doses are 
5 mg BID to 25 mg BID.  Doses of ruxolitinib should be self-administered approximately 12 hours apart 
without regard to food. 
Study Schedule/Procedures: 
Subjects will have regularly scheduled study visits at the clinical site as part of a 21-day cycle or 28-day 
cycle depending upon treatment regimens.  
Study visits are as follows: 
Parts 1 and 2: 
• Screening  
• Cycle 1:  Day 1, Day 2, Day 8 (± 3 days), Day 15 (± 3 days) 
• Cycle 2 and beyond:  Day 1 (± 3 days), Day 2 (Cycle 2 – food-effect only), and Day 11 (± 4 days) 
• End of treatment (+ 3 days from last dose of study medication) 
• Safety follow-up (30-35 days after end of treatment) 
• Disease status follow-up (every 9 weeks)  
• Survival follow-up (every 12 weeks) 
 
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Parts 3 and 4: 
• Screening  
• Cycle 1 Day 1 and Day 1 of each subsequent cycle or at appropriate intervals.  Additional study visits 
may be required during some cycles for safety, efficacy, PK, and PD assessments as described below. 
• End of treatment (+ 3 days from last dose of study medication) 
• Safety follow-up (30-35 days after end of treatment) 
• Disease status follow-up (every 9 weeks; except Part 3 C-TGC and Part 4 C-TGC E1) 
• Survival follow-up (every 12 weeks) 
Local Laboratory Tests: 
All study visits will include sample collection for hematology and chemistry (including liver function 
panels).  Coagulation, lipid, and urinalysis testing will be performed at defined intervals throughout the 
treatment phase.  Additionally, the screening visit will include hepatitis serology testing and pregnancy 
testing.  Subjects with diseases that are typically monitored though bone marrow examination, for 
example, AML, MDS, MDS/MPN, MF, and MM, will have bone marrow aspirate/biopsy at screening 
and as part of the disease response assessment performed by a local laboratory. 
Central Laboratory Tests: 
Pharmacokinetic and PD/tumor tissue samples will be collected at specific study timepoints and shipped 
to the sponsor or designee for analysis. 
Clinical Assessments: 
Adverse event assessments, physical examinations, vital signs, ECOG performance status, skeletal 
survey, and tumor/disease response assessments will be performed by the investigative site.  
Electrocardiograms (ECGs) will be performed at the site; data will be submitted to a central reader.  An 
objective assessment of disease status will be performed for all subjects at screening, appropriate to the 
malignancy type.  Subsequent disease assessments for AML, MDS, MPN, MM, and subsets of 
lymphoproliferative disorders will be performed at each cycle (excluding definitive bone marrow 
examination, which occurs at specified intervals for AML, MDS, MDS/MPN and MF, and otherwise to 
confirm complete response); subsequent disease assessments for lymphoma will be conducted every 
9 weeks. 
Estimated Duration of Participation:  Subjects may continue on study until withdrawal criteria are 
met.  Treatment duration will vary significantly between subjects but is expected to average 
approximately 4 to 6 months. 
Estimated Number of Subjects:   
Part 1:  Approximately 3 to 30 subjects per treatment group. 
Part 2:  Up to 75 subjects. 
Part 3: Approximately 3 to 10 subjects per dose-finding treatment group 
Part 4:  Up to 102 subjects. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................23 
1. 
INTRODUCTION ......................................................................................................27 
1.1. 
Background .................................................................................................................27 
 
27 
 
27 
 
28 
 
29 
 
29 
1.3. 
Overview of Standard-of-Care Agents Selected for Combination .............................29 
1.3.1. 
Cytarabine ...................................................................................................................29 
1.3.2. 
Azacitidine ..................................................................................................................30 
1.3.3. 
Ruxolitinib ..................................................................................................................31 
1.4. 
Potential Risks and Benefits of the Treatment Regimens ..........................................31 
1.4.1. 
Potential Risks of INCB053914 Based on Preclinical Safety ....................................31 
1.4.2. 
Potential Risks of INCB053914 Based on Preliminary Clinical Experience .............33 
1.4.2.1. 
ALT/AST Elevations ..................................................................................................34 
1.4.2.2. 
Rash ............................................................................................................................34 
1.4.3. 
Potential Risks Related to Standard-of-Care Agents Selected for 
Combination ...............................................................................................................35 
1.4.3.1. 
Cytarabine ...................................................................................................................35 
1.4.3.2. 
Azacitidine ..................................................................................................................35 
1.4.3.3. 
Ruxolitinib ..................................................................................................................35 
1.4.4. 
Potential Risks Related to the Combination of INCB053914 and Selected 
Standard-of-Care Agents ............................................................................................36 
1.4.5. 
INCB053914 Potential Benefits .................................................................................36 
1.5. 
Study Rationale ...........................................................................................................36 
1.5.1. 
Rationale for Combining INCB053914 With Cytarabine and Azacitidine in 
AML ...........................................................................................................................36 
1.5.2. 
Rationale for Combining INCB053914 With Ruxolitinib in Myelofibrosis ..............37 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................38 
2.1. 
Study Objectives .........................................................................................................38 
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2.1.1. 
Primary Objectives .....................................................................................................38 
2.1.2. 
Secondary Objectives .................................................................................................38 
 
38 
2.2. 
Study Endpoints ..........................................................................................................39 
2.2.1. 
Primary Endpoint ........................................................................................................39 
2.2.2. 
Secondary Endpoints ..................................................................................................39 
 
39 
3. 
SUBJECT ELIGIBILITY ...........................................................................................40 
3.1. 
Study Population .........................................................................................................40 
3.1.1. 
Parts 1 and 2 ................................................................................................................40 
3.1.2. 
Parts 3 and 4 ................................................................................................................40 
3.2. 
Subject Inclusion Criteria ...........................................................................................40 
3.3. 
Subject Exclusion Criteria ..........................................................................................42 
4. 
INVESTIGATIONAL PLAN .....................................................................................45 
4.1. 
Overall Study Design ..................................................................................................45 
4.1.1. 
Part 1 Monotherapy Dose Escalation .........................................................................46 
4.1.2. 
Part 2 Monotherapy Dose Expansion .........................................................................47 
4.1.3. 
Part 3 Combination Therapy Dose-Finding ................................................................49 
4.1.3.1. 
Standard-of-Care Agent Combination Cohort Dose-Finding Strategy ......................49 
4.1.4. 
Part 4 Combination Expansion Cohorts .....................................................................51 
4.2. 
Measures Taken to Avoid Bias ...................................................................................51 
4.3. 
Number of Subjects ....................................................................................................52 
4.3.1. 
Planned Number of Subjects ......................................................................................52 
4.3.2. 
Replacement of Subjects .............................................................................................52 
4.4. 
Duration of Treatment and Subject Participation .......................................................52 
4.5. 
Overall Study Duration ...............................................................................................52 
4.6. 
Study Termination ......................................................................................................52 
5. 
TREATMENT ............................................................................................................53 
5.1. 
Study Drug and Treatment Assignment .....................................................................53 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................53 
5.1.2. 
Randomization and Blinding ......................................................................................53 
5.1.3. 
INCB053914 ...............................................................................................................53 
5.1.3.1. 
Description and Administration ..................................................................................53 
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5.1.3.2. 
Supply, Packaging, and Labeling ...............................................................................53 
5.1.3.3. 
Storage ........................................................................................................................54 
5.1.3.4. 
Instructions to Subjects for Handling Study Drug ......................................................54 
5.1.4. 
Cytarabine ...................................................................................................................54 
5.1.5. 
Azacitidine ..................................................................................................................55 
5.1.6. 
Ruxolitinib ..................................................................................................................55 
5.1.7. 
Treatment Compliance ................................................................................................56 
5.2. 
Treatment of Subjects .................................................................................................56 
5.2.1. 
Starting Dose ..............................................................................................................56 
5.2.2. 
Dose Modifications .....................................................................................................56 
5.2.3. 
Dose-Limiting Toxicity and Determination of Maximum-Tolerated Dose ...............56 
5.2.3.1. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................58 
5.2.3.2. 
Follow-Up of Dose-Limiting Toxicities .....................................................................58 
5.2.3.3. 
Procedures for Cohort Review and Dose Escalation ..................................................58 
5.2.4. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ............................................................................................................................58 
5.2.5. 
Criteria for Permanent Discontinuation of Study Drug ..............................................61 
5.2.6. 
Dose Increases ............................................................................................................62 
5.2.7. 
Withdrawal of Subjects From Study Treatment .........................................................62 
5.2.7.1. 
Withdrawal Criteria ....................................................................................................62 
5.2.7.2. 
Withdrawal Procedures ...............................................................................................63 
5.2.8. 
Concomitant Medications ...........................................................................................63 
5.2.8.1. 
Restricted Medications ...............................................................................................63 
5.2.8.2. 
Prohibited Medications ...............................................................................................64 
6. 
STUDY ASSESSMENTS ..........................................................................................64 
6.1. 
Screening ....................................................................................................................86 
6.2. 
Treatment ....................................................................................................................86 
6.2.1. 
Day 1 ...........................................................................................................................86 
6.2.2. 
Visit Scheduling ..........................................................................................................87 
6.3. 
End of Treatment ........................................................................................................87 
6.4. 
Follow-Up ...................................................................................................................88 
6.4.1. 
Safety Follow-Up ........................................................................................................88 
6.4.2. 
Disease Status Follow-Up ...........................................................................................88 
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6.4.3. 
Survival Follow-Up ....................................................................................................88 
6.5. 
Unscheduled Visits .....................................................................................................88 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................89 
7.1. 
Administration of Informed Consent Form ................................................................89 
7.2. 
Interactive Response Technology Procedure ..............................................................89 
7.3. 
Demography and Medical History ..............................................................................89 
7.3.1. 
Demographics and General Medical History .............................................................89 
7.3.2. 
Transfusion History Status (Ruxolitinib Combination Cohorts Only) .......................89 
7.3.3. 
Screening Symptom Form (Ruxolitinib Combination Cohorts Only) ........................89 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................89 
7.5. 
Safety Assessments .....................................................................................................90 
7.5.1. 
Adverse Events ...........................................................................................................90 
7.5.2. 
Physical Examinations ................................................................................................90 
7.5.2.1. 
Comprehensive Physical Examination .......................................................................90 
7.5.2.2. 
Targeted Physical Examination ..................................................................................90 
7.5.3. 
Vital Signs ..................................................................................................................90 
7.5.4. 
Electrocardiograms .....................................................................................................91 
7.5.4.1. 
Twelve-Lead Electrocardiograms ...............................................................................91 
7.5.4.2. 
Electrocardiogram Procedures ....................................................................................91 
7.5.4.3. 
Additional Instruction for Timed Electrocardiograms ...............................................91 
7.5.5. 
Laboratory Assessments .............................................................................................91 
7.5.5.1. 
Chemistry, Hematology, Urinalysis, Liver Function Panel, Coagulation 
Panel, and Hepatitis Screening ...................................................................................91 
7.5.5.2. 
Pregnancy Testing ......................................................................................................92 
7.5.5.3. 
Hepatitis Screening Tests ...........................................................................................92 
7.6. 
Efficacy Assessments .................................................................................................92 
7.6.1. 
Lymphoma, Chronic Lymphocytic Leukemia, and Myelofibrosis:  CT Scan 
or MRI ........................................................................................................................93 
 
93 
7.6.2. 
Lymphoma:  FDG-PET or Combined PET-CT ..........................................................94 
7.6.3. 
AML, MDS, MDS/MPN, MF, Lymphoproliferative Disorders, and Multiple 
Myeloma:  Bone Marrow Examination ......................................................................94 
7.6.4. 
AML, MDS, and MDS/MPN:  Peripheral Blood Myeloid Blast Percentage .............95 
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8.3.2. 
Reporting ..................................................................................................................104 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................105 
8.5. 
Pregnancy .................................................................................................................105 
8.6. 
Warnings and Precautions ........................................................................................105 
8.7. 
Data Monitoring Committee .....................................................................................105 
8.8. 
Product Complaints ..................................................................................................106 
9. 
STATISTICS ............................................................................................................106 
9.1. 
Study Populations .....................................................................................................106 
9.2. 
Selection of Sample Size ..........................................................................................106 
9.2.1. 
Sample Size in Part 1 ................................................................................................106 
9.2.2. 
Sample Size in Part 2 ................................................................................................107 
9.2.3. 
Sample Size in Part 3 ................................................................................................107 
9.2.4. 
Sample Size in Part 4 ................................................................................................107 
9.3. 
Level of Significance ................................................................................................107 
9.4. 
Statistical Analyses ...................................................................................................108 
9.4.1. 
Primary Analysis ......................................................................................................108 
9.4.2. 
Secondary Analyses ..................................................................................................108 
 
108 
9.4.4. 
Safety Analyses ........................................................................................................109 
9.4.4.1. 
Adverse Events .........................................................................................................109 
9.4.4.2. 
Clinical Laboratory Tests .........................................................................................109 
9.4.4.3. 
Vital Signs ................................................................................................................109 
9.4.4.4. 
Electrocardiograms ...................................................................................................110 
9.4.4.5. 
Adverse Events of Special Interest ...........................................................................110 
9.4.5. 
Pharmacokinetic Analysis ........................................................................................110 
9.5. 
Interim Analysis ........................................................................................................110 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................111 
10.1. 
Investigator Responsibilities .....................................................................................111 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................112 
10.3. 
Data Management .....................................................................................................113 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................115 
10.5. 
Financial Disclosure .................................................................................................115 
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LIST OF FIGURES 
Figure 1: 
Monotherapy Study Design ........................................................................................46 
Figure 2: 
Combination Therapy Study Design ..........................................................................48 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Term 
Explanation 
aCML 
atypical chronic myeloid leukemia 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
Ara-C 
cytarabine 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CLL 
chronic lymphocytic leukemia 
Cmax  
maximum observed plasma or serum concentration 
CMML 
chronic myelomonocytic leukemia 
CNS 
central nervous system 
CR 
complete response/remission 
CRc 
cytogenetic complete remission 
CRi 
complete remission with incomplete recovery 
CRm 
molecular complete remission 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
C-TGA 
Combination Treatment Group A 
C-TGA E1 
Combination Treatment Group A Expansion Cohort 1 
C-TGA E2 
Combination Treatment Group A Expansion Cohort 2 
C-TGB 
Combination Treatment Group B 
C-TGB E1 
Combination Treatment Group B Expansion Cohort 1 
C-TGC 
Combination Treatment Group C 
C-TGC E1 
Combination Treatment Group C Expansion Cohort 1 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
 
 
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Term 
Explanation 
EBMT 
European Group for Blood and Marrow Transplant 
EDC 
electronic data capture 
EOT 
end of treatment 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
 
 
 
 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FDG-PET 
positron emission tomography using [18F] fluorodeoxyglucose 
FISH 
fluorescence in situ hybridization 
FLC 
free light chain 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HbA1c 
hemoglobin A1c 
HBV 
hepatitis B virus 
HBV-DNA 
hepatitis B virus deoxyribonucleic acid 
HCV 
hepatitis C virus 
HCV-RNA 
hepatitis C virus ribonucleic acid 
HDL 
high-density lipoprotein 
HED 
human equivalent dose  
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
I-DAC 
intermediate-dose cytarabine 
IEC 
independent ethics committee 
IgM 
immunoglobulin M 
IL 
interleukin 
IN 
Investigator Notification 
INR 
international normalized ratio 
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Term 
Explanation 
IRB 
institutional review board 
IMWG 
International Myeloma Working Group 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
IWG 
International Working Group 
IV 
intravenously 
L-DAC 
low-dose cytarabine 
LDi 
longest diameter 
LFT 
liver function test 
LDL 
low-density lipoprotein 
MDS 
myelodysplastic syndrome 
MDS/MPN-U 
myelodysplastic/myeloproliferative neoplasms unclassifiable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MM 
multiple myeloma 
MPN 
myeloproliferative neoplasms 
 
 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
ORR 
objective remission rate 
 
 
PAD 
pharmacologically active dose 
PASK 
PAS kinase 
pBAD 
phosphorylated Bcl-2–associated death promoter protein 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PET-MF 
post–essential thrombocythemia myelofibrosis 
PHL 
potential Hy's law 
 
 
P-gp 
P-glycoprotein 1 
PIM 
proviral integration site of Moloney murine leukemia virus 
PK 
pharmacokinetics 
PMF 
primary myelofibrosis 
PPD 
primary progressive disease 
PPV-MF 
post–polycythemia vera myelofibrosis 
PR 
partial remission 
PRBC 
packed red blood cells 
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Term 
Explanation 
PT 
prothrombin time 
QTcF 
QT interval corrected using the Fridericia formula 
QD 
once daily 
RARS-T 
refractory anemia with ring sideroblasts and thrombocytosis 
RBC 
red blood cell 
RD 
resistant disease 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SC 
subcutaneously 
SD 
stable disease 
SDi 
smallest diameter 
SOC 
standard-of-care 
SUSAR 
suspected unexpected serious adverse reaction 
TGA 
Treatment Group A 
TGA E1 
Treatment Group A Expansion Cohort 1 
TGA E2 
Treatment Group A Expansion Cohort 2 
TGA E3 
Treatment Group A Expansion Cohort 3 
TGB 
Treatment Group B 
TGB E1 
Treatment Group B Expansion Cohort 1 
TGB E2 
Treatment Group B Expansion Cohort 2 
TGC 
Treatment Group C 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal  
UPM 
unit probability mass 
Vdss 
volume of distribution at steady state 
WBC 
white blood cell 
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1. 
INTRODUCTION 
1.1. 
Background 
Protein kinases regulate diverse biological processes, including cell growth, survival, and 
differentiation, and play specialized roles in a host of human diseases, including cancer.  One 
such family of kinases involved is the proviral integration site of Moloney murine leukemia virus 
(PIM) family of serine/threonine kinases.  Three members of this kinase family, PIM1, PIM2, 
and PIM3, were initially identified in mouse models of cancer.  Subsequently, overexpression of 
permutations of these kinases has been demonstrated in multiple types of human cancers, 
predominantly in hematological malignancies.  Enhanced activity of PIM kinases contributes to 
the development of malignancies by promoting tumor cell proliferation and survival.  As 
opposed to numerous other cancer-related protein kinases, which require activation by 
phosphorylation, ligand engagement, or genetic modification (mutation or translocation), the 
PIM kinases are constitutively active (Qian et al 2005), and in fact, most known mutations in the 
PIM somatic hypermutation region do not alter kinase activity significantly (Kumar et al 2005).  
Expression of PIM kinases is induced by cytokines and growth factors.  Among the cytokines 
activating the transcription of PIM kinases are those which signal through the Janus kinase/signal 
transducer and activator of transcription pathway, such as interleukin (IL) 6, IL-10, and 
granulocyte macrophage colony–stimulating factor. 
Dysregulated expression of PIM kinases is detected in a wide variety of hematologic and solid 
cancers.  Overexpression of various family members have been noted in multiple myeloma 
(MM), acute myeloid leukemia (AML), pancreatic and hepatocellular cancers (Amson et al 
1989, Claudio et al 2002, Fujii et al 2005, Li et al 2006, Mizuki et al 2003).  Additionally, PIM1 
overexpression is associated with poor prognosis in mantle cell lymphoma, esophageal, gastric, 
and head and neck cancers (Hsi et al 2008, Liu et al 2010, Peltola et al 2009, Warnecke-Eberz 
et al 2009).  PIM1 is overexpressed in Myc driven prostate tumors (Ellwood-Yen et al 2003) 
while PIM2 overexpression is associated with an aggressive clinical course in a subset of diffuse 
large B-cell lymphoma (DLBCL) patients (Gomez-Abad et al 2011).  Overexpression is often 
seen where Myc is overexpressed and PIM kinases can convey resistance to traditional 
chemotherapeutic agents and radiation (Chen et al 2009, Isaac et al 2011, Peltola et al 2009).  As 
such, these data suggest that inhibition of PIM kinases may result in therapeutic benefit in cancer 
patients.  INCB053914 is a selective inhibitor of PIM1, PIM2, and PIM3 and is proposed for the 
treatment of advanced malignancies. 
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1.3. 
Overview of Standard-of-Care Agents Selected for Combination 
1.3.1. 
Cytarabine 
Cytarabine is an antimetabolic, neoplastic cytotoxic agent that exhibits cell phase specificity, 
primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions 
blocking the progression of cells from the G1 phase to the S-phase.  Although its mechanism of 
action is not completely understood, it appears that cytarabine acts through the inhibition of 
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DNA polymerase (Cytarabine 2016).  Cytarabine has served as one of the lynchpin treatments to 
induce remission in AML for over 30 years (Löwenberg et al 1999).  Cytarabine in combination 
with other approved anticancer drugs is indicated for remission induction in acute 
nonlymphocytic leukemia of adults and children (Cytarabine 2016), and cytarabine monotherapy 
or in combination is also used widely in relapsed or refractory AML patients 
(NCCN Guidelines).  In the Phase 3 VALOR study (Ravandi et al 2015), where vosaroxin plus 
cytarabine was compared with placebo plus cytarabine in subjects with first relapsed or 
refractory AML, mOS was 7.5 months in the vosaroxin group (n = 356) versus 6.1 months in the 
intermediate-dose cytarabine (I-DAC) group (n = 350), with HR = 0.87, p = 0.061 unstratified, 
and p = 0.024 stratified by prespecified randomization factors, with complete remission rate 
(CR) 30% versus 16%, and remission rate (CR/CRp/CRi) 37% versus 19%.  Of subjects in the 
I-DAC arm, 84% experienced treatment-emergent adverse events (TEAEs) ≥ Grade 3 (all grade 
and all causality), of which the majority were hematological adverse events (AEs; febrile 
neutropenia, anemia, thrombocytopenia, and neutropenia), and most of nonhematologic AEs 
were Grades 1 and 2, including nausea, constipation, diarrhea, pyrexia, headache, and fatigue.   
1.3.2. 
Azacitidine 
Azacitidine is a nucleoside metabolic inhibitor that is approved by the FDA for the treatment of 
patients with several different subtypes of myelodysplastic syndrome (MDS; Vidaza 2016).  
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).  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 Guidelines).  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; mOS was improved (10.4m vs 6.5m, HR=0.85, P=0.10009), 
however, which did not reach statistical significance; mOS did reach statistical significance 
(12.1m vs 6.9m, 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 different 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 CR of 19.5% vs 21.9% with 
conventional therapies, CR/CRi 27.8% vs 25.1%; the most common TEAEs ≥G3 occurring in 
≥20% of patients in the azacitidine arm were febrile neutropenia, neutropenia, thrombocytopenia, 
pneumonia, 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 INCB053914 and 
azacitidine is not anticipated. 
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1.3.3. 
Ruxolitinib 
Ruxolitinib, a potent and selective inhibitor of JAKs 1 and 2, is approved for use in patients with 
intermediate- or high-risk MF, including primary myelofibrosis (PMF), post–polycythemia vera 
myelofibrosis (PPV-MF), and post–essential thrombocythemia myelofibrosis (PET-MF).  
Registration studies showed improvement in spleen size, symptom burden, and overall survival 
(OS) with ruxolitinib use in this patient population (Harrison et al 2012, Cervantes et al 2013, 
Mesa et al 2013a, Mesa et al 2013b, Verstovsek et al 2012, Verstovsek et al 2013, 
Vannucchi et al 2015). 
In the 2 pivotal, Phase 3 studies of ruxolitinib in MF, INCB 18424-351 and CINC424A2352, 
301 subjects had a median duration of exposure to ruxolitinib of 9.6 months (range, 2 weeks to 
17 months).  The majority of subjects (55.8%) were treated for at least 9 months.  The most 
frequently reported AEs were thrombocytopenia and anemia.  Hematologic AEs (any CTCAE 
grade) included anemia (81.7%), thrombocytopenia (67.4%), and neutropenia (15.3%).  Anemia, 
thrombocytopenia, and neutropenia are dose-related effects.  The 3 most frequently reported 
nonhematologic AEs were bruising (18.6%), dizziness (14.0%), and headache (12.6%).  The 
3 most frequently reported nonhematologic laboratory abnormalities were elevated alanine 
aminotransferase (ALT; 26.2%), elevated aspartate aminotransferase (AST; 18.6%), and 
hypercholesterolemia (16.6%).  In Phase 3 clinical studies, discontinuation because of AEs, 
regardless of causality, was observed in 9.6% of subjects. 
1.4. 
Potential Risks and Benefits of the Treatment Regimens 
1.4.1. 
Potential Risks of INCB053914 Based on Preclinical Safety 
Nonclinical safety studies with INCB053914 included single and repeat-dose studies of up to 
28 days in duration in rats and dogs using a QD dose regimen.  In the 28-day pivotal GLP 
studies, doses were 0 mg/kg, 55 mg/kg, 110 mg/kg, and 250 mg/kg per day for the rat and 
0 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg per day for the dog.  The target organs observed in 
the pivotal 28-day GLP studies included the liver, the hematopoietic system, and the respiratory 
tract.  Liver effects were primarily seen in the bile ducts (ie, proliferation, epithelial 
degeneration/necrosis, periportal inflammation).  The hematopoietic effects (ie, hematologic 
changes, bone marrow hypocellularity) were attributed to the pharmacology of PIM inhibition.  
Respiratory tract findings (inflammation/hemorrhage), which were the cause of mortality in both 
species, resulted from aspiration of the drug and or stomach contents following reflux (rats) or 
emesis (dogs) and thus are not considered to be related to a systemic effect of INCB053914. 
The main INCB053914-related target organ toxicity following repeat-dose exposure to 
INCB053914 in both rats and dogs was hepatotoxicity.  In the 28-day rat GLP study, minimal to 
moderate biliary changes were observed in all high-dose animals (250 mg/kg per day; human 
equivalent dose [HED] = 2400 mg), characterized as bile duct proliferation with epithelial 
degeneration/necrosis and periportal inflammation.  These findings were accompanied by 
minimal to mild hepatocellular necrosis in some animals.  Hepatocellular necrosis may have 
been secondary to the biliary changes, as there were no findings of hepatocellular necrosis in the 
absence of biliary change, whereas biliary changes without necrosis were frequently observed.  
No fibrosis was observed.  In rats, there were no changes in serum chemistry parameters 
associated with biliary changes in the absence of hepatocellular necrosis.  However, elevated 
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serum ALT, AST, and sorbitol dehydrogenase levels were observed in animals with mild to 
moderate hepatocellular necrosis.  Minimal biliary changes were observed in 1 male and 
1 female at the mid dose (110 mg/kg per day; HED = 1056 mg), with no hepatocellular necrosis.  
There were no histologic findings in the liver of high-dose animals after a 4-week recovery 
period, suggesting that these findings were fully reversible.  In the 28-day dog study, minimal 
biliary hyperplasia was observed in a single high-dose dog (30 mg/kg per day; HED = 972 mg), 
with associated increases in serum alkaline phosphatase (ALP), gamma-glutamyl transferase, and 
transient body weight loss.  There were no histologic findings in the liver of high-dose animals 
after a 4-week recovery period. 
Bone marrow effects consistent with the pharmacologic activity of INCB053914 were observed 
in both rats and dogs.  In the 28-day study in rats, hypocellularity of bone marrow was observed 
in animals dosed with ≥ 10 mg/kg (HED = 324 mg), and lower reticulocyte and platelet counts 
were observed in high-dose males (30 mg/kg per day; HED = 972 mg).  In dogs, hematologic 
changes (lower total leukocyte and absolute neutrophil, monocyte, eosinophil, basophil, platelet, 
and reticulocyte counts) were observed at all doses in the 28-day study, although there were no 
histologic changes in the bone marrow.  Slightly lower reversible values of the mean corpuscular 
volume, mean corpuscular hemoglobin, and/or mean corpuscular hemoglobin concentration 
accompanied by slight increase of hemoglobin distribution width were observed on 10-day and 
28-day rat studies.  Comparable hematologic findings were noted in high-dose males in the 
28-day dog study.  Similar hematologic findings have been described in a PIM 1/2/3 triple 
knockout mouse model (Mikkers et al 2004). 
In the 28-day studies, mortality was observed in rats at the mid (110 mg/kg per day; 
HED = 1056 mg; 1 female) and high dose (250 mg/kg per day; HED = 2400 mg; males and 
females), and 2 dogs (one mid [10 mg/kg per day; HED 324 mg] and one high dose [30 mg/kg 
per day; HED 972 mg]) were euthanized in extremis.  Deaths in both species were due to 
respiratory findings consistent with aspiration.  In rats, these findings were attributed to 
aspiration following reflux of INCB053914 formulation and/or stomach contents (as evidenced 
primarily by acute necrotizing inflammation of larynx, trachea, and lung), and in dogs were 
attributed to aspiration following emesis.  These findings were likely mediated by local 
concentrations and irritant effects of the drug in the stomach and/or upper respiratory tract (as 
evidenced by acute inflammation and hemorrhage in the trachea and large bronchi), not systemic 
exposure.  Furthermore, the findings in rats are typical of those described with gavage-related 
reflux and so could, at least in part, be associated with the oral gavage delivery of the compound 
(Damsch et al 2011b).  Hence, respiratory findings were attributed to high local INCB053914 
concentrations in the stomach leading to reflux/emesis and aspiration.  Emesis, while 
compound-related, is a common finding in dogs; also, dogs are prone to aspiration.  Reflux and 
aspiration, while uncommon in rats, have been described following oral gavage administration of 
irritating compounds (Damsch et al 2011a, Damsch et al 2011b), which would not be relevant for 
patients administered tablets.  Moreover, the high gastric concentrations associated with these 
findings in rats would not be achieved over the projected dose range for clinical studies of 
INCB053914.  Symptoms such as nausea, vomiting, reflux, and heartburn are easily monitored 
in patients.  Thus, these findings are not considered relevant for human subjects and were not 
used in defining the safe starting dose. 
The following histologic findings were noted in the rats administered 500 mg/kg per day 
(HED = 4800 mg) in the 10-day range-finding study:  ulceration of the nonglandular stomach, 
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diffuse acinar cell hypertrophy in the salivary gland, reduced luminal sperm in the epididymides, 
diffuse hypertrophy of the adrenal cortex.  These findings occurred at exposures representing 
high multiples of anticipated human exposure and were not observed on 28-day study. 
INCB053914 is an inhibitor of PASK and theoretically may have an effect on glucose 
metabolism.  Glucose levels will be appropriately monitored in clinical studies. 
INCB053914 was negative in the Ames mutagenicity assay. 
The proposed safe starting dose for the Phase 1 study is based on liver findings in rats and dogs.  
The no-observed-adverse-effects levels for these findings were 110 mg/kg per day in rats 
(660 mg/m2 per day) and 30 mg/kg per day in dogs (600 mg/m2 per day) in the 28-day pivotal 
studies.  The HEDs associated with these doses are 1056 mg and 960 mg, respectively; applying 
a 10-fold safety factor for the rat and 6-fold safety factor in the dog results 106 mg and 162 mg, 
respectively.  Thus, a starting dose of INCB053914 100 mg QD is proposed for the first in 
human study. 
Lower mean testis, epididymis and prostate gland weights that correlated with microscopic 
findings of testes immaturity were noted in all treatment groups of a 3-month dog study.  
Immaturity in the testes persisted post-42 day recovery period at the two highest doses (10 mg/kg 
and 20 mg/kg per day). 
Refer to the INCB053914 IB for more details on the nonclinical toxicology. 
1.4.2. 
Potential Risks of INCB053914 Based on Preliminary Clinical Experience 
As of 31 DEC 2016, 34 subjects with various hematologic malignancies had been enrolled in 
Part 1 of the study (monotherapy dose escalation) and received starting doses of INCB053914 of 
either 100 mg QD (n = 4; all in Treatment Group A [TGA]), 50 mg BID (n = 11; 6 in TGA, 4 in 
Treatment Group B [TGB] and 1 in Treatment Group C [TGC]), 65 mg BID (n = 4; all in TGA), 
80 mg BID (n = 3; all in TGA), 100 mg BID (n = 6; 4 in TGA and 2 in TGB), or 115 mg BID 
(n = 6; all in TGA) continuous study drug administration for 21-day cycles.  As of the data cutoff 
date, 2 dose-limiting toxicities (DLTs) have been observed.  Two of 6 subjects experienced 
DLTs (1 subject with AML experienced Grade 3 rash and 1 subject with AML experienced 
Grade 4 ALT elevation) in the TGA 115 mg BID cohort; as such 115 mg BID was deemed to be 
the nontolerated dose for TGA.  Subsequent to the determination of the nontolerated dose , a 
100 mg BID cohort was opened for enrollment in TGA.  One subject with AML in the TGA 100 
mg BID cohort experienced Grade 3 ALT/AST elevation and Grade 3 rash toxicities in Cycle 2.  
Additionally, after the 31 DEC 2016 data cutoff date, it was reported that 1 subject with DLBCL 
in the TGB 100 mg BID cohort experienced a DLT of Grade 3 ALT elevation. 
Aside from the DLTs reported, which have been asymptomatic, INCB053914 has been generally 
well tolerated.  Based on preliminary unaudited data as of 31 DEC 2016, 32 of the 34 enrolled 
subjects (94%) reported a TEAE.  The most common AEs reported (> 25% incidence, any 
causality) were anemia (38%), ALT increased (35%), fatigue (35%), AST increased (32%), 
nausea (32%), and diarrhea (26%).  Twenty-seven subjects (79%) reported a Grade 3 or greater 
AE (CTCAE v4.03).  The most common Grade 3/4 AEs reported (≥ 15% incidence, any 
causality) were anemia (35%), platelet count decreased/thrombocytopenia (24%), febrile 
neutropenia (21%), and pneumonia (15%).  Seventeen subjects (50%) reported an AE that led to 
an interruption, reduction, or withdrawal of study drug.  There were treatment-emergent serious 
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adverse events (SAEs) reported in 20 subjects (59%), 9 of which were considered related to 
study drug as per investigator assessment.  The most common SAEs reported of any causality 
were febrile neutropenia (21%) and pneumonia (15%), while the most common SAEs reported as 
related to study drug were maculopapular rash (9%), ALT increased (6%), and AST increased 
(6%). 
As of 31 DEC 2016, 6 of 34 subjects continue to receive study drug; 28 of 34 subjects 
permanently discontinued treatment (20 because of disease progression, 3 because of an AE, 
2 because of death, 2 because of subject decision, and 1 because of physician decision).  
Seventeen subjects have died as of the cutoff date (12 from disease progression, 3 from unknown 
causes, 1 from disease-related intracerebral hemorrhage, and 1 from disease-related 
pneumonia/sepsis). 
1.4.2.1. 
ALT/AST Elevations 
As of 31 DEC 2016, based on a review of raw, unaudited laboratory data, 22 subjects with 
baseline AST or ALT values within normal limits (62%) experienced treat-emergent ALT or 
AST elevations of any grade. 
Eighteen subjects across all cohorts experienced treatment-emergent Grade 1 (worst grade) ALT 
or AST elevation.  None of these subjects required dose interruptions or modifications. 
Two subjects in the TGA 100 mg QD cohort experienced Grade 2 ALT elevations, and study 
drug administration was interrupted per the guidelines in Protocol Amendment 2.  The ALT 
elevation resolved (values returned to baseline or Grade 1) in approximately 1 week after dose 
interruption, and study drug administration was restarted at a lower dose (50 mg QD) per 
Protocol guidelines.  No further issue occurred. 
As noted above, ALT and AST elevations ≥ Grade 3 have been reported in 3 subjects; 1 subject 
(Grade 4 ALT/Grade 3 AST) in the TGA 115 mg BID cohort and 1 subject (Grade 3 ALT/AST) 
in the TGA 100 mg BID cohort as of the 31 DEC 2016 cutoff date, as well as 1 subject (Grade 3 
ALT) in the TGB 100 mg BID cohort after the data cutoff date.  Study drug was interrupted in all 
3 cases.  The ALT and AST levels in the 2 subjects who received 100 mg BID were resolved 
after approximately 1 week off study drug.  The ALT in the subject who received 115 mg BID 
also showed significant improvement immediately after treatment interruption; however, the 
subject's liver function test (LFT) elevation was considered not resolved at the time of death due 
to disease progression, which occurred 3 days after treatment interruption. 
Investigators should closely monitor serum chemistry and coagulation markers of liver function 
as noted in the relevant schedules of assessments in Section 6, treatment interruption guidelines 
in Section 5.2.4, and assessment of potential Hy's law (PHL) cases as noted in Appendix S. 
1.4.2.2. 
Rash 
As of the 31 DEC 2016 data cutoff date, 3 subjects (2 in the TGA 115 mg BID cohort and 1 in 
the TGA 100 mg BID cohort) have experienced Grade 3 treatment-emergent maculopapular 
rashes.  The majority of these rashes have been nonpruritic and asymptomatic, but did warrant 
treatment interruption, and all resolved with or without supportive care. 
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1.4.3. 
Potential Risks Related to Standard-of-Care Agents Selected for Combination 
1.4.3.1. 
Cytarabine 
Cytarabine is a potent bone marrow suppressant, and as such, dose and schedule-dependent 
pancytopenias, as well as cellular changes in the morphology of bone marrow and peripheral 
smears, can be expected as a result of cytarabine treatment.  Subjects receiving this drug must be 
under close medical supervision and during induction therapy; bone marrow and peripheral 
blood parameters will be monitored according to the Protocol schedule, local institutional 
guideline, or as clinically indicated.  Infections in any location of the body may be associated 
with the use of cytarabine. 
Other frequent toxicities following cytarabine treatment include anorexia, hepatic dysfunction, 
nausea, fever, vomiting, rash, diarrhea, thrombophlebitis, oral and anal inflammation, or 
ulceration and bleeding (all sites).  Periodic checks of liver and kidney functions should be 
performed in subjects receiving cytarabine treatment according to the Protocol schedule, local 
institutional guideline, or as clinically indicated. 
A complete discussion of risks associated with cytarabine can be found at 
http://dailymed.nlm.nih.gov/. 
1.4.3.2. 
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 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.  Periodic checks of bone marrow, liver, and kidney 
functions should be performed in subjects receiving azacitidine treatment according to the 
Protocol schedule, local institutional guideline, or as clinically indicated.  A complete discussion 
of risks associated with azacitidine can be found at http://dailymed.nlm.nih.gov/. 
1.4.3.3. 
Ruxolitinib 
The primary clinical risks with ruxolitinib treatment are the potential sequelae of decreased 
hematopoietic proliferation attributable to the inhibition of growth factor pathways associated 
with JAK inhibition.  Dose-dependent, reversible thrombocytopenia has been observed in studies 
of subjects with MF.  Anemia and, less frequently, neutropenia have also been observed in 
studies in subjects with MF.  Increased rates of infection and anemia are potential risks of 
myelosuppression, and there are multiple sequelae of anemia, including the burden and risks of 
transfusion.  A complete discussion of risks associated with ruxolitinib can be found at 
http://dailymed.nlm.nih.gov/. 
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1.4.4. 
Potential Risks Related to the Combination of INCB053914 and Selected 
Standard-of-Care Agents 
INCB053914 has not been combined with cytarabine, azacitidine, or ruxolitinib in the clinic 
previously.  Therefore, the safety profiles of each combination are unknown.  The most common 
AE associated with the standard-of-care (SOC) agents is myelosuppression.  The expected 
treatment-emergent AE of INCB053914 is ALT/AST elevation.  The effects of each combination 
are being assessed in this Protocol.  There is not an expected overlap or interaction between 
INCB053914 and the SOC agents.  Hematology and blood chemistry, including LFT panels, will 
be closely monitored in all study subjects.  In addition, all AEs will be monitored to identify 
occurrences of any new safety signal or potentiation of any SOC agent-related side effects. 
1.4.5. 
INCB053914 Potential Benefits 
INCB053914 represents a novel compound that demonstrates potent inhibitory activity across 
several PIM kinases, including PIM1, PIM2, and PIM3.  Because PIM kinases have been shown 
to play a role in many hematologic malignancies, PIM kinase inhibition may provide a method to 
treat these diseases either alone or in combination with chemotherapeutics or other targeted 
agents.  The degree of PIM inhibition that is being targeted in the current study may result in 
clinical benefit. 
1.5. 
Study Rationale 
In many advanced malignancies, dysregulated cytokine and growth factor receptor signaling 
results in the overexpression of PIM kinases and support the establishment, growth, and survival 
of tumors.  Therefore selective inhibition of PIM proteins may be efficacious in the treatment of 
these diseases.  Preliminary data from ongoing Phase 1 studies with the pan-PIM inhibitor 
PIM447 (formerly LGH447) have shown a tolerable safety profile for the class with preliminary 
indications of efficacy in relapsed and refractory MM.  The planned study will evaluate the 
safety, tolerability, and pharmacological activity of INCB053914 in subjects with advanced 
malignancies.  An expansion phase will further evaluate the safety, tolerability, and preliminary 
efficacy of the recommended Phase 2 dose (RP2D) of INCB053914 in selected malignancies. 
1.5.1. 
Rationale for Combining INCB053914 With Cytarabine and Azacitidine in 
AML 
For relapsed or refractory AML, high-dose cytarabine monotherapy or cytarabine-based 
combination regimens are often used as aggressive salvage therapy, and L-DAC or 
hypomethylating agents such as azacitidine is used as less aggressive therapy.  For newly 
diagnosed AML in patients ≥ 60 years old, azacitidine is recommended as a low-intensity 
induction therapy, primarily in patients who are unfit for high- or intermediate-intensity 
regimens; L-DAC is also one of the recommended treatment regimens in this population 
(NCCN Guidelines).  However, in both disease populations, all the conventional therapy 
regimens result in limited efficacy, and as such, new approaches are urgently needed and patients 
are encouraged to enroll in clinical trials.  It is hypothesized that the combination of 
INCB053914 with either cytarabine or azacitidine will be able to achieve better clinical efficacy 
in order to increase clinical remission rate and duration and OS. 
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1.5.2. 
Rationale for Combining INCB053914 With Ruxolitinib in Myelofibrosis 
Despite statistically significant improvements in signs and symptoms of MF and OS rates, 
compared with either placebo or best available therapy demonstrated in the registration studies, 
ruxolitinib monotherapy fails to provide adequate and/or sustained response for some patients.  A 
subgroup analysis of the Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I 
study did not identify subgroups (age, MF subtype, International Prognostic Scoring System risk 
group, baseline ECOG score, baseline platelet or hemoglobin level, baseline spleen volume 
quartile, baseline symptom burden quartile, or presence/absence of V617F mutation) that did not 
benefit from ruxolitinib therapy (Verstovsek et al 2013); however, additional systemic and 
genetic factors may influence the response magnitude and duration in an individual patient.  It is 
possible that for some patients, declining hemoglobin or platelet counts associated with 
ruxolitinib use preclude maintenance at optimal ruxolitinib dosages.  Alternatively, some patients 
may have increases in inflammatory pathway signaling that are not JAK-mediated as a primary 
driver for their disease.  Therefore, new approaches such as combination therapy are needed to 
provide adequate and/or sustained responses for MF patients who do not achieve such with 
ruxolitinib monotherapy. 
Mazzacurati et al (2015) recently treated JAK2-V617F–dependent MPN model cells and primary 
MPN patient cells with a combination of pan-PIM inhibitors and ruxolitinib.  While PIM 
inhibitor monotherapy had little effect on MPN model cell line, the combination therapy 
demonstrated a synergistic effect on MPN cell growth due to enhanced apoptosis, as well as a 
synergistic suppression of colony formation of primary MPN cells.  Moreover, PIM inhibitors 
resensitized ruxolitinib-resistant MPN cells to ruxolitinib by inducing apoptosis.  Finally, 
exogenous expression of PIM1 induced ruxolitinib resistance in MPN model cells.  These data 
suggest that PIM kinases may play a role in MPNs and that combining a pan-PIM inhibitor such 
as INCB053914 with the JAK inhibitor ruxolitinib may offer an efficacious approach to treating 
patients with MF who have been unable to achieve a satisfactory response on ruxolitinib 
monotherapy. 
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3. 
SUBJECT ELIGIBILITY 
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. 
Study Population 
3.1.1. 
Parts 1 and 2 
Subjects diagnosed with acute leukemia, high-risk MDS, MDS/MPN, MF, MM, or 
lymphoproliferative neoplasms that are unresponsive to currently available therapy and have no 
SOC options in the opinion of the investigator. 
3.1.2. 
Parts 3 and 4 
Subjects diagnosed with relapsed/refractory AML, subjects with newly diagnosed AML who are 
≥ 65 years of age and unfit for intensive chemotherapy, and subjects with primary or secondary 
MF who are currently experiencing a suboptimal response on ruxolitinib monotherapy. 
3.2. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Men and women, aged 18 or older.  Subjects in the Part 4 C-TGB Expansion Cohort 1 
(C-TGB E1) and the optional C-TGA Expansion Cohort 2 (C-TGA E2) must be 
≥ 65 years old. 
2. Part 1 monotherapy dose escalation 
a. TGA:  Subjects with histologically confirmed diagnosis of acute leukemia, high-risk 
MDS, or MDS/MPN (including atypical chronic myeloid leukemia [aCML], chronic 
myelomonocytic leukemia [CMML], myelodysplastic/myeloproliferative neoplasm 
unclassifiable [MDS/MPN-U], and refractory anemia with ring sideroblasts and 
thrombocytosis [RARS-T]). 
b. TGB:  Subjects with MM, lymphoma, and other lymphoproliferative neoplasms. 
Part 2 monotherapy dose expansion 
Subjects with histologically confirmed and measureable/evaluable disease: 
c. TGA Expansion Cohort 1 (TGA E1):  AML. 
d. TGA Expansion Cohort 2 (TGA E2):  MDS/MPN. 
e. TGA Expansion Cohort 3 (TGA E3):  MF. 
f. TGB Expansion Cohort 1 (TGB E1):  MM. 
g. TGB Expansion Cohort 2 (TGB E2):  DLBCL. 
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Part 3 combination dose-finding 
Subjects with histologically confirmed and measureable/evaluable disease: 
h. Combination Treatment Group A (C-TGA): relapsed/refractory AML.  Subjects with 
acute promyelocytic leukemia are excluded. 
i. Combination Treatment Group B (C-TGB): relapsed/refractory AML or subjects 
≥ 65 years of age with newly diagnosed AML (de novo or secondary) and unfit for 
intensive chemotherapy.  Subjects with acute promyelocytic leukemia are excluded. 
j. Combination Treatment Group C (C-TGC):  primary or secondary MF who are 
currently experiencing a suboptimal response on ruxolitinib monotherapy, defined as 
follows: 
− Palpable spleen of > 10 cm below the left subcostal margin on physical 
examination at the screening visit OR 
− Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical 
exam AND active symptoms of MF at the screening visit as demonstrated by 
presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening 
Symptom Form (Appendix O). 
Part 4 combination expansion 
Subjects with histologically confirmed and measureable/evaluable disease: 
k. C-TGA Expansion Cohort 1 (C-TGA E1):  relapsed/refractory AML.  Subjects with 
acute promyelocytic leukemia are excluded. 
l. C-TGB Expansion Cohort 1 (C-TGB E1):  newly diagnosed AML (de novo or 
secondary) who are ≥ 65 years and unfit to receive intensive chemotherapy.  Subjects 
with acute promyelocytic leukemia are excluded. 
m. C-TGC Expansion Cohort 1 (C-TGC E1):  primary or secondary MF who are 
currently experiencing a suboptimal response on ruxolitinib monotherapy, defined as 
follows: 
− Palpable spleen of > 10 cm below the left subcostal margin on physical 
examination  at the screening visit OR 
− Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical 
exam AND active symptoms of MF at the screening visit as demonstrated by 
presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening 
Symptom Form (Appendix O). 
3. Parts 1 and 2 
a. Must be unresponsive to currently available therapy, and there is no further SOC 
therapy available in the judgment of the investigator. 
b. Must not currently be a candidate for curative treatment, including hematopoietic 
stem cell transplant. 
Parts 3 and 4 
c. Subjects with relapsed/refractory AML must have received either induction 
chemotherapy for AML or hypomethylating agents for hematologic disease before 
AML. 
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d. Elderly subjects (≥65 years) with newly diagnosed AML must be treatment-naive and 
unfit for intensive chemotherapy. 
e. Subjects with MF must be receiving ruxolitinib monotherapy at a stable dose for 
≥ 8 weeks before Study Day 1.  One dose reduction due to toxicities within the 8 
weeks before Study Day 1 will be permitted.  Acceptable doses are 5 mg BID to 25 
mg BID; QD doses are not allowed. 
4. Willingness to undergo a pretreatment bone marrow biopsy and/or aspirate (as 
appropriate to disease), or archival sample obtained since completion of most recent 
therapy (as appropriate to subjects with existing bone marrow disease or for whom bone 
marrow examination is a component of disease status assessment).  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. 
5. ECOG performance status: 
a. Part 1:  0 or 1. 
b. Parts 2 through 4:  0, 1, or 2. 
6. Life expectancy > 12 weeks or ≥ 24 weeks for Part 3 and Part 4 MF subjects. 
7. Willingness to avoid pregnancy or fathering children based on the following criteria: 
a. Postmenopausal woman (ie, surgically sterile with a hysterectomy and/or bilateral 
oophorectomy OR ≥ 12 months of amenorrhea and at least 50 years of age.) 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 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 subject and their 
understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through 90 days after the last dose of study 
medication.  Permitted methods that are at least 99% effective in preventing 
pregnancy (see Appendix A) should be communicated to the subject and their 
understanding confirmed. 
3.3. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Inadequate bone marrow function demonstrated by any of the following: 
Laboratory Parameter 
TGB (Part 1) 
TGB (Part 2) 
C-TGC (Parts 3 and 4) 
Hemoglobin (g/dL) 
< 8.0 
< 8.0 
Subjects unwilling to receive red 
blood cell transfusions to treat low 
hemoglobin levels are excluded. 
Platelets (× 109/L) 
< 75 
< 50 
< 50 in 2 weeks before screening or 
platelet transfusions within 4 weeks of 
screening. 
Absolute neutrophils  (× 109/L) 
< 1.0 
< 1.0 
< 0.5 in the 2 weeks before screening. 
Note:  No specific hematologic exclusion criteria apply for TGA (Parts 1 and 2), Part 3 C-TGA and C-TGB, and Part 4 
C-TGA E1 and C-TGB E1 cohorts. 
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2. Inadequate organ function demonstrated by any of the following, unless approved by the 
medical monitor: 
Part 1 and Part 3 
a. Total bilirubin > upper limit of normal (ULN; except total bilirubin > ULN is 
acceptable if direct bilirubin is ≤ 1.2 × ULN.  Subjects with Gilbert's syndrome who 
have total bilirubin ≤ 2 × ULN may be enrolled with medical monitor approval). 
b. AST or ALT > 1.5 × ULN. 
c. Creatinine clearance < 50 mL/min (< 30 mL/min for MM) based on Cockroft-Gault 
formula or 24-hour urine analysis. 
Part 2 and Part 4 
d. Total bilirubin > ULN (except total bilirubin > ULN is acceptable if direct bilirubin is 
≤ 1.2 × ULN.  Subjects with Gilbert's syndrome who have total bilirubin ≤ 2 × ULN 
may be enrolled with medical monitor approval). 
e. AST or ALT > 1.5 × ULN. 
f. Creatinine clearance < 40 mL/min (< 30 mL/min for MM) based on Cockroft-Gault 
formula or 24-hour urine analysis. 
3. Receipt of anticancer medications or investigational drugs within the following interval 
before the first administration of study drug (note:  subjects enrolling in C-TGC must 
continue to receive their ruxolitinib throughout the study): 
a. < 5 half-lives or 14 days, whichever is longer, for any investigational agent. 
b. < 28 days for any antibodies or biological therapies. 
c. < 5 half-lives for all other nonbiologic anticancer medications, or sponsor approval. 
d. < 6 weeks for mitomycin-C or nitrosoureas. 
e. The following are allowed:  hydroxyurea for controlling proliferative disease and 
low-dose corticosteroids (prednisone or equivalent ≤ 10 mg per day).  Hydroxyurea 
should not be used within 48 hours before and on the day of PD sample collection or 
during or 72 hours before or after azacitidine administration.  Note:  Concomitant 
hydroxyurea is prohibited in subjects with MF within 8 weeks before enrolling 
(Day 1) into C-TGC. 
4. Unless approved by the medical monitor, may not have received an allogeneic 
hematopoietic stem cell transplant within 6 months before treatment, or have active 
graft-versus-host disease following allogeneic transplant, or have received 
immunosuppressive therapy (including, but not limited to, cyclosporine, tacrolimus, 
mycophenolate mofetil, or corticosteroids [> 10 mg/day prednisone equivalent]) 
following allogeneic transplant within 2 weeks of Cycle 1 Day 1. 
5. Unless approved by the medical monitor, may not have received autologous 
hematopoietic stem cell transplant within 3 months before treatment.  
6. Has any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable 
chronic toxicities (≤ Grade 2) not expected to resolve, such as stable Grade 2 peripheral 
neuropathy. 
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7. Radiotherapy within the 2 weeks before initiation of treatment.  Palliative radiation 
treatment to nonindex or bone lesions performed less than 2 weeks before treatment 
initiation may be considered with medical monitor approval.  In Part 3 and Part 4, MF 
subjects may not have had splenic irradiation within 6 months of the first dose of 
INCB053914. 
8. Part 1 and Part 3 only:  Hemoglobin A1c (HbA1c) > 8.0% (all subjects will have HbA1c 
tested at screening). 
9. Part 1 and Part 3:  Any history of disease involving the central nervous system (CNS). 
Part 2 and Part 4:  Known active disease involving the CNS, for example, brain 
metastasis or spinal cord compression, except primary CNS lymphoma. 
10. Known HIV infection. 
11. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as defined in 
Section 7.5.5.3. 
12. Active and uncontrolled infectious disease requiring systemic antibiotic, antifungal, or 
antiviral treatment. 
13. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Screening QTc interval > 470 milliseconds is excluded.  For subjects with 
an intraventricular conduction delay (QRS interval 120 msec), the JTc interval may be 
used in place of the QTc with sponsor approval.  Subjects with left bundle branch block 
are excluded.  QTc prolongation due to a pacemaker may enroll if the JT is normal or 
with MM approval. 
14. History of clinically significant or uncontrolled cardiac disease, including recent (within 
last 6 months) unstable angina or acute myocardial infarction, or New York Heart 
Association Class III or IV congestive heart failure, or clinically significant arrhythmias 
not controlled by medication.  Subjects with a pacemaker and well-controlled rhythm for 
at least 1 month before the first dose of study drug will be allowed. 
15. Part 1 and Part 3:  Current diagnosis of any chronic or acute respiratory condition or 
ongoing sequelae from any previously diagnosed respiratory condition that is significant 
in the judgment of the investigator or the sponsor's medical monitor. 
Part 2 and Part 4:  Current diagnosis of any severe or uncontrolled obstructive or 
restrictive respiratory condition (eg, Global Initiative for Chronic Obstructive Lung 
Disease [GOLD] 3 or GOLD 4 chronic obstructive pulmonary disease). 
16. Gastroesophageal reflux disease not controlled by medication (ie, currently symptomatic 
or endoscopic evidence of esophagitis) within 30 days before Cycle 1 Day 1.  
17. Prior receipt of a PIM inhibitor. 
18. Current use of prohibited medication as described in Section 5.2.8.2. 
19. Use of any potent CYP3A4 inhibitors or inducers (Appendix M) within 14 days or 
5 half-lives (whichever is longer) before the first dose of study drug. 
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20. Subject has known hypersensitivity or severe reaction to any of the active substances or 
excipients in INCB053914, cytarabine, azacitidine, ruxolitinib, or similar compounds as 
appropriate to the relevant treatment group. 
21. Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the 
dose regimen and study evaluations. 
22. Currently breastfeeding. 
23. Any condition in the investigator's judgment that would 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. 
24. Unable to swallow and retain oral medication. 
25. Unable to comprehend or unwilling to sign the informed consent form (ICF). 
26. Any known contraindications to the use of cytarabine, azacitidine, or ruxolitinib as 
appropriate to the relevant treatment group. 
27. Excessive alcohol use (eg, > 2 drinks per day). 
28. Excessive chronic acetaminophen use (> 2 g per day). 
29. Part 1 and Part 3 only:  Type 1 diabetes or uncontrolled Type 2 diabetes. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an open-label, dose-escalation study of the PIM kinase inhibitor INCB053914 as 
monotherapy and in combination with SOC agents in subjects with advanced malignancies.  
Subjects will receive INCB053914 in 21- or 28-day cycles (as applicable to regimen schedules) 
until withdrawal criteria are met.  The study will be conducted in 4 parts:  Parts 1 and 2 will 
evaluate INCB053914 as monotherapy (Figure 1) and Parts 3 and 4 will evaluate INCB053914 
in combination with select SOC agents (Figure 2).  Part 1 (monotherapy dose escalation) will be 
conducted in 2 disease-specific treatment groups (Treatment Groups A and B) and will 
determine the maximum tolerated dose (MTD) of INCB053914 and/or a tolerated 
pharmacologically active dose (PAD [defined as a plasma concentration exceeding average PK 
that is projected to inhibit pBAD level > 50% for approximately 12 hours]) that will be taken 
forward into Part 2 of the study (ie, the RP2D).  Part 2 (monotherapy dose expansion) will 
further evaluate the safety, efficacy, PK, and PD of the RP2D in specific disease indications in 
which PIM kinases are particularly relevant, including leukemias and myeloproliferative and 
lymphoproliferative disorders, such as AML, MDS/MPN, MF, DLBCL, and MM.  Part 3 
(combination dose-finding) will consist of 3 disease-specific combination treatment groups 
(Combination Treatment Groups A, B, and C [C-TGA, C-TGB, C-TGC]) and will determine the 
optimal doses of INCB053914 in combination with the selected SOC agents based on the MTD 
and/or tolerated PAD at the discretion of the sponsor and investigators.  Part 4 (combination dose 
expansion) will further evaluate the safety, efficacy, PK, and PD of the selected combination 
dose regimens identified in Part 3 in up to 3 expansion cohorts in specific indications relevant to 
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the drug combinations (2 AML; 1 MF).  A Simon 2-stage design will be implemented in the 
2 AML combination expansion cohorts (Part 4). 
Pending emerging scientific and/or clinical data, all of the cohorts in each part may not open in 
parallel, and/or certain cohort(s) may not open for enrollment. 
Figure 1: 
Monotherapy Study Design 
 
4.1.1. 
Part 1 Monotherapy Dose Escalation 
Between 3 and up to approximately 30 subjects will be enrolled into each of 2 treatment groups.  
Treatment Group A will include acute leukemia, high-risk MDS, and MDS/MPNs (including 
aCML, CMML, MDS/MPN-U, and RARS-T).  Treatment Group B will include MM, 
lymphoma, and other lymphoproliferative neoplasms.  Dose escalation for TGA and TGB will 
proceed independently, with each treatment group following a 3 + 3 design.  At least 3 subjects 
will be enrolled and treated in each cohort.  If no DLTs are observed in the initial 3 subjects, the 
next cohort will begin enrollment at the next higher dose level.  If 1 DLT is observed in the first 
3 subjects, 3 additional subjects will be enrolled in that cohort.  If a DLT occurs in one-third or 
more of the total cohort (ie, ≥ 2 of 6 subjects), then the MTD will be deemed to have been 
exceeded, and the next lower dose level will be deemed to be the MTD.  Thus, the MTD will be 
defined as 1 dose level below that at which one-third or more of subjects in a particular cohort 
report DLTs.  If the first cohort exceeds the MTD, a dose de-escalation will be considered.  The 
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initial dose level in each treatment group will be 100 mg QD, with dose increases up to 2-fold 
until a Grade 2 toxicity that has a reasonable possibility of being related to INCB053914 is 
observed in that treatment group or until a total daily dose of 300 mg has been reached in that 
treatment group, after which dose increases will be limited to ≤ 50%.  The sponsor, in 
consultation with participating investigators, may implement alternate administration, such as 
intermediate doses, alternate dose regimens, or alternate formulations, depending on emerging 
PK, PD, and safety results.  Each subject will be observed for 1 cycle to be evaluable to assess 
safety and tolerability of the dose.  The RP2D will be selected based on the totality of the data 
within each treatment group for further investigation in the expansion cohorts, and it is possible 
that the RP2D could be different among disease types.  If there is a distinct discrepancy in 
tolerability among different disease types in the same treatment group, separate disease-specific 
dose-escalation schedules may be initiated.  If a PAD (defined as a plasma concentration 
exceeding average PK that is projected to inhibit pBAD level > 50% for approximately 12 hours) 
is reached before the MTD, the PAD (rather than the MTD) may be selected as the RP2D based 
on the clinical data at the discretion of the sponsor.  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, PD, and safety data. 
4.1.2. 
Part 2 Monotherapy Dose Expansion 
Upon identification of the RP2D(s), up to 5 expansion cohorts will enroll subjects to further 
determine safety, tolerability, efficacy, PK, and PD of the selected dose(s) as follows: 
• TGA Expansion Cohort A1:  At least 5 and up to approximately 15 subjects with 
AML will be enrolled and treated at the RP2D identified in Part 1 TGA. 
• TGA Expansion Cohort A2:  At least 5 and up to approximately 15 subjects with 
MDS/MPN (including aCML, CMML, MDS/MPN-U, and RARS-T) will be enrolled 
and treated at the RP2D identified in Part 1 TGA. 
• TGA Expansion Cohort A3:  At least 5 and up to approximately 15 subjects with 
MF will be enrolled and treated at the RP2D identified in Part 1 TGA. 
• TGB Expansion Cohort B1:  At least 5 and up to approximately 15 subjects with 
MM will be enrolled and treated at the RP2D identified in Part 1 TGB. 
• TGB Expansion Cohort B2:  At least 5 and up to approximately 15 subjects with 
DLBCL will be enrolled and treated at the RP2D identified in Part 1 TGB. 
Individual dose titration will be permitted according to Protocol-defined safety parameters.  
Subjects will continue to receive INCB053914 in 21-day cycles until withdrawal criteria are met. 
Part 2 will also include a food-effect study.  At least 12 and up to 18 subjects across all 
expansion cohorts who are able to participate in the food study will have additional PK 
assessments on Cycle 2 Day 1 and Cycle 2 Day 2, as per Section 7.8.4. 
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Figure 2: 
Combination Therapy Study Design 
 
 
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4.1.3. 
Part 3 Combination Therapy Dose-Finding 
Part 3 (combination dose-finding) will comprise up to 3 disease-specific treatment groups 
(Combination Treatment Groups A through C [C-TGA – C-TGC]) and will determine the MTD 
and/or a tolerated PAD of INCB053914 in combination with 3 SOC agents.  The combination 
dose-finding will use a 3 + 3 design to identify an optimal dose regimen in up to 3 different 
combination expansion cohorts. 
• Combination Treatment Group A (C-TGA):  INCB053914 + cytarabine in 
subjects with relapsed/refractory AML. 
• Combination Treatment Group B (C-TGB):  INCB053914 + azacitidine in 
subjects with relapsed/refractory AML or elderly subjects (≥ 65 years) with newly 
diagnosed AML (de novo or secondary) who are unfit to receive intensive 
chemotherapy. 
• Combination Treatment Group C (C-TGC):  INCB053914 + ruxolitinib in 
subjects with primary or secondary MF (PPV-MF or PET-MF) who are currently 
experiencing a suboptimal response on ruxolitinib monotherapy, defined as follows: 
− Palpable spleen of > 10 cm below the left subcostal margin on physical 
examination  at the screening visit OR 
− Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical 
exam AND active symptoms of MF at the screening visit as demonstrated by 
presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening 
Symptom Form (Appendix O). 
4.1.3.1. 
Standard-of-Care Agent Combination Cohort Dose-Finding Strategy 
Between 3 and up to approximately 10 subjects will be enrolled into cohorts under each of the 
SOC treatment groups, C-TGA, C-TGB, and C-TGC, as described above.  Dose-finding for 
C-TGA, C-TGB, and C-TGC will proceed independently, with each treatment group following a 
3 + 3 cohort design.  At least 3 subjects will be enrolled and treated at each dose level.  If no 
DLTs are observed in the initial 3 subjects, the next cohort will begin enrollment at the next 
higher dose level of INCB053914.  If 1 DLT is observed in the first 3 subjects, 3 additional 
subjects will be enrolled in that cohort.  If a DLT occurs in one-third or more of the total cohort 
(ie, ≥ 2 of 6 subjects), then the MTD will be deemed to have been exceeded, and the next lower 
dose level will be deemed to be the MTD.  Thus, the MTD will be defined as 1 INCB053914 
dose level below that at which one-third or more of subjects in a particular cohort report DLTs.  
If the first cohort exceeds the MTD, a dose de-escalation of INCB053914 will be considered.   
A conventional regimen of the SOC agents will be used in all dose-finding cohorts within a 
given SOC combination treatment group and will remain fixed throughout the dose-finding 
portion of the study. 
The starting dose of INCB053914 in the combination treatment groups will be a PAD and 1 dose 
level below the highest tolerated dose of INCB053914 monotherapy identified in Part 1 of this 
study.  At the current data cutoff date, the highest tolerated dose of INCB053914 monotherapy 
was 80 mg BID, which also met the criteria of protocol-defined PAD; thus, the planned starting 
dose for Part 3 will be 65 mg BID (Dose Level 1 dose).  The INCB053914 dose used in Part 3 
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will never exceed the monotherapy MTD dose to be identified in Part 1 of the study.  Table 1, 
Table 2, and Table 3 summarize the planned starting doses to be used in the SOC combination 
dose-finding cohorts.  An alternative starting dose and/or subsequent INCB053914 doses (Dose 
Level 1, 2, and/or 3) may be selected pending emerging safety, PK, and PD data in Part 1. 
The sponsor, in consultation with participating investigators, may implement alternate 
INCB053914 administration, such as intermediate doses, alternate dose regimens, or alternate 
formulations, depending on emerging PK, PD, and safety results.  Each subject will be observed 
for 1 cycle to be evaluable to assess safety and tolerability of the assigned INCB053914 dose in 
combination with the chosen SOC regimen.  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, PD, and safety data.  The INCB053914 RP2D of the 
combination treatment group will be selected based on the totality of the data within each 
treatment group for further investigation in the expansion cohorts, and it is possible that the 
RP2D could be different among disease types. 
Table 1: 
Planned C-TGA Combination Dose-Finding Cohorts 
Dose Level 
I-DAC dose 
INCB053914 Dose
a 
-1 
1 g/m2; given as 2-hour infusion on Days 1-5 
50 mg BID 
1 (starting dose) 
1 g/m2; given as 2-hour infusion on Days 1-5 
65 mg BID 
2 
1 g/m2; given as 2-hour infusion on Days 1-5 
80 mg BID 
3 
1 g/m2; given as 2-hour infusion on Days 1-5 
100 mg BID 
a INCB053914 starting dose and subsequent cohort doses may change based on emerging Part 1 safety, PK, and PD data.  
Table 2: 
Planned C-TGB Combination Dose-Finding Cohorts 
Dose Level 
Azacitidine Dose 
INCB053914 Dose
a 
-1 
75 mg/m2 SC or IV; given on Days 1-5 and 8-9 of a 28-day cycle 
50 mg BID 
1 (starting dose) 
75 mg/m2 SC or IV; given on Days 1-5 and 8-9 of a 28-day cycle 
65 mg BID 
2 
75 mg/m2 SC or IV; given on Days 1-5 and 8-9 of a 28-day cycle 
80 mg BID 
3 
75 mg/m2 SC or IV; given on Days 1-5 and 8-9 of a 28-day cycle 
100 mg BID 
IV = intravenously; SC = subcutaneously. 
a INCB053914 starting dose and subsequent cohort doses may change based on emerging Part 1 safety, PK, and PD data.  
Table 3: 
Planned C-TGC Dose-Finding Cohorts 
Dose Level 
Ruxolitinib Dose 
INCB053914 Dose
a 
-1 
Subject's current stable dose (between 5 mg BID and 25 mg BID) 
50 mg BID 
1 (starting dose) 
Subject's current stable dose (between 5 mg BID and 25 mg BID) 
65 mg BID 
2 
Subject's current stable dose (between 5 mg BID and 25 mg BID) 
80 mg BID 
3 
Subject's current stable dose (between 5 mg BID and 25 mg BID) 
100 mg BID 
a INCB053914 starting dose and subsequent cohort doses may change based on emerging Part 1 safety, PK, and PD data.  
See Sections 5.1.4, 5.1.5, and 5.1.6 for information on the specific dose regimens for cytarabine, 
azacitidine, and ruxolitinib, respectively. 
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4.1.4. 
Part 4 Combination Expansion Cohorts 
Upon identification of the RP2D combination regimens in the combination dose-finding 
treatment groups, up to 4 expansion cohorts will enroll to further determine safety, tolerability, 
efficacy, PK, and PD in the subject populations.  The 2 AML expansion cohorts will use a Simon 
2-stage design to evaluate the efficacy of the combination regimens. 
• C-TGA Expansion Cohort 1 (C-TGA E1) will enroll subjects with 
relapsed/refractory (r/r) AML who will be treated with INCB053914 in combination 
with I-DAC using the regimen identified from the Part 3 dose-finding.  This cohort 
will use a Simon 2-stage design, details of which can be referenced in Section 9.2.4.  
If an insufficient number of responders are observed in the cohort at Stage 1, further 
enrollment in the cohort will be terminated.  
• C-TGB Expansion Cohort 1 (C-TGB E1) will enroll subjects with newly diagnosed 
AML (de novo or secondary) who are ≥ 65 years at screening and unfit to receive 
intensive chemotherapy and who will be treated with INCB053914 in combination 
with azacitidine using the regimen identified from the Part 3 dose-finding.  This 
cohort will use a Simon 2-stage design, details of which can be referenced in 
Section 9.2.4.  If an insufficient number of responders are observed in the cohort at 
Stage 1, further enrollment in the cohort will be terminated. 
• C-TGC Expansion Cohort 1 (C-TGC E1) will enroll up to 16 subjects with PMF or 
secondary MF (PPV-MF or PET-MF) who are currently experiencing a suboptimal 
response on ruxolitinib monotherapy and who will be treated with INCB053914 in 
combination with ruxolitinib using the dose identified from the Part 3 dose-finding. 
• Optional C-TGA Expansion Cohort 2 (C-TGA E2) 
If the Part 3 C-TGB dose-finding does not yield a tolerable combination of 
INCB053914 and azacitidine, or if the Part 4 C-TGB E1 Simon Stage 1 does not yield 
favorable efficacy data, then the sponsor may elect to evaluate INCB053914 in 
combination with a L-DAC regimen in this population.  This option will use an 
INCB053914 dose deemed tolerable in combination with I-DAC and will reference 
safety and tolerability data obtained from the Part 3 C-TGA dose-finding.  If the 
sponsor and investigators believe that the optimal dose regimen of INCB053914 in 
combination with L-DAC will be different from that of INCB053914 in combination 
I-DAC, a separate dose-finding cohort will be initiated to identify the optimal dose 
regimen of INCB053914 in combination with L-DAC. 
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 3 to 30 subjects per treatment group may be enrolled in Part 1 of the study, and 
up to 75 subjects may be enrolled in Part 2.  In Part 3, approximately 3 to 10 subjects will be 
enrolled per treatment group, and in Part 4, up to 102 subjects may be enrolled. 
4.3.2. 
Replacement of Subjects  
In Part 1 and Part 3, if a subject is not evaluable (eg, at least 80% of the prescribed study drug 
and SOC agent doses during the first cycle are not taken due to dose interruption, reduction, or 
discontinuation), 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 21- or 
28-day cycles depending upon the treatment regimen.  If the subject discontinues all study 
treatment, the subject will enter follow-up (see Section 6.4).  Subjects may continue on study 
until withdrawal criteria are met.  Treatment duration will vary significantly between subjects but 
is expected to average approximately 4 to 6 months. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the informed consent.  The end of the study will 
occur when all subjects have discontinued study drug and have completed the safety follow-up 
visit; the sponsor may elect to continue to monitor survival outcome and subsequent therapies for 
subjects enrolled in Parts 2 and 4.  The overall study duration is expected to be approximately 
42 months. 
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 IRB/IEC in writing of the 
study's completion or early termination, and send a copy of the notification to the sponsor or 
sponsor's designee and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively or if required by regulatory decision.  If the study 
is terminated prematurely, the sponsor will notify the investigators, the IRBs and IECs, and 
regulatory bodies of the decision and reason for termination of the study.   
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5. 
TREATMENT 
5.1. 
Study Drug and Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Upon screening a subject, study sites will contact the IRT in order to receive a subject number.   
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 fail screening, withdraw consent, or discontinue from the 
study after being assigned a subject number will retain their initial number. 
Upon enrolling the subject, the site staff will contact the IRT to register the quantity of study 
drug allocated at the initial visit and all subsequent visits at which study drug is dispensed.  Refer 
to the IRT manual for detailed information. 
5.1.2. 
Randomization and Blinding 
Not applicable. 
5.1.3. 
INCB053914 
5.1.3.1. 
Description and Administration 
INCB053914 drug product is formulated as immediate release (IR) tablets. 
INCB053914 will be self-administered orally BID beginning with the Cycle 1 Day 1 morning 
dose and continuously thereafter in 21- or 28-day cycles, or appropriate visit intervals, depending 
on the treatment group regimen until treatment withdrawal criteria are met.  Exceptions are noted 
in the Schedule of Assessment tables (Table 6, Table 9, Table 12, Table 15, Table 18), when the 
morning dose will be administered in the clinic to accommodate PK sample collection.  Dose 
increases will be accomplished using the following options:  1) increasing the number of tablets 
taken at each QD administration, or 2) increasing administration frequency to BID, or 3) 
increasing the number of tablets taken at 1 or more dose administrations and increasing the 
frequency to BID.  The sponsor may implement alternate administration, such as intermediate 
doses, alternate dose regimens, or alternate formulations, depending upon PK, PD, and safety 
results.  All BID doses will be taken with water in the morning and evening, approximately 
12 hours apart and at least 2 hours after a meal.  If possible, subjects should refrain from eating 
for 1 hour after administration   
See Section 10.2 for details regarding the accountability, handling, and disposal of study drug.   
Refer to the INCB053914 IB for additional detail about the respective investigational products. 
5.1.3.2. 
Supply, Packaging, and Labeling 
INCB053914 will be provided as 15 mg and 50 mg round, white to off-white tablets packaged in 
high-density polyethylene bottles.  The 15 mg tablets will be smaller than the 50 mg tablets.   
No preparation of INCB053914 is required. 
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All Incyte investigational product will be labeled with the following statement, "Caution:  New 
Drug—Limited by the United States law to investigational use," or in accordance with local 
regulatory requirements as applicable. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.1.3.3. 
Storage 
INCB053914 drug product should be stored according to the conditions stipulated on the 
investigational product labels. 
5.1.3.4. 
Instructions to Subjects for Handling Study Drug 
The subject must be instructed in the handling of study medication as follows: 
• To store the study medication according to the conditions listed on the investigational 
product bottle label. 
• To only remove from the study drug bottle(s) the amount 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. 
• When taking the study drug at home, take the tablets with a glass of water at least 
2 hours after the last meal.  It is preferable to refrain from food or drink (other than 
water) for 1 hour after the dose (unless otherwise advised by the sponsor after 
completion of food-effect testing). 
• To report any missed doses, including any missed injections of cytarabine or 
azacitidine. 
• If the subject vomits after taking study medication, 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 medication bottles and syringes (if applicable) to 
the site at each visit. 
• If a dose of INCB053914 is missed by more than 4 hours, that dose should be 
skipped, and the next scheduled dose should be administered at the usual time. 
5.1.4. 
Cytarabine 
In the Part 3 C-TGA dose-finding cohorts and Part 4 combination expansion 1 (C-TGA E1) 
cohort, I-DAC will be administered to relapsed/refractory AML subjects as an open-label 
commercial product at a dose of 1 g/m² per day, 2-hour infusion on Days 1 through 5.  A second 
induction cycle may be started between 15 days and 8 weeks after initiation of Cycle 1, at the 
discretion of the investigator, in subjects with residual leukemia upon bone marrow assessment 
during initial induction, provided all drug-related toxic effects had resolved to ≤ Grade 1.  Up to 
2 additional cycles may be given as consolidation therapy in subjects who achieved CR or 
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complete remission with incomplete platelet recovery, at the discretion of the investigator.  The 
start of subsequent induction or consolidation cycles of I-DAC should be coordinated with the 
Day 1 of the INCB053914 21-day visit cycle when feasible. 
If the Part 3 C-TGB dose-finding does not yield a tolerable combination of INCB053914 and 
azacitidine, or if the Part 4 C-TGB E1 Simon Stage 1 does not yield favorable efficacy data, then 
the sponsor may elect to evaluate INCB053914 in combination with a L-DAC regimen to treat 
elderly subjects (≥ 65 years) with newly diagnosed AML (de novo or secondary) who are unfit 
for intensive chemotherapy.  In this event, L-DAC will be administered as an open-label 
commercial product at a dose of 20 mg SC on Days 1 through 10 of a 28- to 42-day cycle, 
depending upon hematologic recovery.  Low-dose cytarabine therapy may continue until 
Protocol withdrawal criteria are met, or until subject's condition worsens, per investigator's 
clinical judgment, and warrants withdrawal. 
Cytarabine dose modifications for toxicity may be made at the investigator's discretion. 
Investigative sites must provide subjects with administration and storage instructions, as per 
cytarabine package insert or institution standard, for L-DAC SC syringes dispensed to subjects 
for administration away from the investigative site. 
5.1.5. 
Azacitidine 
In the Part 3 C-TGB dose-finding cohorts and Part 4 C-TGB E1 expansion cohort, azacitidine 
(Vidaza 2016) will be administered as an open-label commercial product at a dose of 75 mg/m2 
SC or IV for 7 days during 9-day or less period (ie, a 2-day break allowed on weekend, if 
needed) of each 28-day treatment cycle.  Dose modifications for toxicity will be permitted at the 
discretion of the investigator. 
Azacitidine dose modifications for toxicity may be made at the investigator's discretion. 
Investigative sites must provide subjects with administration and storage instructions, as per 
Vidaza® package insert or institution standard, for azacitidine SC syringes dispensed to subjects 
for administration away from investigative site. 
5.1.6. 
Ruxolitinib 
In the Part 3 C-TGC dose-finding cohorts and Part 4 C-TGC E1 expansion cohort, ruxolitinib 
(Jakafi 2016) will be administered as an open-label commercial BID oral treatment using the 
dose designated as the stable dose at the time of the screening visit for each subject.  Acceptable 
doses are 5 mg BID to 25 mg BID. 
Doses of ruxolitinib should be self-administered approximately 12 hours apart without regard to 
food. 
Note that subjects must be instructed to withhold the morning dose or ruxolitinib until reaching 
the clinic for each study visit where administration will occur.  The dose may need to be reduced 
or interrupted for declining platelet count or ANC as described in Section 5.2.4 and will be 
increased or restarted with recovery of hematologic parameters. 
Ruxolitinib should be stored in accordance with the Jakafi® package insert. 
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5.1.7. 
Treatment Compliance 
Treatment compliance with all study-related medications should be emphasized to the subject by 
the site personnel, and appropriate steps should be taken to optimize compliance during the 
study.  Compliance with INCB053914 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-related medications 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. 
5.2. 
Treatment of Subjects 
5.2.1. 
Starting Dose 
The starting dose of INCB053914 in Part 1 will be 100 mg QD.  Dose escalation in Part 1, 
dose-finding in Part 3, and the determination of the Part 2 monotherapy dose and Part 4 
combination regimens will proceed as per Section 4.1. 
5.2.2. 
Dose Modifications 
Dose interruptions and modifications 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 or dose-finding portion of the study will have the option 
of escalating to a dose found to be tolerated in a subsequent cohort (see Section 5.2.6). 
5.2.3. 
Dose-Limiting Toxicity and Determination of Maximum-Tolerated Dose 
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities in Table 4 
occurring up to and including Day 21 or Day 28 (per regimen cycle schedule), except those with 
a clear alternative explanation (eg, disease progression) or transient (≤ 72 hours) abnormal 
laboratory values without associated clinically significant signs or symptoms based on 
investigator determination.  All DLTs will be assessed by the investigator using CTCAE v4.03 
criteria.  Subjects who receive at least 80% of the INCB053914 doses at the level assigned 80% 
of the planned doses for the SOC agents or have a DLT will be considered evaluable for 
determining tolerability of the dose.  Subjects receiving dose reductions (but not meeting DLT 
criteria) that result in < 80% of the prescribed dose being administered will not be considered 
evaluable for the purposes of determining the MTD and will be replaced. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of dose cohort 
escalation/de-escalation/dose-finding and determining the MTD of INCB053914 monotherapy or 
the optimal doses of INCB053914 in combination with the selected SOC agents, decisions will 
be made based on events that are observed from the first day of study drug administration 
through and including the final day of Cycle 1 (Day 21 or Day 28).  A lower MTD may 
subsequently be determined based on relevant toxicities that become evident after Day 21 or 
Day 28, respectively. 
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5.2.3.1. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications (following 
discussion with the sponsor when feasible), necessary to optimally treat the subject. 
5.2.3.2. 
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 4 weeks.  During follow-up, subjects should be seen as often as medically indicated 
to assure safety. 
5.2.3.3. 
Procedures for Cohort Review and Dose Escalation 
Regular 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. 
5.2.4. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drug 
Treatment with INCB053914, L-DAC, azacitidine, or ruxolitinib may be delayed up to 2 weeks 
(≤ 14 days) to allow for resolution of toxicity.  The second induction or consolidation cycles of 
I-DAC may be delayed until subject has recovered from I-DAC–related toxicities.  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 treatment with INCB053914, 
L-DAC, azacitidine, or ruxolitinib. 
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 or SOC agents, 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.  
Hematologic events (eg, thrombocytopenia, anemia, neutropenia) occurring in Part 1 TGB 
precipitating dose interruptions during Cycle 1 of treatment will be evaluated as potential DLTs 
(Table 4) and managed as per the guidelines in Section 5.2.3.  Hematologic AEs that precipitate 
dose interruptions should be monitored for recovery at least every 3 days, if feasible. 
 
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Table 5: Guidelines for Interruption and Restarting of Study Drug 
CHEMISTRY 
Adverse Event 
Trigger 
Action Taken 
ALT and/or AST 
elevation 
Grade 1 
• Continue study drug: 
− Monitor LFTs at least weekly until < Grade 1 or baseline. 
− Carefully examine subject's concomitant medications for any that 
may contribute to LFT elevations.  Hold these concomitant 
medications or switch to an alternative; consult medical monitor if 
needed. 
− Subjects with persistent but stable low-grade elevations (eg, < 1.5 × 
ULN) may revert to the routine LFT evaluation schedule as noted 
in Section 6. 
Grade 2 
• Continue study drug: 
− Take actions as noted for Grade 1 elevations until LFTs have 
resolved to ≤ Grade 1 or baseline. 
− Refer to Appendix S for PHL case evaluation. 
− If Grade 2 elevation lasts ≤ 14 days, no action required. 
− If Grade 2 elevation lasts > 14 days, interrupt drug, monitor LFTs at 
least weekly, AND: 
 If resolved within 14 days after interruption, resume study drug 
at the same dose, monitor LFTs at least weekly during the next 
month and according to Protocol schedule thereafter. 
 If LFTs do not resolve to ≤ Grade 1 or baseline within 14 days 
after interruption lasts, discuss with medical monitor. 
Grade 3 or 4 
• Refer to Appendix S for PHL case evaluation 
• Complete a coagulation panel on the subject. 
• Interrupt study drug and monitor LFTs at least weekly until ≤ Grade 1 
or baseline: 
− If resolved within 14 days after interruption subject may resume 
study drug at next lower dose (or at 25% reduction [Part 2 or 
Part 4], rounded down to the nearest strength). 
− If LFTs do not resolve to ≤ Grade 1 or baseline within 14 days after 
interruption, discuss with medical monitor. 
• Carefully examine subject's concomitant medications for any that may 
contribute to LFT elevations.  Hold these concomitant medications or 
switch to an alternative; consult medical monitor if needed. 
Total bilirubin 
elevation 
> 2 ×ULN 
• Refer to Appendix S for PHL case evaluation 
• If > 3 × ULN, interrupt treatment. 
ALT and/or AST > 3.0 × ULN AND 
total bilirubin > 2.0 × ULN (Hy's 
law) 
• Interrupt treatment 
• Refer to Appendix S for PHL case evaluation 
• Monitor LFTs according to Protocol schedule or more frequently if clinically indicated. 
• If Grade 2 or Grade 3 AST or ALT elevations recur upon restart of study drug, follow guidelines above, and if 
eligible to restart, resume study drug at next lower dose (or at 25% reduction [Part 2 or Part 4], rounded down 
to the nearest strength).  If Grade 4 elevation recurs upon restart of study drug, discontinue study drug. 
• In subjects with liver metastasis-related elevations at baseline, contact sponsor to discuss clinical management 
and possible dose reductions. 
• Actions taken with any of the SOC combination agents in response to LFT elevations should be in accordance 
with the respective agents prescribing information. 
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Table 5: 
Guidelines for Interruption and Restarting of Study Drug (Continued) 
HEMATOLOGY 
Parameter 
Subjects 
Trigger 
Action Taken 
Platelet count 
(× 109/L) 
Part 1 TGB 
≥ 25 to < 50 sustained 
for > 7 days OR 
w/associated bleeding 
• Hold until resolved to ≥ 50. 
• Restart study drug at same dose and monitor. 
< 25 
• Hold until resolved to ≥ 50. 
• If recovery to ≥ 50 in ≤ 7 days, restart study drug 
at same dose and monitor.  If recovery to ≥ 50 in 
> 7 days, restart study drug at next lower dose 
and monitor. 
Part 2 TGB 
Expansion Cohorts 
< 25 
• Hold until resolved to ≥ 25. 
• If recovery to ≥ 25 in ≤ 7 days, restart study drug 
at same dose and monitor.  If recovery to ≥ 25 in 
> 7 days, restart study drug at next lower dose 
and monitor. 
Part 1 TGA 
Part 2 TGA 
Expansion Cohorts 
N/A 
Thrombocytopenia should be managed as per 
institutional standard, relevant to the underlying 
disease.  If there is a suspected causal relationship 
to INCB053914 in the setting of a decreasing 
platelet count, hold INCB053914 and discuss with 
the medical monitor. 
Part 3 All Cohorts 
Part 4 All Cohorts 
≥ 50% decrease from 
baseline platelet count 
(Subjects with 
baseline platelet 
count < 75) 
• Evaluate underlying disease based on peripheral 
blood and bone marrow assessment as needed. 
• Consider dose interruption if cytopenias are NOT 
due to underlying disease or treatment with 
standard-of-care agents. 
• Restart study drug at next lower dose (or 25% 
reduction if in expansion cohort, rounded down to 
the nearest tablet strength); monitor as clinically 
indicated. 
ANC 
(× 109/L) 
Part 1 TGB 
Part 2 TGB 
Expansion Cohorts 
< 0.5 
• Hold until resolved to ≥ 0.5. 
• If recovery to ≥ 0.5 in ≤ 7 days, restart study drug 
at same dose and monitor.  If recovery to ≥ 0.5 in 
> 7 days, restart study drug at next lower dose 
and monitor. 
Part 1 TGA 
Part 2 TGA 
Expansion Cohorts 
N/A 
Neutropenia should be managed as per institutional 
standard, relevant to the underlying disease.  If 
there is a suspected causal relationship to 
INCB053914 in the setting of a decreasing ANC, 
hold INCB053914 and discuss with the medical 
monitor. 
Part 3 All Cohorts 
Part 4 All Cohorts 
≥ 50% decrease from 
baseline ANC 
(Subjects with 
baseline ANC <  1.0 
only) 
• Evaluate underlying disease based on peripheral 
blood and bone marrow assessment as needed. 
• Consider dose interruption if cytopenias are NOT 
due to underlying disease or treatment with 
standard-of-care agents. 
• Restart study drug at next lower dose (or 25% 
reduction if in expansion cohort, rounded down to 
the nearest tablet strength); monitor as clinically 
indicated. 
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Table 5: 
Guidelines for Interruption and Restarting of Study Drug (Continued) 
HEMATOLOGY 
Parameter 
Subjects 
Trigger 
Action Taken 
Hemoglobin 
(g/dL) 
All treatment 
groups/cohorts 
< 6.5 
• Hold until resolved to ≥ 6.5, restart at same dose, 
and monitor. 
• If recovery to ≥ 6.5 does not occur within 14 days 
of dose interruption or is refractory to transfusion 
support, discontinue study drug treatment(s) and 
follow-up per Protocol. 
OTHER TOXICITIES 
Adverse Event 
Action Taken 
Any Grade 1 or Grade 2 toxicity. 
Continue study drug treatment and treat the toxicity; monitor as clinically 
indicated. 
Any Grade 3 toxicity, if clinically 
significant and not manageable by 
supportive care. 
• Interrupt study drug up to 2 weeks (14 days), until toxicity resolves to 
≤ Grade 1 or to baseline.  
• Resume study drug at same dose.  If assessed as related to study drug, 
resume at next lower dose (or 25% reduction, whichever is the smaller 
increment, rounded down to the nearest pill strength); monitor as 
clinically indicated. 
Any recurrent Grade 3 toxicity after 
2 dose reductions. 
Discontinue study drug and follow-up per Protocol.  (Exceptions require 
approval of sponsor.) 
Any other Grade 4 toxicity. 
Discontinue study drug and follow-up per Protocol. 
Note:  Dose reductions in Part 2 or Part 4 will use the next lowest dose evaluated in Part 1 or combination regimen in Part 3, 
respectively. 
Up to 2 dose reductions of cytarabine, azacitidine, and ruxolitinib may be made at the discretion 
of the investigator. 
5.2.5. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity related to study drug treatment 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 which, 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, unless further dose reductions are 
approved by the medical monitor. 
• Persistent AE requiring a delay of therapy for more than 2 weeks (14 days) unless a 
greater delay has been approved by the medical monitor. 
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5.2.6. 
Dose Increases 
Intrasubject dose escalation will be permitted in Part 1 and Part 3 with sponsor preapproval in the 
following circumstances: 
• The Protocol eligibility criteria are met at the time of escalation (hepatitis serology 
and pregnancy testing do not need to be repeated). 
• The subject has received ≥ 4 cycles of study drug without drug-related toxicity 
≥ Grade 2.  
• The next dose level(s) has been determined to be safe based on the MTD criteria.  
• Subjects in the monotherapy groups must be willing to submit to the PK sampling and 
ECG schedule as in Cycle 1 of Table 8.  Supplemental PK sampling at the escalated 
dose is optional for subjects in the SOC combination groups and should be considered 
only if the subject is continuing to receive the combination agent. 
• 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. 
5.2.7. 
Withdrawal of Subjects From Study Treatment 
5.2.7.1. 
Withdrawal Criteria 
Subjects must be withdrawn from treatment for the following reasons: 
• Disease progression or treatment failure has occurred, as assessed by the appropriate 
disease-specific assessment criteria.  If, in the investigators opinion, the subject is 
receiving clinical benefit despite meeting criteria for progressive disease, the subject 
may continue to receive treatment with sponsor approval.  
• An AE defined as unacceptable toxicity occurs (see Section 5.2.5). 
• The subject becomes pregnant. 
• Consent is withdrawn.   
• 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. 
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. 
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5.2.7.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the subject will 
be withdrawn from the study and the end-of-treatment (EOT) visit should be conducted.  
Reasonable efforts should be made to have the subject return for a follow-up visit.  These visits 
are described in Sections 6.3 and 6.4.  The last date of the last dose of study drug and the reason 
for subject withdrawal will be recorded in the electronic case report form (eCRF). 
If a subject is withdrawn from study treatment: 
• 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 (see Section 6.3). 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
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. 
5.2.8. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 30 days before enrollment (Cycle 1 Day 1) will be recorded in the 
eCRF.  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. 
5.2.8.1. 
Restricted Medications 
• Chronic use of systemic corticosteroid doses ≤ 10 mg/day prednisone (or equivalent) 
is permitted but discouraged from the screening visit through the EOT visit or last 
dose of study drug. 
• Short courses of systemic corticosteroid doses > 10 mg/day prednisone (or 
equivalent) are permitted (eg, for transfusion reaction prophylaxis) but discouraged 
from the screening visit through the EOT visit or last dose of study drug. 
• Chronic acetaminophen use is discouraged; however, if it is required and no 
alternative therapies are available, acetaminophen less than 2 g per day is permitted. 
• Use of weak or moderate inducers or inhibitors of CYP3A4 (Appendix M) is 
discouraged, and investigators should seek other options where possible. 
• P-glycoprotein substrates with a narrow therapeutic index (Appendix N) should be 
used with caution. 
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• Hydroxyurea should not be used within 48 hours before and on the day of PD sample 
collection or during or 72 hours before or after azacitidine administration.  
Hydroxyurea is prohibited in C-TGC subjects. 
• For subjects taking INCB053914 in combination with ruxolitinib only: 
− Aspirin in doses exceeding 125 mg/day is not permitted.  Low-dose aspirin 
(≤ 125 mg/day) is permitted. 
− Caution should be used when administering ibuprofen or other nonsteroidal 
anti-inflammatory drugs with long elimination half-lives; subjects should be 
monitored closely for toxicity, especially for myelosuppression and renal and 
gastrointestinal toxicity. 
Additional timed PK testing following the serial timepoints schedule for the respective 
monotherapy or combination regiment may be required if subjects initiate or require a dose 
modification of inhibitors or inducers of CYP3A4 or of P-gp substrates during the study. 
5.2.8.2. 
Prohibited Medications 
The following medications are prohibited: 
• Any concomitant anticancer therapy to treat the disease under study. 
• Potent inducers and inhibitors of CYP3A4 with the exception of topical ketoconazole, 
based on its low overall bioavailability (see Appendix M). 
• Any investigational study drug, for any indication. 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments relevant to 
subjects' study part, treatment group and combination regimen, as applicable (see Table 6, 
Table 9, Table 12, Table 15, and Table 18), and all laboratory assessments will be performed as 
indicated in Table 7, Table 10, Table 13, Table 16, and Table 19.  The order of assessments is 
suggested by the order of mention within the schedule.  Table 21 presents a summary of clinical 
laboratory analytes to be assessed.  The following tables outline the PK, PD, and ECG schedule 
during Cycle 1 and Cycle 2 where applicable: Table 8, Table 11, Table 14, Table 17, and 
Table 20.  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: 
Laboratory Assessments for INCB053914 Monotherapy Cohorts 
Visit Day 
Section 
Screening 
Treatment 
(21-Day Cycles) 
EOT 
Safety Follow-Up 
Cycle 1 
Cycle 2 and Beyond 
Day -28 to  
Day -1 
D1 
D2 
D8 
D15 
D1 
D2 
D11 
+ 3 Days 
EOT + 30-35 Days 
Evaluation/Window 
 
± 3 Days 
 
± 4 Days 
Overnight fast before assessments 
Table 8 
 
X 
 
X 
 
X
a 
 
 
 
 
Comprehensive blood chemistries 
Table 21 
X
b 
Xb 
X 
X 
X 
X 
 
X 
X 
X 
Hematology with differential 
Table 21 
Xb 
Xb 
X 
X 
X 
X 
 
X 
X 
X 
LFT panel
c 
Table 21 
Xb 
Xb 
X 
X 
X 
X 
 
X 
X 
X 
Coagulation panelc 
Table 21 
Xb 
Xb 
 
X 
X 
X 
 
 
X 
X 
Urinalysis 
Table 21 
X 
 
 
 
 
X
d 
 
 
X 
X 
Lipid panel 
Table 21 
X 
 
 
 
 
Xd 
 
 
 
 
Hepatitis screening 
Table 21 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test  
7.5.5.2  
X 
X
e 
 
 
 
 
 
 
 
X 
PK – plasma
f,g 
7.8.1 
 
X 
X 
X 
X 
Xf 
 
 
 
 
PK – food effectg 
7.8.4 
 
 
 
 
 
X 
X 
 
 
 
PD – whole bloodg 
7.9.4  
 
X 
 
X 
 
 
 
 
 
 
PK – urineg 
7.8.2  
 
 
 
X 
 
 
 
 
 
 
a Applicable to Part 2 subjects in the food-effect study at Cycle 2 only.  See Section 7.8.4 for details. 
b Blood chemistry (including LFTs) and hematology screening assessments used to determine eligibility must be collected within 14 days before Cycle 1 Day 1.  Cycle 1 Day 1 
blood chemistry, hematology, LFT panel, and coagulation panel assessments may be omitted if the screening assessments were performed within 3 days before Cycle 1 Day 1. 
c Additional LFT and coagulation monitoring may be required as per Table 5 and Appendix S. 
d Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles there after (eg, Cycle 10, Cycle 13, etc). 
e If screening serum pregnancy testing is performed within 7 days of treatment initiation, it does not need to be repeated at Cycle 1 Day 1. 
f Untimed PK sample should be performed at Cycle 2 Day 1; however, Cycle 2 Day 1 untimed PK does not apply to subjects in the food-effect study. 
g See Table 8 for sample collection details.  The Cycle 2 PK samples only pertain to Part 2 subjects who participate in the food-effect study. 
 
 
 
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c Reinduction with I-DAC is permitted at the discretion of the investigator in subjects who have residual disease per Day 15 bone marrow examination provided all drug-related 
toxicities have returned to ≤ Grade 1.  Additionally, subjects who achieve CR or CRp may receive up to 2 cycles of I-DAC consolidation therapy at the discretion of the 
investigator. 
d All study drug for Cycle 1 will be dispensed at Cycle 1 Day 1; subject will bring unused study drug to clinic for compliance check on Cycle 1 Days 5, and 14.  Drug will only be 
dispensed at Day 1 of all subsequent cycles and will bring unused study drug to clinic for compliance check on Day 11. 
e EOT visit - compliance check only. 
f Height only assessed at screening.  Weight is only required at screening, Day 1 of each cycle, EOT, and the follow-up visit 
g During I-DAC infusions, vital signs and laboratory assessments may be performed per institution standard, however only preinfusion assessments on Day 1 and Day 5 are 
required to be entered into the eCRF. 
h Subjects must be followed for AEs for 30 days (+ 5 days) after the EOT visit (or after the last dose of study drug if the EOT visit was not performed.) 
i Bone marrow biopsy and/or aspirates performed as clinically indicated or at Cycle 1 Day 15 (+ 2 weeks, depending upon chemotherapy recovery), Day 15 (+ 2 weeks) of any 
cycle where I-DAC is administered, and 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).  Note:  For subjects who have a significant blast count reduction (as determined by the investigator) but have not completely cleared 
circulating blasts, the bone marrow during Cycle 2 is still strongly encouraged to be performed to assess the impact of treatment on the bone marrow blast content.  See 
Section 7.6 for additional details. 
j If a biopsy is not possible or contraindicated, or if the tissue requirement cannot be satisfied, then this requirement may be waived with approval from the medical monitor.  
Subjects with a history of allogenic hematopoietic stem cell transplantation should have tissue 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. 
k Immunophenotyping appropriate to AML will be conducted by flow cytometry at screening and when confirming CR. 
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c If subjects have not sufficiently recovered from chemotherapy-related toxicities after 28 days, they should be seen weekly until such time that a subsequent cycle can be started.  
These visits should be entered as unscheduled visits in the eCRF.  If subjects cannot start a subsequent cycle within 42 days, the site should contact the medical monitor. 
d Azacitidine will be administered as 75 mg/m2 SC or IV for 7 days during 9-day or less period (ie, a 2-day break allowed on weekend, if needed) of 28-day cycle. 
e All study drug for Cycle 1 will be dispensed at Cycle 1 Day 1; subject will bring unused study drug to clinic for compliance check on Cycle 1 Day 15.  Drug will only be 
dispensed at Day 1 of all subsequent cycles and compliance will be checked at the start of the next subsequent cycle. 
f Compliance check only. 
g If needed. 
h Height measured at screening only.  Weight required at screening, Day 1 of each cycle, EOT, and the follow-up visit. 
i Subjects must be followed for AEs for 30 days (+ 5 days) after the EOT visit (or after the last dose of study drug if the EOT visit was not performed). 
j 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).  Note:  For subjects who have a significant blast 
count reduction (as determined by the investigator) but have not completely cleared circulating blasts, the Cycle 4 Day 1 bone marrow is still strongly encouraged to be 
performed to assess the impact of treatment on the bone marrow blast content.  See Section 7.6 for additional details. 
k 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.  Subjects 
with a history of allogenic hematopoietic stem cell transplantation should have tissue 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. 
l Immunophenotyping appropriate to AML will be conducted by flow cytometry at screening and when confirming CR. 
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Table 15: 
Schedule of Assessments for Ruxolitinib Combination Cohorts 
Visit Day (Range) 
Section 
Screening 
Treatment Phase
a 
EOT 
Follow-up Phase 
Day -28 to 
Day -1 
Day 1 
Weeks 
1, 2, 3
b 
Weeks 
4, 8 
± 5 
Days 
Week 
12 
± 5 
Days 
Weeks 
16, 20 
± 5 
Days 
Week 
24 
± 5 
Days 
Extension 
Visits (Q12W 
After 
Week 24) 
± 7 Days 
+3 
Days 
Safety 
Follow-Up 
+ 30-35 Days 
After EOT 
Survival 
Follow-Up 
Every 
12 Weeks 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3 
X 
X 
 
 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Medical and cancer history  
7.3.1 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medication 
7.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Transfusion history/status 
7.3.2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Screening Symptom Form 
7.3.3 
X 
 
 
 
 
 
 
 
 
 
 
Administer INCB053914 in clinic 
Table 17 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Administer ruxolitinib in clinic 
Table 17 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Drug dispense/compliance check 
5.1.7 
 
X 
 
X 
X 
X 
X 
X 
X
c 
 
 
Comprehensive physical 
examination 
7.5.2.1 
X 
 
 
 
 
 
X 
 
X 
X 
 
Targeted physical examination 
7.5.2.2 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
ECOG performance status 
7.7.1 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs/height/weight
d 
7.5.3 
Xd 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
7.5.4 
X 
X 
 
 
 
 
X 
 
X 
X 
 
AE assessment
e 
7.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Laboratory assessments 
Table 16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Buccal swab 
7.9.2 
X 
 
 
 
 
 
 
 
 
 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CT = computed tomography; ECG = electrocardiogram; MRI = magnetic resonance imaging, PGIC = Patient Global Impression of Change. 
a See Table 16 for scheduled visits where only lab assessments are collected (lab-only visits). 
b Week 1 and Week 3 visits only pertain to Part 3 subjects. 
c Compliance check only. 
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d Height is only assessed at screening. 
e Subjects must be followed for AEs for 30 days (+ 5 days) after the EOT visit (or after the last dose of study drug if the EOT visit was not performed). 
 
 
 
 
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f EOT visit - compliance check only. 
g Height measured at screening only.  Weight required at screening, Day 1 of each cycle, EOT, and the follow-up visit. 
h Subjects must be followed for AEs for 30 days (+ 5 days) after the EOT visit (or after the last dose of study drug if the EOT visit was not performed). 
i Bone marrow biopsy and/or aspirates for response is to be performed at Cycle 2 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).  Note, for subjects who have a significant blast 
count reduction (as determined by the investigator) but have not completely cleared circulating blasts, the Cycle 2 Day 1 bone marrow is still strongly encouraged to be 
performed to assess the impact of treatment on the bone marrow blast content.  See Section 7.6 for additional details. 
j 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.  Subjects 
with a history of allogenic hematopoietic stem cell transplantation should have tissue 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. 
k Immunophenotyping appropriate to AML will be conducted by flow cytometry at screening and when confirming CR. 
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Table 21: 
Clinical Laboratory Analytes 
Blood Chemistries 
Hematology 
Hepatitis Screening 
Albumin  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
HbA1c
a 
Lactate dehydrogenase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric acid 
Complete blood count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes
b 
• Monocytes 
• Neutrophilsb 
• Blasts
c 
Hepatitis B surface antibody 
Hepatitis B surface antigen 
Hepatitis B core antibody 
HBV-DNA
d 
HCV antibody 
HCV-RNAd 
Pregnancy 
Female subjects of childbearing potential 
require a serum test at screening.  
 
Pregnancy tests (serum or urine) should be 
repeated during the study as required by 
local regulations.   
Coagulation Panel 
PT 
aPTT 
INR 
LFT Panel 
Lipids 
Urinalysis With Microscopic Examination 
Alkaline phosphatase 
ALT 
AST  
Total bilirubin 
Direct bilirubin
e 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
aPTT = activated partial thromboplastin time; HDL = high-density lipoprotein; INR = international normalized ratio; 
LDL = low-density lipoprotein; PT = prothrombin time. 
a HbA1c to be performed on all Part 1 and Part 3 subjects at screening only. 
b Absolute values must be provided for lymphocytes and neutrophils. 
c Required at intervals specified in Table 6, Table 9, Table 12, Table 15, and Table 18 for diseases where peripheral blast count 
is part of disease assessments such as AML, MDS, MDS/MPN, and MF. 
d Screening hepatitis B and C viral loads by PCR assay are required for all ruxolitinib combination subjects (C-TGC).  For all 
other subjects, hepatitis B and C viral loads by PCR assay only need to be assessed when respective serology results are 
positive.  Hepatitis B virus DNA does not need to be performed if the HBV surface antibody is the only positive result 
(indicating immunity due to vaccination). 
e Direct bilirubin should only be performed when total bilirubin is > ULN and subject does not have Gilbert's syndrome. 
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6.1. 
Screening 
The screening phase is the interval between signing the ICF and the day the subject is enrolled in 
the study (Day 1).  The screening phase may not exceed 28 days.  Informed consent must be 
obtained before performing any study-specific procedures not considered SOC.   
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging studies) 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. 
Assessments that are required to demonstrate eligibility may be performed over the course of 
1 or more days during this phase.  Blood chemistry and hematology screening laboratory 
assessments used to determine subject eligibility must be collected within 14 days before Day 1.  
Results from the screening visit evaluations will be reviewed by the investigator to confirm 
subject eligibility before enrollment or the administration of study drug.  Tests with results that 
fail eligibility requirements may be repeated during screening if the investigator believes the 
results to be in error.  For screening assessments that are repeated, the most recent available 
result before study drug administration will be used to determine subject eligibility.  
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). 
Additionally, the screening phase will be used to determine the baseline assessments of clinical 
condition and disease status.  Tumor assessments appropriate to the type of malignancy will be 
performed and recorded in the eCRF. 
6.2. 
Treatment 
6.2.1. 
Day 1 
The treatment phase begins on the day the subject receives the first dose of study drug; this is 
defined as Day 1 (or Cycle 1 Day 1) and continues until a decision is made to permanently 
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discontinue the study drug.  At Day 1 (Cycle 1 Day 1), results from screening phase should be 
reviewed to determine if the subject continues to meet the eligibility requirements as specified in 
the Protocol.  See Table 7, Table 8, Table 10, Table 11, Table 13, Table 14, Table 16, Table 17, 
Table 19, and Table 20 for discussion of details regarding the laboratory assessments performed 
at Day 1 (Cycle Day 1).  Day 1 (Cycle 1 Day 1) blood chemistry and hematology assessments 
may be omitted if the screening laboratory samples are collected are within 3 days before Day 1 
(Cycle 1 Day 1).  If Day 1 (Cycle 1 Day 1) laboratory samples are collected, the blood draws 
should be performed before administration of first dose of study drug. 
6.2.2. 
Visit Scheduling  
Dates for subsequent study visits will be determined based on Day 1 (Cycle 1 Day 1) and should 
occur within the allotted visit window unless delayed for safety reasons.  If study drug or SOC 
regimen administration must be interrupted at the beginning of a new planned cycle, the cycle 
will be delayed until the study drug or SOC regimen can be restarted as noted below.  All 
planned assessments are shown in Table 6, Table 9, Table 12, Table 15, and Table 18. 
• Visit schedules for Part 3 and Part 4 C-TGA subjects receiving I-DAC will be based 
on 21-day cycles anchored to the INCB053914 administration.  If I-DAC is given as 
reinduction or consolidation, the regimen start should align with a Day 1 of the 
21-day cycle whenever possible. 
• Visit schedules for Part 3 and Part 4 C-TGB subjects will be based on the start of 
subsequent cycles of azacitidine.  Should a cycle start be delayed, subjects should 
continue to receive INCB053914 if appropriate. 
• Part 3 and Part 4 C-TGC subjects will be seen every 4 weeks through Week 24 and 
every 12 weeks thereafter irrespective of whether INCB053914 and/or ruxolitinib are 
on hold.  The study visits (Week 1, Week 2, etc) were named to align with the 
completion of a week's worth of study drug (ie, Week 1 is planned to occur on 
Study Day 8, or the end of 1 week of study drug). 
• If the optional C-TGA E2 (L-DAC combination) is conducted, visit schedules for 
these subjects will be based on the start of subsequent cycles of L-DAC.  Should a 
cycle start be delayed, subjects should continue to receive INCB053914 if 
appropriate. 
During the treatment phase, regular study visits (physician visits) and laboratory-only visits will 
occur as denoted on the respective Schedules of Assessment and Laboratory Assessment tables.   
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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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.  
Subjects of childbearing potential must agree to take appropriate measures to avoid pregnancy in 
order to participate in the study (see Appendix A). 
7.2. 
Interactive Response Technology Procedure 
The interactive response technology (IRT) will be contacted to obtain a subject ID number when 
a subject enters the screening phase.  Additionally, the IRT will be contacted at each visit at 
which study drug is dispensed to update the study drug supply and upon the decision to 
discontinue treatment.  Refer to the IRT manual for detailed instructions. 
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening.  
This will include date of birth, race, ethnicity, and medical and surgical history for the disease 
under study.  Details regarding the disease for which the subject has enrolled in this study (eg, 
date of diagnosis, primary tumor histology, prior systemic therapies, surgeries, radiation therapy, 
and stage of cancer) will be recorded separately and not listed in medical history. 
7.3.2. 
Transfusion History Status (Ruxolitinib Combination Cohorts Only) 
All transfusions of red blood cell products or platelets from at least 16 weeks before the 
screening visit will be recorded.  The product(s) delivered, date of transfusion, and units 
delivered will be recorded on the CRF. 
7.3.3. 
Screening Symptom Form (Ruxolitinib Combination Cohorts Only) 
In order to satisfy inclusion criteria for Part 3 C-TGC and Part 4 C-TGC E1, active symptoms of 
MF at the screening visit as demonstrated by presence of 1 symptom score ≥ 5 or 2 symptom 
scores ≥ 3 using the Screening Symptom Form (Appendix O) will be recorded on the CRF. 
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 procedures performed within 30 days before the first dose and through 
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the safety follow-up period 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, 
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. 
If a subject experiences a treatment-emergent rash, photographic images of the rash should be 
collected and retained as part of the subject's medical record.  De-identified copies of the images 
should be submitted to the sponsor at its request so the character of the rash can be better 
evaluated. 
7.5.2. 
Physical Examinations 
7.5.2.1. 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
The comprehensive physical examination will include 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 will be a symptom-directed evaluation conducted by the 
investigator or a medically qualified designee.  The targeted physical examination will include 
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, body temperature, height 
(at screening), and body weight.  Blood pressure and pulse will be taken with the subject in the 
recumbent, semirecumbent, or sitting position after 5 minutes of rest. 
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7.5.4. 
Electrocardiograms 
7.5.4.1. 
Twelve-Lead Electrocardiograms 
A central ECG vendor will be used.  The 12-lead ECGs will be interpreted by the investigator at 
the site for immediate subject management.  The trace will also be transmitted to the central 
ECG vendor for analysis by a central reader, and data archiving.  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 consultation with the sponsor's 
medical monitor, as appropriate.  Any treatment-emergent ECG finding occurring on study that 
is abnormal and clinically significant in the judgment of the investigator should be reported as 
an AE. 
7.5.4.2. 
Electrocardiogram Procedures 
All 12-lead ECGs will be performed with the subject in a recumbent position after 5 minutes of 
rest and should not be performed within 15 minutes after a blood collection. 
7.5.4.3. 
Additional Instruction for Timed Electrocardiograms 
Timed ECGs will be conducted before the clinic administration of study drug (predose) and 
using the schedule shown in Electrocardiograms conducted before administration (establishing 
the baseline for the day) should be performed in triplicate (Table 8).  The ECGs should be 
conducted before, but within 15 minutes of, the PK blood collection at the corresponding 
timepoint.  The specified postdose timepoints may be adjusted based on emerging PK data. 
7.5.5. 
Laboratory Assessments 
7.5.5.1. 
Chemistry, Hematology, Urinalysis, Liver Function Panel, Coagulation Panel, 
and Hepatitis Screening 
Chemistry, hematology, liver function panel, coagulation panel, and hepatitis screening will all 
be analyzed by the local site laboratory.  The investigative site will enter the local laboratory 
results and laboratory normal ranges into the eCRF.  All local laboratory assessments (ie, blood 
chemistries, hematology assessments, LFTs, coagulation tests, lipid testing, and urinalysis) 
should be performed using standard procedures on the days indicated in Table 7, Table 10, 
Table 13, Table 16, and Table 19.  Table 5 lists additional timepoints for increased frequency of 
LFT panel and coagulation panel assessments should subjects experience treatment-emergent 
liver enzyme elevations.  Table 21 lists the required laboratory tests in each category; additional 
testing may be required by the sponsor based on emerging safety data.  Additional tests may also 
be performed if clinically indicated. 
Blood chemistry (including LFTs) and hematology screening assessments used to determine 
subject eligibility must be collected within 14 days before Cycle 1 Day 1.  On Day 1, laboratory 
data from the screening evaluations must be reviewed to confirm eligibility.  Cycle 1 Day 1 
blood chemistry, hematology, LFT, and coagulation assessments may be omitted if the screening 
laboratory samples are collected within 3 days before Cycle 1 Day 1.  If Cycle 1 Day 1 
laboratory samples are needed, they must be collected before administration of the first dose of 
study drug.  After Cycle 1, predose laboratory procedures can be conducted up to 72 hours 
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before study drug administration (within the 3-day study window), and results should be 
reviewed by the investigator or qualified designee and found to be acceptable before a new cycle 
of treatment is initiated. 
7.5.5.2. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential before first dose 
of study drug as shown in Table 7, Table 10, Table 13, Table 16, and Table 19.  Subsequently, 
pregnancy tests (either serum or urine) may be conducted as medically indicated or as required 
per local guidelines. 
7.5.5.3. 
Hepatitis Screening Tests 
Testing for hepatitis (detailed in Table 21) is required at screening, and results should be 
reviewed before Day 1 to confirm eligibility.  Due to the risk of seroconversion with ruxolitinib 
treatment, hepatitis B and C viral loads by PCR assay will be required for all ruxolitinib 
combination cohort subjects.  However, for all other subjects, additional testing for HBV-DNA 
and HCV-RNA by PCR assay to further assess hepatitis status will only be required if hepatitis B 
and/or C serology are positive.  Additionally, HBV-DNA does not need to be performed if the 
HBV surface antibody is the only positive result (indicating immunity due to vaccination). 
The eligibility of any subject with positive viremia (eg, PCR assay targets detected) must be 
discussed with the medical monitor before subject enrollment. 
Generally hepatitis serology tests should be submitted early in the screening process because of 
the length of time frequently needed to obtain the results. 
7.6. 
Efficacy Assessments 
The following disease response criteria will be used for each of the malignancies included in this 
study: 
• Acute myeloid leukemia:  International Working Group Response Criteria for Acute 
Myeloid Leukemia (Cheson et al 2003; Appendix D) 
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7.7. 
Performance and Quality-of-Life Assessments 
7.7.1. 
Eastern Cooperative Oncology Group 
Performance status will be assessed on all subjects using the ECOG performance status scale 
(Appendix C), according to the study schedule (Table 6, Table 9, Table 12, Table 15, and 
Table 18).   
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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 respective tables of PK, 
PD, and ECG assessments (see Table 8, Table 11, Table 14, Table 17, and Table 20) to evaluate 
plasma PK parameters as described in Appendix B.  The study drug(s) will be administered in 
clinic 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.  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 date, time, and type 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 7.10.2).  Instructions for plasma preparation and sample 
shipping will be provided in the Laboratory Manual.  The specified postdose timepoints may be 
adjusted based on emerging PK data. 
7.8.2. 
Urine Sample Collection 
Urine will be collected from each subject in a monotherapy cohort at Cycle 1 Day 8 after 
administration of INCB053914 and a predose void.  Total urine will be collected over an 8-hour 
interval following study drug administration.  Urine containers should be kept at reduced 
temperature (refrigerated or ice bath) during collection.  After the interval, the total urine volume 
and the pH should be measured and recorded in the individual eCRF.  Urine will be mixed 
thoroughly, and a 200 mL aliquot will be collected into a prelabeled, polypropylene storage 
bottle and frozen at or below -20°C.  Shipping and handling instructions will be provided in the 
Laboratory Manual; samples will be analyzed by the sponsor or its designee for parameters 
described in Appendix B. 
7.8.3. 
Bioanalytical Methodology and Analysis 
Plasma samples will be analyzed by the sponsor, or designee, using a validated assay.  
Additionally, residual samples may be used for exploratory analyses to identify metabolites.  
Pharmacokinetic parameters that will be analyzed are shown in Appendix B, and the analysis 
methodology is described in Section 9.4.4.5. 
7.8.4. 
Food-Effect Pharmacokinetic Testing 
Pharmacokinetic testing for food effect on drug exposure will be performed in at least 12 and up 
to 18 subjects enrolled in all monotherapy expansion cohorts who are able to participate in the 
food study.  Subjects may be excused from the food-effect portion of the study if they are unable 
to consume the meal. 
Subjects will have been fasted from food (not including water) overnight for at least 8 hours.  A 
standardized high-fat, high-calorie breakfast will be given to these subjects approximately 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions  
For the purposes of this Protocol, an adverse event (AE) is defined as the appearance of or 
worsening of any pre-existing undesirable sign, symptom, or medical condition 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. 
"Disease progression" should not be recorded as an AE itself unless there are no other 
identifiable AEs 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 event(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. 
Adverse events will be assessed according to the CTCAE v4.03.  The CTCAE Grade 5 severity 
(death) will not be used in this study; rather, AEs with an outcome of death will be reported as 
CTCAE Grade 4, with an outcome of "fatal."  Adverse events leading to death will be recorded 
with the outcome of the event 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 of severity: 
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. 
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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 following: 
• 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 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.  Concomitant medication or nondrug therapy used to 
treat an AE should be recorded on the Adverse Event form as well as 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 it, 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, which 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.  For analysis purposes, this will be considered 1 AE 
for this subject and the maximum severity will be used. 
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 
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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, and/or per the investigator's discretion.  A dose 
modification for the laboratory abnormality may be required (see Section 5.2.3.1) 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 (ie, immediate risk of dying). 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective or preplanned treatment for a pre-existing condition that is unrelated 
to the indication 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 given above and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
− Any SAEs that are expected due to the condition being treated, including if the 
SAE is a primary outcome measure, or where there has been a clear agreement 
with regulators not to consider these as SAEs, provided the information is 
collected elsewhere. 
• Results in persistent or significant disability or incapacity. 
• Constitutes a congenital anomaly or birth defect. 
• Is clinically meaningful (ie, defined as an event that jeopardizes the subject or 
requires potential medical or surgical intervention to prevent 1 of the outcomes listed 
above). 
• 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 upon appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
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8.3.2. 
Reporting 
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has signed the ICF and up to the last study visit, or up to 30 days after the subject has 
stopped study treatment, whichever is later, must be reported to the sponsor (or designee) within 
24 hours of learning of its occurrence.  Any SAEs occurring more than 30 days after the last 
dose of study drug should be reported to the sponsor, or its designee, only if the investigator 
suspects a causal relationship to the study drug.  Recurrent episodes, complications, or 
progression of the initial SAE must be reported as a follow-up to the original episode within 
24 hours of the investigator receiving the information.  An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported SAE should be 
reported separately as a new event.  Previously planned (ie, before providing informed consent) 
surgeries should not be reported as SAEs unless the underlying medical condition worsens over 
the course of the study. 
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 are 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. 
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8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
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 following in order to ensure subject safety: 
• The investigator must notify the sponsor or its designee immediately. 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.2.5 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 INCB053914 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 
A formal Data Monitoring Committee will not be used for this study.  The sponsor will 
continuously monitor safety through frequent contact with the treating investigators, review of 
the clinical data, and formal study meetings.  Routine (weekly or biweekly) teleconferences will 
be held during the dose escalation and expansion phases among participating study sites to 
provide subject-by-subject updates on current study status, interim toxicities reported, and any 
other pertinent information.  Adverse event and laboratory data entered into the clinical database 
will be reviewed periodically for trends and evolving safety signals.  Lastly, formal review 
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meetings will be conducted with investigators during the study to establish consensus on the 
safety and tolerability of a given dose, based on the collective experience of the group. 
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 and any associated AEs 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 safety population is defined as all subjects who are enrolled and received at least 1 dose of 
study drug.  All safety analyses will be based on the safety population. 
The full analysis set (FAS) includes all subjects enrolled in the study who received at least 
1 dose of study medication and have at least 1 postbaseline assessment or who discontinued 
treatment.  All efficacy analyses will be based on FAS. 
The PK/PD-evaluable population includes the safety population who has at least 1 valid PK/PD 
measurement. 
9.2. 
Selection of Sample Size 
9.2.1. 
Sample Size in Part 1 
A 3 + 3 dose escalation design will be used in 2 disease-specific treatment groups.  Dose 
escalation for TGA and TGB will proceed independently.  Based on 3 + 3 algorithm, a minimum 
of 3 and up to 6 subjects will be enrolled at each dose level.  The total sample size in Part 1 will 
depend on the frequency of DLTs and the number of dose levels tested before the MTD or PAD 
is reached.  The details of the 2 dose-escalation groups are in Section 4.1.1. 
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9.4.4. 
Safety Analyses 
9.4.4.1. 
Adverse Events 
Adverse events will be tabulated by the MedDRA preferred term and system organ class.  
Severity of AEs will be based on the CTCAE v4.03.  
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, the AE will be considered treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  
9.4.4.2. 
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 CTC grades for AEs (CTCAE v4.03).  The following 
summaries will be produced for the laboratory data: 
• Tables showing number and percentage of subjects with worst postbaseline CTC 
grade (regardless of baseline value) will be produced.  Each subject will be counted 
only for the worst grade observed postbaseline. 
• Shift tables using CTC grades to compare baseline with the worst postbaseline value 
will be produced with CTC grade. 
• For laboratory parameters where CTC grades are not defined, shift tables to the worst 
postbaseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges. 
9.4.4.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, heart rate, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 24), 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 24: 
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 
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9.4.4.4. 
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 25).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed.  Adverse events will be reported for clinically notable 
abnormalities that are considered clinically significant in the judgment of the investigator. 
Table 25: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
9.4.4.5. 
Adverse Events of Special Interest 
Adverse events of special interest include treatment-emergent ALT and AST elevations and 
treatment-emergent AEs related to liver toxicities. 
Number (%) of subjects reporting any treatment-emergent ALT and AST will be summarized by 
grade.  Any AEs related to liver toxicity will be identified using standard MedDRA queries. 
9.4.5. 
Pharmacokinetic Analysis 
The following PK parameters, Cmax, Tmax, Cmin, AUCt, and Cl/F (see Appendix B) will be 
calculated from the blood plasma concentrations of INCB053914 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.  
Additional details of analyses will be described in the data analysis plan. 
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. 
Interim Analysis 
In Part 4, there are up to 3 planned interim analyses for futility in C-TGA E1, C-TGB E1, and an 
optional C-TGA E2.  The Simon 2-stage design will be applied to each expansion cohort 
independently.  During Stage 1, 13 subjects will be enrolled into each expansion cohort.  If 3 or 
fewer of the first 13 evaluable subjects achieve an objective response, the cohort will be 
terminated for futility.  In any cohort that exceeds this number of responders, additional subjects 
will be enrolled for Stage 2 evaluation. 
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Based on this early termination rule, the probability of early termination is 0.7473 under the 
assumption of historical control response rate; the probability of early termination is 0.1686 
under the assumption of desired response rate. 
The interim analysis for each expansion cohort will be conducted once the first postbaseline bone 
marrow biopsies for Stage 1 subjects within the cohort are available.  Enrollment will be held at 
that time unless a sufficient number of responders (> 3 responders) have been observed before 
that time. 
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. 
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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 EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in 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.  Other data outside the EDC system required in the study conduct 
of the Protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors, and as designated by the sponsor, will have their own data flow 
management plans, or study charters, or biomarker plans, as applicable. 
The sponsor (or designee) will be responsible for: 
• Managing the integrity of the data and the quality of the conduct of the study, such as  
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved Protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated, and/or collected including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
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The investigator will be responsible for: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF.  
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (e.g., laboratory data, imaging data, biomarker data, photographs, diary 
data), or as otherwise specified in the Protocol.   
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator's site. 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, 
depending on the study.  Also, current applicable medical records must be 
available. 
• May have responsibility for sending participants' data, either as unique samples, or 
copies, or photographs, to be evaluated centrally or analyzed centrally, or both, by a 
qualified vendor designated by the sponsor.  
• 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 
participant 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 participants. 
− 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. 
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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. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials 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 Code of Federal Regulations (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. 
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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. 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 (ie, from Hour 0 to 12 for BID administration or from 
Hour 0 to 24 for QD administration), 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 INCB053914 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 (Pharsight Corporation, Cary, NC).  Additional details of analyses will be 
described in the Statistical Analysis Plan. 
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APPENDIX C. EASTERN COOPERATIVE ONCOLOGYGROUP (ECOG) 
PEFORMANCE STATUS 
Grade Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, eg, 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 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 M. CYTOCHROME P450 3A INHIBITORS AND INDUCERS 
Source:  University of Washington School of Pharmaceutics: Drug Interaction Database 
Program. 2002. http://www.druginteractioninfo.org. Accessed October 2016. Highlighted rows 
indicate recent additions to the lists at the time the database search was performed. 
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In Vivo CYP3A Inhibitors 
 
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In Vivo CYP3A Inducers 
 
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APPENDIX N. P-GLYCOPROTEIN SUBSTRATES 
Co-administration with INCB053914 not recommended 
• 
cyclosporin 
• 
everolimus 
• 
itraconazole 
• 
ritonavir 
• 
saquinavir 
• 
sirolimus 
• 
tacrolimus 
• 
tenofovir 
Potential for increased oral absorption with these drugs cannot be ruled out and therefore 
caution should be exercised when used in combination with INCB053914 
• 
aliskiren 
• 
ambrisentan 
• 
apixaban 
• 
atorvastatin 
• 
azithromycin 
• 
buprenorphine 
• 
celiprolol 
• 
cerivastatin 
• 
cetirizine 
• 
dabigatran etexilate 
• 
dicloxacillin 
• 
digoxin 
• 
domperidone 
• 
edoxaban 
• 
erythromycin 
• 
ezetimibe 
• 
fexofenadine 
• 
lapatinib 
• 
ledipasvir 
• 
linezolid 
• 
loperamide 
• 
maraviroc 
• 
methylprednisolone 
• 
mirabegron 
• 
morphine 
• 
nadolol 
• 
naloxegol 
• 
nevirapine 
• 
paroxetine 
• 
pilsicainide 
• 
prednisolone 
• 
prednisone 
• 
proguanil 
• 
quinidine 
• 
ranitidine 
• 
ranolazine 
• 
risperidone 
• 
simvastatin 
• 
sotrastaurin 
• 
tedisamil 
• 
teneligliptin 
• 
ticagrelor 
• 
umeclidinium 
• 
verapamil 
• 
voclosporin 
• 
ximelagatran 
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APPENDIX S. MANAGING POTENTIAL HY'S LAW CASES 
INTRODUCTION 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a subject meets potential 
Hy's law (PHL) criteria at any point during the study. 
The investigator participates, in conjunction with Incyte clinical project and pharmacovigilance 
representatives, in the review and assessment of cases fulfilling PHL criteria to ascertain whether 
there is an alternative explanation for the elevations in liver biochemistry other than drug-
induced liver injury caused by the study drug. 
The investigator fulfils requirements for the recording of data pertaining to PHL or Hy's law 
cases and AE/SAE reporting according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
DEFINITIONS 
For the purpose of this process definitions are as follows 
Potential Hy's Law (PHL) 
An increase in AST or ALT > 3 × ULN and total bilirubin > 2 × ULN at any point during the 
study.  The elevations do not have to be at the same time or within a specified time frame. 
Hy's Law 
An increase in AST or ALT > 3 × ULN and total bilirubin > 2 × ULN, where no other reason can 
be found to explain the combination of increases, eg, elevated serum ALP indicating cholestasis, 
viral hepatitis, another drug. 
ACTIONS REQUIRED IN CASES OF AST OR ALT >  3 × ULN OR TOTAL 
BILIRUBIN ≥  2 × ULN 
Identification and Determination of Potential Hy's Law 
To identify cases of AST or ALT > 3 × ULN or total bilirubin > 2 × ULN and consequently 
determine whether the subject meets PHL criteria, please follow the instructions below: 
• Review the laboratory report and if a subject has AST or ALT > 3 × ULN OR total 
bilirubin > 2 × ULN at any visit: 
− Determine without delay whether the subject meets PHL criteria by reviewing 
laboratory reports from all previous visits. 
− Enter the laboratory data into the laboratory CRF as soon as possible. 
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Potential Hy’s Law Criteria Not Met 
If the subject has NOT had AST or ALT > 3 × ULN AND total bilirubin > 2 × ULN at any point 
in the study (the elevations do not have to be at the same time or within a specified time frame), 
irrespective of ALP, please follow the instruction below: 
• Perform follow-up on subsequent laboratory results according to the guidance provided 
in Section 5.2.4 of the Protocol. 
Potential Hy’s Law Criteria Met 
If the subject has had AST or ALT > 3 × ULN AND total bilirubin > 2 × ULN at any point in the 
study (the elevations do not have to be at the same time or within a specified time frame), 
irrespective of ALP, please follow the instruction below: 
• Have subject interrupt study drug. 
• Notify Incyte study team without delay. 
− The investigator, or designee, should contact the medical monitor to discuss and agree 
upon an approach for the study subject's follow-up and the continuous review of data. 
• Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as medically indicated. 
• Investigate the etiology of the event and perform any relevant diagnostic investigations as 
discussed with the medical monitor. 
• Enter the laboratory data into the laboratory CRF as soon as possible. 
• If at any time (in consultation with the medical monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
REVIEW AND ASSESSMENT 
No later than 3 weeks after the biochemistry abnormality was initially detected and the criteria 
for PHL was met, the medical monitor, Incyte pharmacovigilance physician, and investigator 
will discuss and review available data and agree on whether there is an alternative explanation 
for the elevations in liver biochemistry other than drug-induced liver injury caused by the study 
drug.  Subject matter experts will be included in the review as appropriate. 
Evaluation of Alternative Causes 
In order to gather additional clinical information to seek other possible causes of the observed 
liver test abnormalities, the following alternative etiologies should be considered, including, but 
not limited to, 
• Active viral hepatitis 
• Alcoholic and autoimmune hepatitis 
• Hepatobiliary disorders  
− Biliary tract disease, such as migration of gallstones or intrahepatic lesions, more 
often causes cholestatic injury initially and should be investigated with gall bladder 
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and ductal imaging studies, especially if ALP is increased.  Malignant interruption of 
the biliary tract also should be considered. 
• Concomitant treatment 
• Other causes such as systemic infections (bacterial, fungal, viral), nonalcoholic 
steatohepatitis (NASH), and cardiovascular diseases 
Actions After Review and Assessment 
According to outcome of the review and assessment, please follow the instructions below: 
If there is an agreed alternative explanation for the AST or ALT and total bilirubin elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE. 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF if possible. 
• If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF accordingly 
and follow the standard study processes. 
• Have subject resume study drug as per Protocol guidelines. 
If it is agreed that there is no explanation that would explain the AST or ALT and total bilirubin 
elevations: 
• Have subject permanently discontinue study drug and perform EOT procedures. 
• Report an SAE (report term "Hy's Law").  
− The 'medically important' serious criterion should be used if no other serious criteria 
apply. 
− As there is no alternative explanation for the Hy's law case, a causality assessment of 
related should be assigned. 
• If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for a Hy's law case, then it is assumed 
that there is no alternative explanation until such time as an informed decision can be 
made.  Report an SAE (report term "Potential Hy's Law") applying serious criteria and 
causality assessment as per above. 
ACTIONS REQUIRED FOR REPEAT EPISODES OF AST OR ALT > 3 × ULN AND/OR 
TOTAL BILIRUBIN > 2 × ULN 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
If the alternative cause for the previous occurrence of PHL was not chronic or progressing 
malignant disease, please follow the process for PHL review and assessment as described in this 
appendix. 
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If the alternative cause for the previous occurrence of PHL was chronic or progressing malignant 
disease please follow the instructions below: 
• Determine if there has been a significant change* in the subject's condition. 
− If there is no significant change, no action is required. 
− If there is a significant change, follow the process described for PHL review and 
assessment as described in this appendix. 
* A 'significant' change in the subject's condition refers to a clinically relevant change in ALT, AST, or total 
bilirubin, or associated symptoms.  The determination of whether there has been a significant change will be at the 
discretion of the investigator; this may be in consultation with the medical monitor if there is any uncertainty. 
REFERENCE 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: premarketing clinical 
evaluation. http://www.fda.gov/downloads/Drugs/Guidances/UCM174090.pdf. 
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APPENDIX T. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
17 JUL 2015 
Amendment (Version) 2: 
30 OCT 2015 
Amendment (Version) 3: 
13 JUL 2016 
Amendment (Version) 4: 
26 AUG 2016 
Amendment (Version) 5: 
13 DEC 2016 
Amendment (Version) 6: 
15 MAR 2017 
Amendment (Version) 7: 
25 FEB 2019 
Amendment (Version) 8: 
18 DEC 2019 
Amendment 8 (18 DEC 2019) 
Overall Rationale for the Amendment:  The primary objectives of this amendment are to 
extend the required duration of post-treatment contraception in male subjects and to include 
relevant updates from IB Edition 5. 
1. Synopsis; Section 3.1.2, Parts 3 and 4; Section 3.2, Subject Inclusion Criteria; 
Section 3.3, Subject Exclusion Criteria; Section 4.1.3, Part 3 Combination Therapy 
Dose-Finding; Section 4.1.4, Part 4 Combination Expansion Cohorts 
Description of change:  Inclusion criteria 2j, 2m, and 3e, as well as analogous language 
throughout the protocol were modified to clearly state that eligible subjects must be 
currently experiencing a suboptimal response to a current dose of ruxolitinib 
monotherapy.  Inclusion criterion 7c was modified to extend the duration of post-
treatment contraception for male subjects.  Exclusion criterion 3 was modified to clearly 
state that C-TGC subjects should continue their ruxolitinib throughout the screening 
period.  Exclusion criterion 14 was modified to redefine cardiac disease history window. 
Rationale for change:  Inclusion criteria 2j, 2m, 3e, and exclusion criterion 3, along with 
relevant analogous language throughout the protocol were amended to prevent subject 
enrollment errors.  Inclusion criterion 7c was modified as a precautionary response to 
results of the 3-month dog toxicology study.  Exclusion criterion 14 was modified to 
align with current Incyte standards in this subject population.  
2. Section 1.4.1, Potential Risks of INCB053914 Based on Nonclinical Safety 
Description of change:  A summary of relevant results of the 3-month dog toxicity study 
was added. 
Rationale for change:  To include updated nonclinical toxicology data. 
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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11. Section 6; Study Assessments (Table 7: Laboratory Assessments for INCB053914 
Monotherapy Cohorts; Table 8: Pharmacokinetic, Pharmacodynamic, and 
Electrocardiogram Assessments for INCB053914 Monotherapy Cohorts); Section 
7.9.3, Plasma Pharmacodynamics (Monotherapy Cohorts Only) 
Description of change:  Plasma pharmacodynamic sample collection and analysis was 
removed from the Protocol. 
Rationale:  There is no further need to assess the plasma-based pharmacodynamic 
changes in pBAD. 
12. Incorporation of administrative changes:  Other minor, administrative changes have 
been incorporated throughout the Protocol, including the schedules of assessments, and 
are noted in the redline version of the amendment. 
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Amendment 5 (13 DEC 2016) 
Overall Rationale for the Amendment:  The primary objectives of this amendment are to add 
dose-finding and expansion cohorts to evaluate INCB053914 in combination with select 
standard-of-care (SOC) treatment regimens in advanced malignancies and to update aspects of 
the monotherapy design based on emerging data from the current study. 
This amendment includes changes to Protocol INCB 53914-101 Amendment 4 (26 AUG 2016) 
as 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, Conduct of Study Assessments and 
Procedures; Section 9, Statistics; Appendix O, Screening Symptom Form; Appendix 
P, Patient Global Impression of Change 
Description of change:  The study design was revised to include SOC combination dose-
finding and expansion cohorts.  All relevant Protocol sections, including tables and 
figures, were revised accordingly. 
Rationale:  To provide the background, rationale, study design, study 
objectives/endpoints, inclusion/exclusion criteria, treatment details, study assessments, 
and statistical considerations in order to research INCB053914 in combination with SOC 
regimens in advanced malignancies. 
2. Synopsis; Section 3.3, Subject Exclusion Criteria (Criterion 3e); Section 5.2.8.1, 
Restricted Medications 
Description of change:  Added language to restrict concomitant intake of hydroxyurea 
within 48 hours before and on the day of a pharmacodynamic (PD) sample collection. 
Rationale:  To avoid the effects of hydroxyurea on the levels of circulating, highly 
proliferative cells and  INCB053914 PD data. 
3. Section 1.2.1, Pharmacology of INCB053914; Section 1.2.3, Projected 
Pharmacokinetics of INCB053914 in Humans 
Description of change:  Replaced language pertaining to the human dose projected to 
provide plasma concentrations to achieve IC50 pBAD inhibition in a whole blood assay 
with a reference to the Investigator's Brochure (IB). 
Rationale:  To align Protocol text with the IB version 2 and update now that clinical data 
are available. 
4. Section 1.2.4; Pharmacokinetics of INCB053914 in Study INCB 53914-101 
Description of change:  This section was updated with pharmacokinetic summary data 
inclusive of the 80 mg BID Part 1 TGA cohort. 
Rationale:  To provide updated pharmacokinetic data to support the Part 3 dose-finding 
cohort INCB053914 starting dose. 
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5. Section 1.4.2; Potential Risks of INCB053914 Based on Preliminary Clinical 
Experience 
Description of change:  This section was updated to include a preliminary, unaudited 
summary of safety data from the INCB 53914-101 study inclusive of the 80 mg BID Part 
1 TGA Cohort initial evaluation period. 
Rationale:  To provide updated summary of the adverse event data observed in this 
study. 
6. Section 5.2.4; Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drug (Table 5: Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  The management strategy for Grade 2 alanine 
aminotransaminase (ALT) and aspartate aminotransaminase (AST) elevations was 
updated. 
Rationale:  To allow for more frequent liver enzyme monitoring and ensure investigators 
manage subjects' concomitant medications in the event of ALT/AST elevations. 
7. Section 6; Study Assessments (Table 7: Laboratory Assessments for INCB053914 
Monotherapy Cohorts; Table 8: Pharmacokinetic, Pharmacodynamic, and 
Electrocardiogram Assessments for INCB053914 Monotherapy Cohorts); Section 
7.9.4, Whole Blood Pharmacodynamics (Monotherapy Cohorts Only) 
Description of change:  The collection of whole blood samples for PD analysis, which 
were removed in Protocol Amendment 3 (13 JUL 2016), were added back into the study. 
Rationale:  Assessments were added back into the study based on emerging data and to 
perform further phosphoprotein analysis. 
8. 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 (26 AUG 2016) 
Overall Rationale for the Amendment:  The primary objective of this amendment is to update 
inclusion criterion #3.  With this amendment, inclusion criterion #3 is reverted back to the same 
exact wording as was in Amendment 2 (30 OCT 2015).  
1. Synopsis; Section 3.2, Subject Inclusion Criteria 
Description of change:  Inclusion criterion 3 was updated to indicate that subjects must 
be unresponsive to currently available therapy, and there is no further standard-of-care 
therapy available in the judgment of the investigator. 
Rationale:  Revised per FDA request. 
2. 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 3 (13 JUL 2016) 
Overall Rationale for the Amendment:  The primary objectives of this amendment are to 
update the study design, eligibility criteria, dose-limiting toxicity (DLT) criteria and dose 
interruption/reduction criteria as appropriate to the underlying pathology in the disease-specific 
treatment groups. 
1. Synopsis; Section 3, Subject Eligibility; Section 4.1, Overall Study Design; Section 
5.2.3, Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
(Table 1: Definition of Dose-Limiting Toxicity); Section 5.2.4, Criteria and 
Procedures for Dose Interruptions and Adjustments of Study Drug (Table 2: 
Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  Treatment Group C (TGC; myelodysplastic/ myeloproliferative 
neoplasms [MDS/MPNs], myelofibrosis [MF][) has been removed from the Protocol.  
Subjects with MDS/MPN will be regrouped into Treatment Group A (TGA), and TGA 
eligibility and DLT criteria will apply to these subjects.  Subjects with MF have been 
removed from Part 1 (dose escalation) of the study.  Additionally, the original Part 2 
expansion Cohort D (MDS/MPN or MF subjects) has been replaced with 2 distinct 
expansion cohorts (Cohorts B and C), and the MM and lymphoma cohorts were renamed 
accordingly as Cohorts D and E.  All relevant Protocol sections have been updated 
accordingly. 
Rationale:  Subjects with MDS/MPN and MF considered for this study are in the 
relapsed/refractory stage of disease and will usually present to the clinic with varying 
degrees of pancytopenias (Mughal 2015).  This is consistent with screening experience to 
date in INCB 53914-101.  These pre-existing pancytopenias make it difficult 1) for these 
subjects to meet TGC hematologic eligibility criteria detailed in Protocol Amendment 2, 
2) to appropriately assess these subjects for hematologic DLTs according to the TGC 
DLT criteria, and 3) to appropriately manage on-study hematologic toxicities per the 
mitigating actions for TGC as listed in Table 2 of Protocol Amendment 2.  As per routine 
practice and product labels of compounds (eg, azacitadine, decitabine) approved in 
indications characterized by pancytopenia, decreasing hematologic cell counts do not 
warrant interruption of standard treatments.  Per the azacitidine package insert 
(Vidaza 2016), dose adjustments for subjects whose baseline counts are 
WBC < 3.0 × 109/L, ANC < 1.5 × 109/L, or platelets < 75.0 × 109/L should be based on 
nadir counts and bone marrow cellularity at the time of the nadir.  Including MDS/MPN 
subjects in TGA, along with AML and MDS subjects, is reasonable since clinically 
meaningful differences in treatment-emergent toxicities and their management are not 
expected. 
Given the low disease incidence, subjects with MF were removed from Part 1 (dose 
escalation) in order to accelerate identification of the recommended Phase 2 dose (RP2D) 
and minimize the number of subjects who would be exposed to potentially nonefficacious 
doses during this part of the study. 
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2. Synopsis; Section 3.1, Study Population; Section 4.1, Overall Study Design 
Description of change:  Specified that only subjects with acute leukemia and high-risk 
MDS would be eligible to enroll in this study. 
Rationale:  Text was added to clarify the appropriate subject population for this study. 
3. Synopsis; Section 4.1.1, Part 1 Dose Escalation 
Description of change:  Text added to clarify that different RP2Ds could be identified 
among disease types during dose escalation. 
Rationale:  To make it clear that multiple RP2Ds could be selected for the expansion 
cohorts based on the data from Part 1 of the study. 
4. Synopsis; Section 4.1, Overall Study Design (Figure 1); Section 4.1.2, Part 2 Dose 
Expansion 
Description of change:  Revised the expansion cohort enrollment to at least 5 and up to 
approximately 15 subjects. 
Rationale:  This update provides flexibility with regard to the expansion cohort 
enrollment to allow for a more thorough evaluation of safety, tolerability, efficacy, PK, 
and PD of the selected dose in the defined cohorts. 
5. Synopsis; Section 3.2, Subject Inclusion Criteria 
Description of changes: 
a. Inclusion criterion 3 was updated to indicate that there must be no further standard-
of-care therapy available or that subjects must be intolerant to or refuse any further 
established therapy.  Specific prior therapy requirements for subjects with MM, 
AML, and MF were added. 
b. Inclusion criterion 5 was updated to indicate that the baseline bone marrow biopsy 
and/or aspirate requirement may be waived with approval by the medical monitor if a 
biopsy is not possible or is contraindicated, or the tissue requirement cannot be 
satisfied. 
Rationales: 
a. Text added to further define the subject population appropriate for the study and to 
provide guidance to participating sites with regard to prior therapy requirements for 
select disease types. 
b. Text added so that subjects who were willing to have a baseline bone marrow aspirate 
performed but for whom the procedure is not feasible or is unsuccessful could still 
enroll in the study with medical monitor approval. 
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6. Synopsis; Section 3.3, Subject Exclusion Criteria 
Description of changes: 
a. Exclusion criterion 2 was updated to clarify how subjects' bilirubin and creatinine 
clearance levels should be gauged for study eligibility. 
b. Exclusion criterion 3 was updated to specify the washout period for prior biologic or 
immunotherapies, and bullet "e" was added to provide some additional clarification 
with regard to allowed anticancer therapies. 
c. Exclusion criterion 4 was updated to specify some immunosuppressive therapies that 
fall under this criterion. 
d. Exclusion criterion 8 was modified to allow subjects with well-controlled diabetes 
into Part 1 of the study. 
e. Exclusion criterion 11 was updated to reference the Protocol section regarding 
hepatitis screening. 
f. Exclusion criterion 14 was amended to delineate more appropriate eligibility criteria 
relative to cardiac history. 
Rationales: 
a. The bilirubin criterion was reworded to better follow how sites are directed to report 
bilirubin results (eg, direct bilirubin is only tested if total bilirubin is > 1.5 × ULN).  
The creatinine clearance threshold for non-MM subjects in Part 1 was reduced 
slightly to more closely approximate values observed in the clinic in the subject 
population.  Likewise, the option to measure the creatinine clearance via 24-hour 
urine collection was provided to investigators to allow them to exercise their clinical 
judgment when evaluating subjects during screening. 
b. While most antibodies and biological therapies have long half-lives, the washout 
period for these therapies was reduced to 28 days to minimize gaps in anticancer 
therapy for subjects with advanced, rapidly progressing disease while allowing a safe 
washout period.  Additionally, a washout period of 5 half-lives is not necessary since 
there should be a low risk of overlapping toxicities of INCB053914 and biologics and 
immunotherapies used in this setting. 
c. Exclusion criterion 4 was amended to provide investigators with examples of 
prohibited immunosuppressive therapies. 
d. Exclusion criterion 8 was revised to allow subjects with well-controlled diabetes to 
enroll in Part 1 of the study as there is no evidence of significant increase in risk of 
uncontrollable hyperglycemia and considering the high prevalence of comorbid 
diabetes in the defined subject population. 
e. Because the risk of viral reactivation after exposure to INCB053914 is minimal based 
on the mechanism of action (MOA), the exclusion criteria was modified so that 
subjects who have negative hepatitis B and C serology do not need to have the HBV 
DNA and HCV RNA test, respectively, for which it often takes a long time to receive 
results, and therefore may enroll in the study and begin study treatment sooner, eg, 
for those aggressive diseases such as AML. 
f. To modify the exclusion criteria to reflect the relative cardiac risk of the subject 
population. 
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7. Synopsis; Section 4.3.1, Planned Number of Subjects 
Description of change:  The planned number of subjects for Part 2 was revised to up to 
75 subjects. 
Rationale:  The planned number of subjects was modified to align with the updated 
expansion cohort enrollment estimates. 
8. Section 1.2.4, Pharmacokinetics of INCB053914 in Humans; Section 1.3.2, Potential 
Risks of INCB053914 Based on Preliminary Clinical Experience 
Description of change:  Preliminary INCB 53914-101 pharmacokinetic data and a 
summary of unaudited safety data were added to the Protocol. 
Rationale:  New sections were added to update Protocol with data from the current study 
analyzed to date. 
9. Section 4.1.1, Part 1 Dose Escalation 
Description of change:  The definition of the pharmacologically active dose (PAD) is 
now based on PK projected pBAD inhibition levels. 
Rationale:  The definition of the PAD was updated for clarification. 
10. Section 4.1.2, Part 2 Dose Expansion; Section 7.8.4 Food-Effect Pharmacokinetic 
Testing 
Description of change:  The number of potential subjects for the food-effect study was 
revised to include at least 12 and up to 18 subjects enrolled from all expansion cohorts. 
Rationale:  The number of subjects and enrollment strategy for the food-effect study 
were corrected. 
11. Section 5.1.3.3, Storage; Section 5.1.3.4, Instructions to Subjects for Handling Study 
Drug 
Description of change:  The study drug storage conditions and instructions for subject 
storage of the study drug were updated. 
Rationale:  To reflect that the conditions stipulated on the investigational product label 
should be followed, inclusive of the forthcoming ambient formulation. 
12. Section 5.2.4, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drug (Table 2: Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  The management of liver function test (LFT) elevations was 
modified to provide specific guidelines for each CTCAE grade of ALT or AST elevation, 
as well as to no longer mandate study drug interruptions for transient LFT elevations.  
The criteria for dose interruption for Grade 3 thrombocytopenia in TGB subjects was 
modified to specify that drug should be held if the AE is persistent or associated with a 
bleeding event. 
Rationale:  The criteria to trigger actions taken with study drug interruptions, restarts, 
and dose reductions for LFT elevations and thrombocytopenia (in TGB) were modified to 
provide investigators with toxicity management plans with greater clarity and granularity, 
and that mirror clinical practice more closely.  Specifically for LFT elevations, transient, 
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isolated (not accompanied with bilirubin increase) low-grade increases (≤ Grade 2) can 
have various causes apart from exposure to study drug and often resolve without 
interruption of targeted agents.  In the amended Protocol, subjects with LFT elevations ≥ 
Grade 2 will be monitored more closely (at least weekly) until resolved to baseline or ≤ 
Grade 1.  The amended language allows for subjects who have a Grade 2 elevation to 
continue to receive study drug while LFTs are monitored at least weekly, and only 
interrupt if they do not resolve (≤ Grade 1 or baseline) within 14 days.  If subjects are 
eligible to resume study medication after the first occurrence of a Grade 2 or Grade 3 
LFT elevation requiring interruption resolves, they will be rechallenged at the same study 
drug dose in order to monitor whether LFT elevations will recur and also avoid 
unnecessary dose reductions. 
13. Section 5.2.8.1, Restricted Medications 
Description of change:  The use of corticosteroids during the study was expanded to 
allow for short-course dose regimens > 10 mg/day prednisone (or equivalent). 
Rationale:  Clinical management of this subject population sometimes requires short 
courses of systemic corticosteroids in > 10 mg/day prednisone (or equivalent).  As such, 
the medication restriction was clarified so these instances do not meet the definition of a 
Protocol deviation. 
14. Section 6, Study Assessments (Table 4: Laboratory Assessments, Table 6: Cycle 1 
and Cycle 2 Pharmacokinetic, Pharmacodynamic, and Electrocardiogram 
Assessments); Section 7.9.4, Whole Blood Pharmacodynamics 
Description of change:  Section 7.9.4 was removed from the Protocol as were references 
to the PD-whole blood samples in Table 4 and Table 6.  The collection of untimed PK 
samples at each cycle Day 1 was removed from Table 4.  Cycle 2 Day 1 and Day 2 PD 
plasma samples were removed from the food-effect cohort in Table 6. 
Rationale:  PD-whole blood samples, PK samples beyond Cycle 2, and PD plasma 
samples in the food-effect study subjects are not necessary. 
15. Section 6, Study Assessments (Table 4: Laboratory Assessments); Section 6.1, 
Screening; Section 6.1.1, Day 1; Section 7.5.5.1, Chemistry, Hematology, Urinalysis, 
Coagulation Panel, and Hepatitis Screening 
Description of change:  Section 6.1 was updated to allow for screening assessments that 
fail eligibility requirements to be repeated if the investigator believes the results were in 
error and allow for subjects who fail screening to repeat the screening process once if the 
investigator believes there has been a change in eligibility status.  Section 6.1, Section 
7.5.5.1, and Table 4 were updated to stipulate that blood chemistry and hematology 
screening assessment used to determine subject eligibility must be collected within 
14 days prior to Cycle 1 Day1.  Sections 6.1.1 and 7.5.5.1 was updated to clarify that 
results from the screening phase of the study should be reviewed on Cycle 1 Day 1 to 
confirm eligibility.  Section 6.1.1, Section 7.5.5.1, and Table 4 were also updated to allow 
for Cycle 1 Day 1 blood chemistry and hematology screening assessments to be omitted 
if the blood chemistry and hematology screening evaluations are collected within 3 days 
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before Cycle 1 Day 1, and to remind sites that if Cycle 1 Day 1 laboratory samples were 
needed, they should be collected before the first dose of study drug. 
Rationale:  The updates to Section 6.1 provide the investigator with the opportunities to 
repeat screening assessments or the screening process if they feel the results to be in error 
or that the eligibility of their subject may have changed.  The updates to Sections 6.1.1, 
Section 7.5.5.1, and Table 4 clarify that subject eligibility is based on laboratory values 
obtained during screening and to reduce the phlebotomy burden on subjects who have 
screening assessments completed proximal to their enrollment date.  The stipulation on 
the timing of the screening blood chemistry and hematology assessments being collected 
within 14 days before Cycle 1 Day 1 was added to Section 6.1 and Section 7.5.5.1 to 
ensure that the assessment of subjects' adequate bone marrow and organ functions are 
made closer to study enrollment. 
16. Section 6, Study Assessments (Table 5: Clinical Laboratory Analytes) 
Description of change:  Hemoglobin A1c (HbA1c) was added as an analyte and blasts 
were added as a mandatory part of the CBC differential for subjects with diseases where 
peripheral blast measurements are a part of the disease assessments.  "Serology" was 
modified to "Hepatitis Screening."  Hepatitis B surface antibody was added as a required 
analyte for the hepatitis B screening.  The HBV-DNA and HCV-RNA tests were clarified 
to only be performed if the serology returned positive results. 
Rationale:  HbA1c was added to allow investigators to document adequate glucose 
control of diabetic subjects as per the revised exclusion criterion #8.  Blasts were added 
as an analyte to reiterate mandatory reporting in relevant disease types.  "Serology" was 
amended to "Hepatitis Screening" to clarify that not all tests listed fall under serology and 
help distinguish between the mandatory serological evaluations and the optional PCR 
assays.  The hepatitis B surface antibody analyte was added to the serology panel to help 
further gauge a subject's hepatitis status.  As the risk of viral reactivation after exposure 
to INCB053914 is minimal due to the MOA and PCR assays usually take several days to 
report out in clinical laboratories, the HBV-DNA and HCV-RNA PCR assays were 
relegated from mandatory tests to only be performed if serology is positive.  This will 
allow subjects with negative serology to proceed with enrollment and begin study therapy 
sooner. 
17.  Section 7.5.5.3, Hepatitis Screening Tests 
Description of change:  The language concerning the hepatitis screening was amended 
to support the changes made to exclusion criterion #11 and Table 5, as well as clarify 
when the HBV-DNA and HCV RNA tests should be performed and provide guidance to 
investigators on managing positive viremia results. 
Rationale:  As the risk of viral reactivation after exposure to INCB053914 is minimal 
due to the MOA and PCR assays usually take several days to report out in clinical 
laboratories, the HBV-DNA and HCV-RNA PCR assays were relegated from mandatory 
tests to reflex tests (performed only if serology is positive) to allow subjects with 
negative serology to proceed with enrollment and begin study therapy sooner.  
Additionally, language was added to clarify hepatitis statuses that would meet eligibility 
criteria. 
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Amendment 2 (30 OCT 2015) 
Overall Rationale for the Amendment:  The primary objectives of this amendment are to 
update the hematologic eligibility, dose-limiting toxicity (DLT), and dose interruption/reduction 
criteria appropriate to the underlying pathology in the disease-specific treatment groups. 
1. Synopsis; Section 3.2, Subject Inclusion Criteria; Section 7.9.1, Tumor Tissue 
Collection 
Description of change:  Inclusion criterion #5, pertaining to bone marrow collection 
requirement, and Section 7.9.1 were updated to indicate that bone marrow biopsy or 
aspirate may be performed as appropriate to disease. 
Rationale:  To clarify that type of bone marrow sample collected (ie, biopsy or aspirate) 
and submitted to the sponsor should be relevant to the type of disease. 
2. Synopsis; Section 3.3, Subject Exclusion Criteria 
Description of change:   
a. Exclusion criterion #1, relating to bone marrow function (including platelet count, 
hemoglobin, and absolute neutrophil count), was eliminated for Part 1/Treatment 
Group A (TGA). 
b. The exclusion criterion for hemoglobin was changed from "< 10.0 g/dL" to 
"< 8.0 g/dL" for Part 1/Treatment Groups B and C.  
Rationale: 
a. To modify the exclusion criteria to match the clinical manifestation of the diseases 
under study.  Treatment Group A comprises subjects with diseases of acute myeloid 
leukemia (AML) or myelodysplastic syndrome (MDS), which are typically 
manifested by severe cytopenias; requiring specific parameters would be a significant 
barrier to recruitment and could significantly confound the assessment of toxicities 
associated with the investigational agent in AML and MDS.  
b. To modify the exclusion criteria to match clinical manifestation and management of 
the diseases under study.  Treatment Groups B and C comprise a population that 
includes multiple myeloma, myelodysplastic syndrome/myeloproliferative neoplasm 
overlap syndromes, and myelofibrosis.  Optimal management of patients with these 
diseases in the relapsed and refractory setting typically includes maintaining a 
hemoglobin level of ≥ 8.0 g/dL; thus the criterion is being updated accordingly. 
3. Section 3.3, Subject Exclusion Criteria 
Description of change:  Exclusion criterion #12, which pertains to current infection and 
use of systemic antibiotic, antifungal, or antiviral treatment, was clarified to specify 
"active and uncontrolled" infectious diseases requiring systemic antibiotic, antifungal, or 
antiviral treatment.  
Rationale:  To provide clarification for the exclusion criterion.  The intent of the 
criterion is to ensure that only subjects with active and uncontrolled infections are 
excluded; subjects with current infections that are adequately controlled by antimicrobrial 
agents or those on antimicrobrial agents for infection prophylaxis are not excluded. 
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4. Section 5.2.3, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose (Table 1: Dose-Limiting Toxicity Criteria) 
Description of change:  The dose-limiting toxicity criterion of febrile neutropenia was 
updated to include only subjects in Treatment Groups B and C.  
Rationale:  Treatment Group A comprises subjects with relapsed and/or refractory AML 
and MDS, for whom fever (≥ 38.5°C) in the setting of severe neutropenia (ANC < 1.0 × 
109/L) is a common and expected occurrence due to underlying disease pathology.  
Subjects are routinely monitored for fever, neutropenia, and infection for the duration of 
the study.  Requiring a DLT criterion for febrile neutropenia for Treatment Group A does 
not enhance subject safety and will make AE causality assessment difficult when fever 
and neutropenia are common symptoms of the underlying diseases. 
5. Section 5.2.4, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drug (Table 2: Guidelines for Interruption and Restarting of Study Drug) 
Description of change:  Guidelines for interruption and restarting of study drug for 
neutropenia and thrombocytopenia were updated for Part 1/TGA and Part 2 Cohorts A 
and D. 
Rationale:  Because there are no hematologic eligibility criteria required for Part 1/TGA 
and Part 2 Cohorts A and D, specific degrees of cytopenia are no longer relevant.  
Guidelines for dose interruption and restart were updated to allow for management of 
cytopenias as per institutional standard and to require treatment hold and discussion with 
the sponsor in the setting of suspected causality. 
6. Section 8.1.2, Adverse Event Reporting 
Description of change:  Adverse event reporting guidelines for events associated with 
disease progression were updated. 
Rationale:  To further specify how to report adverse events and serious adverse events 
that are associated with disease progression. 
7. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the red-line/strike-out version 
of the amendment. 
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Amendment 1 (17 JUL 2015) 
Overall Rationale for the Amendment:  The primary objectives of this amendment are to 
change the dose-escalation design in each treatment group from an accelerated titration to a 
conventional 3 + 3 approach, to refine the eligibility criteria to only include subjects with 
advanced hematological malignancies unresponsive to currently available therapy and for whom 
there is no standard of care available, and to update the dose-limiting toxicity criteria as 
appropriate to the diseases included in each dose-escalation treatment group.   
1. Synopsis; Section 4, Investigational Plan; Section 9.2, Selection of Sample Size 
Description of change:  The dose-escalation design in each treatment group was updated 
from an accelerated titration followed by a modified Toxicity Probability Interval design 
to a standard 3 + 3 design. Additionally, the estimated sample size was updated 
accordingly. 
Rationale:  Change requested by FDA.  
2. Synopsis; Section 3, Subject Eligibility 
Description of change:  The eligibility criteria and description of the study population 
were updated to only include subjects with advanced hematological malignancies 
unresponsive to currently available therapy and for whom there is no standard-of-care 
therapy available. 
Rationale:  Change requested by FDA.  
3. Section 5.2.3, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose 
Description of change:  Dose-limiting toxicity criteria in Part 1 were modified, 
consistent with FDA requests, for Treatment Group A, Treatment Group B, and 
Treatment Group C (added in current amendment) and were applied as appropriate to the 
diseases included in each group. 
Rationale:  Change requested by FDA. 
4. Synopsis; Section 3, Subject Eligibility; Section 4, Investigational Plan; Section 5.2, 
Treatment of Subjects; Section 7.8.4, Food-Effect Pharmacokinetic Testing 
Description of change:  Treatment Group A and Expansion Cohort A were updated to 
include only subjects with leukemia and MDS; MDS/MPN (including atypical chronic 
myeloid leukemia [aCML], chronic myelomonocytic leukemia [CMML], 
myelodysplastic/ myeloproliferative neoplasm unclassifiable [MDS/MPN-U], and 
refractory anemia with ring sideroblasts and thrombocytosis [RARS-T]) and MF were 
removed from these groups. Treatment Group C and Expansion Cohort D, which include 
only subjects with MDS/MPN and MF, were added to Part 1 and Part 2, respectively.  
Accordingly, appropriate detail was added to all of the relevant Protocol sections, 
including study design and investigational plan, subject eligibility and number of 
subjects, dose-limiting toxicity and dose interruption/ adjustment criteria, and 
pharmacokinetic assessments, consistent with the newly defined treatment group. 
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Rationale for change:  Per FDA request, Treatment Group B dose-limiting toxicity 
criteria were applied to subjects with MDS/MPN and MF.  To optimally assess the safety 
and tolerability of INCB053914 in subjects with these diseases, separate dose-escalation 
and expansion groups that include only MDS/MPN and MF were added to the study 
Protocol. 
5. Synopsis; Section 2.2.2, Secondary Endpoints 
Description of change:  Secondary endpoint pertaining to pharmacokinetic assessment 
time point at Day 15 was changed to Day 8. 
Rationale for change:  Endpoint was updated to reflect correct visit day at which 
steady-state and serial PK sampling is performed. 
6. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the red-line/strike-out version 
of the amendment. 
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