A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study of INCB057643 in Subjects With Advanced Malignancies
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: Incyte Corporation

Official Title:    A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability Study 
of INCB057643 in Subjects With Advanced Malignancies
NCT Number:  
NCT02711137
Document Date:
Clinical Study Protocol: 22 OCT 2018

Incyte Corporation 
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Protocol INCB 57643-101 Am 7 
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22 OCT 2018 
Clinical Study Protocol 
INCB 57643-101 / NCT02711137
A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and 
Tolerability Study of INCB057643 in Subjects With 
Advanced Malignancies 
Product: 
INCB057643 
IND Number: 
128,688 
EudraCT Number 
2017-002641-29 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
17 DEC 2015 
Amendment (Version) 1: 
18 JAN 2016 
Amendment (Version) 2: 
08 JUL 2016 
Amendment (Version) 3: 
14 MAR 2017 
Amendment (Version) 4: 
07 JUN 2017 
Amendment (Version) 5: 
11 OCT 2017 
Amendment (Version) 6: 
06 MAY 2018 
Amendment (Version) 7: 
22 OCT 2018 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 
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INVESTIGATOR'S AGREEMENT 
I have read INCB 57643-101 Protocol Amendment 7 (Version 7 dated 22 OCT 2018) 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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Protocol INCB 57643-101 Am 7 
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SYNOPSIS 
Name of Investigational Product: INCB057643 
Title of Study:  A Phase 1/2, Open-Label, Dose-Escalation/Dose-Expansion, Safety and Tolerability 
Study of INCB057643 in Subjects With Advanced Malignancies 
Protocol Number:  INCB 57643-101 
Study Phase:  1/2 
Indication:  Advanced Malignancies 
Primary Objective: 
• To assess the safety and tolerability of INCB057643 as monotherapy and in combination with standard 
of care (SOC) agents in subjects with advanced malignancies. 
Secondary Objectives: 
• To evaluate the pharmacokinetics (PK) of INCB057643 when administered as monotherapy in the 
fasted state and in the fed state (food effect; Part 2 only) and when administered in combination with 
SOC agents in the fasted state. 
• To assess the pharmacodynamics (PD) of INCB057643 when administered as monotherapy in subjects 
with advanced malignancies. 
• To evaluate preliminary efficacy of INCB057643 when administered as monotherapy and in 
combination with SOC agents based on the investigator assessment of response using criteria 
appropriate for each disease in subjects with advanced malignancies. 
Primary Endpoint: 
• Safety and tolerability of INCB057643 as monotherapy and in combination with SOC agents as 
assessed by clinical laboratory assessments, physical examinations, 12-lead electrocardiograms (ECGs), 
and adverse events (AEs). 
Secondary Endpoints: 
• Cmax, Tmax, Cmin, AUC0-t, and AUC0-τ of INCB057643 at Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 
Day 1 (food effect; Part 2 only). 
• Pharmacodynamic profile of INCB057643 using a plasma PD assay. 
• Objective response rate (ORR) in subjects with measurable or evaluable diseases as determined by the 
investigator assessment of response using the criteria appropriate for each disease. 
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Overall Study Design: 
This is an open-label, dose-escalation/dose-expansion study of the bromodomain and extra-terminal 
(BET) inhibitor INCB057643 as monotherapy or in combination with SOC agents in subjects with 
advanced malignancies.  Subjects will receive INCB057643 continuously administered orally in 21- or 
28-day cycles, as applicable to regimen schedules in combination.  Alternative administration schedules 
may be assessed if indicated by emerging safety, PK, or PD data.  The study consists of 4 parts.  Parts 1 
and 2 will evaluate INCB057643 as monotherapy, and Parts 3 and 4 will evaluate INCB057643 in 
combination with SOC agents. 
Part 1, Monotherapy Dose Escalation, will determine the maximum tolerated dose (MTD) of 
INCB057643 and/or a tolerated dose that reaches the desired target inhibition (ie, a pharmacologically 
active dose [PAD]; plasma concentration exceeding ex vivo or projected c-Myc IC50 for approximately 
6-12 hours or achieves clinical response).  Part 1 will be conducted in 3 disease-specific treatment groups. 
Part 2, Monotherapy Dose Expansion, will further evaluate the safety, preliminary efficacy, PK, and PD 
of the treatment group−specific dose selected in Part 1 (at ≤ the MTD) in select tumor types postulated to 
be particularly susceptible to inhibition of BET proteins. 
Part 3, Combination Dose-Escalation (C-ES), will determine the MTD and/or a tolerated dose (the 
recommended phase 2 dose [RP2D]) of the combination of INCB057643 with one of the SOC agents.  
Part 3 will be conducted in 6 disease-specific treatment groups.  
Part 4, Combination Dose-Expansion (C-EX), after identification of the RP2D in combination regimens 
in Part 3, will further determine safety, tolerability, efficacy, PK, and PD.  Part 4 will be conducted in 
4 treatment groups.  The sponsor may decide not to expand any or some cohorts. 
As of MAR 2018, no further subjects are being enrolled in all the cohorts due to a less favorable 
benefit/risk assessment based on emerging data, mainly the histopathological finding of cardiac myopathy 
observed in the preclinical 3-month toxicology study in monkeys. 
Part 1 − Monotherapy Dose Escalation 
The study began with dose escalation in Part 1, which comprises 3 disease-specific treatment groups.  
Each treatment group will use a 3 + 3 design to determine the tolerated dose over a 21-day cycle. 
Part 1 will be conducted in 3 disease-specific treatment groups, as follows: 
• Treatment Group A (TGA) will include subjects with any advanced solid tumor or lymphoma. 
• Treatment Group B (TGB) will include subjects with any acute leukemia or high-risk myelodysplastic 
syndrome (HR-MDS), myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN), or MF. 
• Treatment Group C (TGC) will include subjects with multiple myeloma (MM). 
Enrollment into the study began in TGA.  The initial dose level was 8 mg once daily (QD).  Once a PAD 
has been identified in TGA, TGB and TGC will begin parallel enrollment at that PAD.  Subsequently, 
dose escalation will proceed independently in the 3 treatment groups to an MTD (or a tolerated PAD if an 
MTD is not reached), each using a 3 + 3 design.  If there is a distinct discrepancy in tolerability among 
different disease types within the same treatment group, additional disease-specific dose-escalation 
schedules may be initiated.  
Each dose-escalation cohort will initially enroll at least 3 subjects.  If no dose-limiting toxicities (DLTs) 
are observed in the initial 3 subjects, another cohort will begin enrollment at the next highest dose level.  
Dose escalations between cohorts may be up to 100% until a DLT is observed, after which dose 
escalations in the relevant treatment group will be limited to no more than 50% above the previous level. 
If 1 DLT is observed in the first 3 subjects, at least 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 tolerated dose.  Thus, the 
MTD will be defined as 1 dose level below the nontolerated dose (NTD) 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 
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be considered. 
The sponsor, in consultation with participating investigators, may elect to investigate 1 or more dose 
levels less than the NTD or expand a dose cohort(s) deemed tolerable to up to 12 subjects in order to 
obtain additional PK, PD, and safety data before determining the MTD. 
Individual subjects within each cohort will undergo reductions/interruptions in INCB057643 
administration according to prescribed safety parameters.  Subjects tolerating INCB057643 at the 
assigned dose for at least 4 cycles may be considered for a dose increase if a higher dose has been found 
to be tolerated in a subsequent cohort.  Dose escalations will be accomplished using the following 
options:  1) increasing the number of tablets taken at each QD administration, or 2) increasing 
administration frequency to twice daily (BID), or 3) increasing the number of tablets taken at 1 or more 
dose administrations and increasing the frequency to BID.  Subjects will continue to receive INCB057643 
in 21-day cycles until withdrawal criteria are met (eg, toxicity, disease progression). 
Part 2 − Monotherapy Dose Expansion 
Part 2 of the study will evaluate the treatment group−specific dose selected in Part 1 in specific tumor 
types postulated to be particularly susceptible to inhibition of BET proteins.  A dose up to the MTD may 
be selected for use in each expansion cohort by the sponsor and investigators.  More than 1 dose of 
INCB057643 and/or schedule may be assessed pending emerging safety, PK, and PD data.  Part 2/TGA 
will enroll up to approximately 165 subjects with specified solid tumors or lymphoma.  The high-grade 
serous ovarian cancer cohort will include approximately 20 subjects.  At least 5 of these subjects will 
have BRD4 amplification, and at least another 5 will have MYC amplification/ 
overexpression/translocation.  The BRD4 and MYC molecular signature will be identified for enrollment 
eligibility by known status before subject consenting.  The mCRPC cohort will include approximately 
20 subjects.  At least 5 of these subjects will have androgen receptor splice variant 7 (AR-V7) identified 
for enrollment eligibility by known status before subject consenting, and another 5 will have poorly 
differentiated neuroendocrine phenotype identified by local investigators and pathologists before subjects 
sign the informed consent form (ICF).  A non-Hodgkin's lymphoma (NHL) cohort will include 
approximately 45 subjects, 5 to 15 of those having a diagnosis of "double-hit" or "triple-hit" 
(overexpression and/or translocation of MYC and BCL2 and/or BCL6) diffuse large B-cell lymphoma 
(DLBCL), 5 to 15 of those having a diagnosis of follicular lymphoma, and 5 to 15 of those to enroll other 
NHLs such as DLBCL, Burkitt's lymphoma, or B-cell lymphoma, unclassifiable (with features 
intermediate between DLBCL and Burkitt's lymphoma).  The other disease-specific and molecularly 
defined groups in TGA (pancreatic adenocarcinoma, breast cancer, glioblastoma multiforme, and Ewing's 
sarcoma) will enroll approximately 5 to 15 subjects each.  Efforts should be made to identify subjects 
with a pathway alteration relevant to BET signaling such as MYC or BRD amplification in these tumor 
types.  An additional group of up to approximately 20 subjects with any other tumor (except those 
specified previously) known to have pathway alteration relevant to BET protein signaling will also be 
enrolled with medical monitor approval.  Part 2/TGB will enroll approximately 45 subjects (5 to 15 in 
each tumor type) with acute myeloid leukemia (AML), HR-MDS, MDS/MPN, and MF.  Part 2/TGC will 
enroll approximately 5 to 15 subjects with MM. 
If ≥ 33% of subjects in a Part 2 expansion cohort experience DLTs during Cycle 1, then further 
enrollment to the cohort will be stopped, and a lower dose level may be explored. 
During dose escalation and expansion, the small number of subjects in each group and heterogeneity of 
dose and subject characteristics within the groups is the reason for not having predefined efficacy 
stopping criteria. 
Individual dose titration will be permitted according to Protocol-defined safety parameters.  Subjects will 
continue to receive INCB057643 in 21-day cycles until withdrawal criteria are met (eg, toxicity, disease 
progression).  Additional PK assessments for food effect on drug exposure will be performed in the first 
12 subjects enrolled into Part 2/TGA.  Additional subjects may be enrolled if there are data quality issues 
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among the initial 12 subjects. 
Part 3 − Combination Dose Escalation (C-ES) 
Part 3 will determine the MTD and/or a tolerated dose of the combination (the RP2D) of the combination 
of INCB057643 and one of the SOC agents in relapsed or refractory advanced or metastatic solid tumor 
and hematologic malignancies.  The starting dose of INCB057643 in the combination treatment groups 
will be the PAD or 1 dose level below the MTD of INCB057643 monotherapy identified in Part 1 of this 
study.  Pending emerging data in Part 1 and Part 2, a lower starting dose of INCB057643 could be 
selected for all or several combinations in Part 3 (eg, 2 dose levels below the MTD of INCB057643 in 
Part 1).  Starting doses of the SOC combination agents will be selected from conventional dose regimens 
for the first dose cohort and can be modified for the subsequent cohorts, pending emerging safety data,.  
INCB057643 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 and/or a 
tolerated dose (the RP2D) of the combinations is identified and will be followed by independent 
expansion cohorts at the selected dose(s) in Part 4.  Pending emerging data, more than 1 RP2D dose could 
be explored in each expansion cohort in Part 4.  
Dose escalation will follow the 3 + 3 design.  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. 
Part 3 will be conducted in 6 disease-specific treatment groups, as follows: 
• C-ES-TGA (INCB057643 in combination with gemcitabine):  any solid tumor for which treatment with 
gemcitabine is relevant. 
• C-ES-TGB (INCB057643 in combination with paclitaxel):  any solid tumor for which treatment with 
paclitaxel is relevant. 
• C-ES-TGC (INCB057643 in combination rucaparib; conducted in the United States only):  any solid 
tumor for which treatment with rucaparib is relevant. 
• C-ES-TGD (INCB057643 in combination with abiraterone):  any mCRPC subjects eligible to receive 
abiraterone plus prednisone. 
• C-ES-TGE (INCB057643 in combination with ruxolitinib; conducted in the United States only):  any 
MF subjects currently receiving ruxolitinib with an inadequate response. 
• C-ES-TGF (INCB057643 in combination with azacitidine):  any AML and HR-MDS subjects eligible 
to receive azacitidine. 
Part 4 − Combination Dose Expansion (C-EX) 
After identification of the RP2D in combination regimens in Part 3, Part 4 will enroll subjects with 
relapsed or refractory advanced or metastatic solid tumor and hematologic malignancies to further 
determine safety, tolerability, efficacy, PK, and PD in 4 disease-specific treatment groups.  The sponsor 
may decide not to expand any or some cohorts pending emerging data. 
Part 4 will be conducted in 4 disease-specific treatment groups, as follows: 
• C-EX-TGA (INCB057643 in combination rucaparib; conducted in the United States only):  any BRCA 
wild type platinum-resistant mHGSOC (epithelial ovarian/fallopian tube/primary peritoneal cancer) 
subjects eligible to receive rucaparib. 
• C-EX-TGB (INCB057643 in combination with abiraterone):  any mCRPC subjects who have 
progressed on first-line enzalutamide for metastatic disease and who are eligible to receive abiraterone 
plus prednisone (chemotherapy treatment naive); OR any mCRPC subjects who have demonstrated 
prostate-specific antigen (PSA) progression with or without radiologic progression while being treated 
with abiraterone plus prednisone and who are clinically stable and will remain on abiraterone plus 
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prednisone (prior chemotherapy is allowed). 
• C-EX-TGC (INCB057643 in combination with ruxolitinib; conducted in the United States only):  any 
MF subjects currently receiving ruxolitinib with an inadequate response. 
• C-EX-TGD (INCB057643 in combination with azacitidine):  any AML and HR-MDS subjects eligible 
to receive azacitidine. 
Study Population: 
Subjects with relapsed or refractory advanced or metastatic malignancies as noted below. 
Key Inclusion Criteria: 
- Men and women aged 18 years or older. 
- Histologically or cytologically confirmed diagnosis of advanced malignancy: 
Part 1 – Monotherapy Dose Escalation: 
o TGA:  Advanced solid tumor or lymphoma 
o TGB:  Acute leukemia (any), HR-MDS, MDS/MPN, or MF 
o TGC:  MM 
Part 2 – Monotherapy Dose Expansion: 
o TGA:  
• Pancreatic adenocarcinoma 
• mCRPC 
• Breast cancer 
• High-grade serous ovarian cancer 
• Glioblastoma multiforme  
• NHL 
• Ewing's sarcoma 
• Any solid tumor or lymphoma (except specified above) with any pathway alteration relevant to 
BET protein signaling, 
, which is hypothesized to be susceptible to 
INCB057643 monotherapy (require approval by medical monitor). 
o TGB:  AML, HR-MDS, MDS/MPN, or MF 
o TGC:  Measureable/evaluable MM, defined as one or more of the following: 
• Serum M-protein ≥ 0.5 g/dL 
• Urine M-protein ≥ 200 mg/24 h 
• Serum free light chain (FLC):  Involved FLC level ≥ 10 mg/dL provided serum FLC ratio is 
abnormal 
Part 3 – Combination Dose Escalation (C-ES): 
o C-ES-TGA:  any solid tumor for which treatment with gemcitabine is relevant.  
o C-ES-TGB:  any solid tumor for which treatment with paclitaxel is relevant.  
o C-ES-TGC (conducted in the United States only):  any solid tumor for which treatment with rucaparib 
is relevant. 
o C-ES-TGD:  any mCRPC subjects eligible to receive abiraterone plus prednisone.  
o C-ES-TGE (conducted in the United States only): any MF subjects currently receiving ruxolitinib 
with an inadequate response. 
o C-ES-TGF:  any AML and HR-MDS subjects eligible to receive azacitidine. 
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Part 4 Combination Dose Expansion (C-EX): 
o C-EX-TGA (conducted in the United States only):  any BRCA wild type platinum-resistant mHGSOC 
(epithelial ovarian/fallopian tube/primary peritoneal cancer) subjects eligible to receive rucaparib. 
• Platinum-resistant disease is defined by disease progression within 6 months of completing 
platinum-based therapy.   
• Known BRCA wild type by a validated assay before consenting. 
• Subjects must be poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor naive or have 
had a clinical response (complete response or partial response) to a prior PARP inhibitor and 
progressed and have a BRCA status that was shown to be BRCA wild type at the time of consent.  
o C-EX-TGB:  any mCRPC subjects who have progressed on first-line enzalutamide for metastatic 
disease and who are eligible to receive abiraterone plus prednisone (chemotherapy treatment naive); 
OR any mCRPC who have demonstrated PSA progression with or without radiologic progression 
while being treated with abiraterone plus prednisone and who are clinically stable and will remain on 
abiraterone plus prednisone (prior chemotherapy is allowed).  
• Progression is defined by the Prostate Cancer Working Group 3 (PCWG3) Guidelines (blood-based 
PSA or imaging [nodes, viscera, and bone] at study entry).  
• mCRPC subjects must maintain a castrate level of testosterone documented (< 50 ng/dL) during the 
screening period and while on study. 
o C-EX-TGC (conducted in the United States only):  any MF subjects currently receiving ruxolitinib 
with an inadequate response, as defined below: 
• Palpable spleen of > 10 cm below the left subcostal margin on physical examination at screening 
OR 
• Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical examination AND 
active symptoms of MF at screening as demonstrated by presence of 1 symptom score ≥ 5 or 
2 symptom scores ≥ 3 using the Screening Symptom Form.  
• MF subjects must be receiving ruxolitinib for ≥ 6 months with a stable dose for ≥ 8 weeks 
(acceptable doses are 5 to 25 mg BID). 
o C-EX-TGD:  any AML and HR-MDS subjects eligible to receive azacitidine. 
• Confirmed AML or high-risk MDS (International Prognostic Scoring System -2, or high risk) in 
accordance with WHO diagnostic criteria 
• Failure of prior therapy with HMA, defined as one of the following:  
 Progression to AML 
 % increase in bone marrow blasts  
 Relapsed disease after response 
 At least 4 cycles of treatment without clinical benefit (hematological improvement or better) 
• Prior therapy, as follows: 
o For Parts 1 and 2/TGA and TGB, subjects must have progressed following at least 1 line of prior 
therapy, and there is no further established therapy that is known to provide clinical benefit (including 
subjects who are intolerant to, not eligible for, or refuse the established therapy).  
• Subjects with AML are eligible if they have relapsed and/or refractory disease, if they are 
≥ 65 years of age and are not candidates for or have refused standard chemotherapy, or if they have 
no established standard of care that is known to provide clinical benefit in the judgement of the 
investigator. 
• Subjects with MF must be resistant, refractory, or intolerant to ruxolitinib therapy.  
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o For Parts 1 and 2/TGC, MM subjects must have relapsed from or have been refractory to ≥ 2 prior 
treatment regimens, including a proteasome inhibitor and an immunomodulatory drug, and have no 
current standard options available. 
o For Parts 3 and 4, subjects must have progressed following at least 1 line of prior therapy, and the 
treatment with the select SOC is relevant for the specific disease cohort.   
• For subjects with solid tumors and lymphoma in all parts of the study (where applicable), willingness to 
undergo a pretreatment core or excisional tumor biopsy (except for glioblastoma) or availability of a 
tumor block or 25 unstained slides from biopsy or resection of primary tumor or metastasis that is 
preferably ≤ 1 year old and obtained after completion of last treatment.  For subjects with hematologic 
malignancies in which bone marrow biopsy and/or aspirate is part of the disease assessment, 
willingness to undergo a pretreatment bone marrow biopsy and/or aspirate (as appropriate to disease).  
If a biopsy is not possible or contraindicated, or the tissue requirement cannot be satisfied, this may be 
omitted with approval from the medical monitor.  In all cases, preferably, biopsies will be confirmed to 
contain adequate tumor tissue by a local pathology review. 
• Life expectancy > 12 weeks; for MF subjects in Parts 3 and 4, life expectancy > 24 weeks. 
• ECOG performance status score: 
• Parts 1 and 3:  0 or 1 
• Parts 2 and 4:  0, 1, or 2  
• Willingness to avoid pregnancy or fathering children based on the criteria below: 
− Women of childbearing potential must have a negative serum pregnancy test at screening and 
immediately before the first dose (within 24 hours) of study drug.  
− Women of nonchildbearing potential are defined as surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 24 months of amenorrhea and at least 50 years of age. 
− Men and women of childbearing potential must agree to take appropriate precautions (ie, use at least 
2 forms of contraception) to avoid pregnancy or fathering children from screening through follow-up 
(at least 28 days after the last dose of all study medications).  Permitted methods that are at least 99% 
effective in preventing pregnancy should be communicated to the subjects and their understanding 
confirmed. 
• Females must agree to abstain from breastfeeding during study participation and for 28 days after study 
drug discontinuation.  
• Males must also agree to refrain from donating semen or sperm during treatment and for 28 days after 
discontinuation from this study. 
• Ability to comprehend and willingness to sign an ICF. 
Key Exclusion Criteria:   
• Inadequate bone marrow function demonstrated by any of the following:  
Laboratory 
Parameter 
Part 1/ 
TGA 
Part 2/ 
TGA 
Parts 1 and 2/ 
TGCa 
Part 3-C-ES/TGA/ 
TGB/TGC/TGD and 
Part 4/C-EX-TGA/TGB 
Part 3/C-ES-TGE and  
Part 4/C-EX-TGC 
Hemoglobin (g/dL) 
< 10.0 
< 8.0 
< 8.0 
< 9.0 
Subjects unwilling to receive 
red blood cell transfusion to 
treat low hemoglobin levels are 
excluded. 
Platelet count 
(× 109/L) 
< 100 
< 100 
< 75 
< 100 
< 50 in 4 weeks before 
screening or platelet 
transfusions within 8 weeks of 
screening. 
Absolute neutrophil 
count (× 109/L) 
< 1.5 
< 1.0 
< 1.0 
< 1.5 
< 0.5 in the 4 weeks before 
screening. 
Note:  No specific hematologic exclusion criteria apply for subject with AML/HR-MDS in Parts 1 and 2/TGB, Part 3 C-ES-TGF 
or Part 4 C-EX-TGD.  The medical monitor will review all complete blood count parameters before approving enrollment into 
the study. 
a Multiple myeloma subjects in Part 2 only:   < 50 × 109/L if 50% of bone marrow nucleated cells are plasma cells. 
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• Inadequate organ function demonstrated by any of the following, unless due to the underlying disease 
and approved by the medical monitor: 
o All Parts:  Total bilirubin > 1.5 × upper limit of normal (ULN).  Total bilirubin > 1.5 × ULN is 
acceptable if direct bilirubin ≤ 1.2 × ULN or with a diagnosis of Gilbert's syndrome. 
o Parts 1 and 3:  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN. 
o Parts 2 and 4:  AST and ALT > 2.5 × ULN or > 5 × ULN for subjects with liver metastases.  
o All Parts:  Creatinine clearance < 50 mL/min based on Cockroft-Gault formula or 24-hour urinalysis 
(< 30 mL/min for MM). 
o All Parts:  Alkaline phosphatase (ALP) ≥ 2.5 × ULN. 
• Subjects with 1) bone metastases AND 2) no hepatic parenchymal metastases on screening 
radiographic examinations may enroll if ALP is ≤ 5 × ULN.  Subjects with 1) bone metastases 
AND 2) hepatic parenchymal metastases on screening radiographic examinations may enroll if 
ALP is ≤ 5 × ULN only with medical monitor approval. 
• Receipt of anticancer medications or investigational drugs within the following intervals before the first 
administration of study drug, unless with medical monitor approval: 
o < 5 half-lives or 14 days, whichever is longer, for any investigational agent. 
o < 5 half-lives for all other chemotherapy or targeted small molecule anticancer medications. 
o < 6 weeks for mitomycin-C or nitrosoureas. 
o < 4 weeks for immunotherapy or antibody therapy. 
o The following medications are allowed: 
• Subjects with mCRPC may be maintained on androgen deprivation, chemical or surgical, at the 
discretion of the investigator, with a castrate level of testosterone documented (< 50 ng/dL) during 
the screening period and while on study.  
• Low-dose corticosteroids (prednisone or the equivalent ≤ 10 mg per day) may be administered.  
Use of inhaled or topical steroids and prophylactic corticosteroids for radiographic procedures is 
permitted. 
• For hematologic malignancies:   Hydroxyurea for controlling proliferative disease may be 
administered.  Hydroxyurea should not be used within at least 48 hours before and on the day of the 
 sample collection (bone marrow and blood) or during or 72 hours before or after 
azacitidine administration. 
• For Parts 1 and 2/TGC:  Receipt of less than 160 mg dexamethasone within 14 days before 
receiving the first dose of study drug is allowed. 
• Denosumab and zoledronic acid are permitted to treat cancer-related bone diseases. 
• 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 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. 
• Any unresolved toxicity ≥ Grade 2 (except stable Grade 2 peripheral neuropathy or alopecia) from 
previous anticancer therapy. 
• 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/C-ES-TGE and Part 4/C-EX-TGC, MF subjects may not have 
had splenic irradiation within 6 months of the first dose of INCB057643. 
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• Type 1 diabetes or uncontrolled Type 2 diabetes. 
o All Parts:  HbA1c ≥ 8% (all subjects will have HbA1c test at screening).   
o For Parts 1 and 3 only:  fasting blood glucose > 160 mg/dL (> 8.9 mmol/L). 
• Known human immunodeficiency virus infection (HIV; HIV 1/2 antibodies). 
• Evidence of hepatitis B virus or hepatitis C virus infection. 
• Currently active and uncontrolled infectious disease requiring systemic antibiotic, antifungal, or 
antiviral treatment. 
• Untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have 
progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms 
attributable to brain/CNS metastases).  Subjects with previously treated and clinically stable brain/CNS 
metastases and off all corticosteroids for ≥ 2 weeks before Cycle 1 Day 1 are eligible.  Primary CNS 
lymphoma will only be permitted in Part 2/TGA.  Subjects with glioblastoma are not subjected to this 
criterion with medical monitor approval. 
• History or presence of abnormal ECG that, in the investigator's opinion, is clinically meaningful.  A 
screening QTc interval of > 470 msec 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.  Subjects with QTc prolongation due to 
a pacemaker may enroll if the JT is normal or with medical monitor approval.  In the event that a single 
QTc is > 470 msec, the subject may enroll if the average QTc for the 3 ECGs is < 470 msec. 
• Known additional malignancy that is progressing or requires active treatment.  Exceptions include basal 
cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy. 
• International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time 
(aPTT) > 1.5 × ULN (unless the subject is receiving anticoagulant therapy, in which case, the subject 
may be included as long as the INR, PT, and aPTT are within therapeutic range of intended use of 
anticoagulants). 
Note:  Partial thromboplastin time may be used in place of aPTT per institutional standards. 
• All parts of the study (where applicable) for solid tumors and lymphomas:  Subjects with a history of 
bleeding related to cancer under study requiring a medical intervention (eg, embolization procedure, red 
blood cell transfusion, or hospitalization) within 30 days of study enrollment.   
• Clinically significant bleeding within 14 days of Cycle 1 Day 1. 
INCB057643 Dosage and Mode of Administration:   
Part 1 and Part 2 Monotherapy 
INCB057643 tablets will be administered orally in 21-day treatment cycles.  The starting dose in 
Part 1/TGA will be 8 mg QD.  The starting dose for Part 1/TGB and Part 1/TGC will be the PAD 
identified in Part 1/TGA.  Dose escalation during Part 1 of the study will proceed using the dose-
escalation rules described above.  The dose of INCB057643 in Part 2 will be the treatment group−specific 
MTD or PAD identified in Part 1.  More than 1 dose of INCB057643 and/or schedule may be assessed in 
Part 2 pending emerging safety, PK, and PD data. 
Subjects will fast least 2 hours before and 1 hour after study drug administration except on days when 
serial PK and PD sampling is conducted, then subjects will refrain from food consumption at least 8 hours 
before the study drugs or as indicated in the PK section.  
Dose escalations for INCB057643 in Part 1 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 dosing schedules, or alternate formulations, depending on PK, PD, and 
safety results. 
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Part 3 and Part 4 Combination Therapy 
Study Drug 
The starting dose of INCB057643 in Part 3 will be the PAD or 1 dose level below the MTD of 
INCB057643 monotherapy identified in Part 1 of the study.  Pending emerging data in Part 1 and Part 2, a 
lower starting dose of INCB057643 could be selected for all or several combinations in Part 3 (eg, 2 dose 
levels below the MTD of INCB057643 in Part 1).  The 12 mg QD dose of INCB057643 was identified as 
the MTD in Part 1/TGA; thus the 8 mg QD dose of INCB057643 will be the starting dose for Part 3 
C-ES-TGA/TGB/TGC/TGD.  The starting dose of INCB057643 in Part 4 will be the treatment group–
specific RP2D identified in Part 3.  Study drug QD doses will be taken in the morning in a continuous 21- 
or 28-day treatment cycle depending on the SOC agent administered in combination.  The subjects will 
fast at least 2 hours before and 1 hour after study drug administration except on days when serial PK and 
PD sampling is conducted, then subjects will fast at least 8 hours before the study drugs or as indicated in 
the PK sampling section.  Subjects will continue to receive combination therapy as long as they are 
deriving benefit and have not met any of the Protocol-defined conditions for discontinuation of treatment.  
Intra-subject dose escalation is not permitted in combination therapy treatment groups.    
Standard of Care Agents 
Conventional regimens of the SOC agents will be used throughout Part 3 and Part 4 of the study.  
Subjects will continue to receive combination therapy as long as they are deriving benefit and have not 
met any of the Protocol-defined conditions for discontinuation of treatment.  Dosing adjustment (dosing 
delay and/or dose reduction) during treatment is allowed.  Intra-subject dose-escalation is not permitted. 
• Gemcitabine (Part 3 Only):  Will be administered as 1000 mg/m2 by a 30-minute intravenous (IV) 
infusion (± 5 minutes) on Days 1 and 8 of each 21-day cycle.  Subjects may receive prophylactic 
granulocyte colony-stimulating factor (G-CSF) support with filgrastim (Neupogen®) per institutional 
guidelines, however, it should not be given in the first cycle unless discussed with the medical monitor. 
• Paclitaxel (Part 3 Only):  Will be administered as 80 mg/m2 by a 1-hour IV infusion (± 15 min) on 
Days 1, 8, and 15 of each 21-day cycle.  Treatment continuation following clinical response will be at 
the discretion of the investigator.  Subjects must receive premedications (IV or orally [PO]) with 
corticosteroids, H1- and H2-antagonists, antihistamines, and antiemetics based on institutional 
guidelines, investigator practice, or local prescribing information or standards of care.  Subjects may 
receive prophylactic G-CSF support with filgrastim (Neupogen) per institutional guidelines, however, it 
should not be given in the first cycle unless discussed with the medical monitor. 
• Rucaparib:  Will be administered as 600 mg (two 300 mg tablets) PO BID in a continuous dosing 
regimen with or without food.  This oral agent is prepared as 200, 250, and 300 mg tablets. 
• Abiraterone:  Will be administered as 1000 mg (two 500 mg tablets or four 250 mg tablets) PO QD in a 
continuous dosing regimen in combination with prednisone 5 mg PO BID.  Abiraterone should be taken 
on an empty stomach; no food should be consumed for at least 2 hours before the dose is taken and for 
at least 1 hour after the dose is taken.   
• Ruxolitinib:  Will be administered as a dose of 5 to 25 mg PO BID in a continuous dosing regimen 
using the dose designated as the stable dose at the time of screening for each subject.  Doses of 
ruxolitinib should be self-administered approximately 12 hours apart without regard to food. 
• Azacitidine:  Will be administered as a dose of 75 mg/m2 IV or subcutaneously for 7 days during a 
9-day or less period (ie, a 2-day break allowed on weekend, if needed) of each 28-day treatment cycle. 
Study Schedule:   
All subjects will have a screening visit, which may occur up to 28 days before enrollment.  Screening will 
begin at the time the subject signs the ICF and will continue until the date the subject is enrolled in the 
study (Cycle 1 Day 1). 
 
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During treatment, subjects will have regularly scheduled study visits as follows:  
Part 1 and Part 2 INCB057643 Monotherapy:  21-Day Cycles 
• Cycle 1:  Days 1, 2, 8 (± 3 days), and 15 (± 3 days) 
• Cycle 2 and beyond:  Days 1 (± 3 days), 2 (Part 2/TGA; food-effect only), and 11 (± 3 days) 
Part 3 (C-ES) and Part 4 (C-EX) INCB057643 Combination Therapy: 
• Gemcitabine (Part 3 Only):  21-Day Cycles (Cycles 1 and 2:  Days 1, 8 [± 3 days], and 15 [± 3 days]; 
Cycle 3 and beyond:  Days 1 [± 3 days] and 8 [± 3 days]) 
• Paclitaxel (Part 3 Only):  21-Day Cycles (Cycles 1 and 2:  Days 1, 8 [± 3 days], and 15 [± 3 days]; 
Cycle 3 and beyond:  Days 1 [± 3 days], 8 [± 3 days], and 15 [± 3 days]) 
• Rucaparib:  21-Day Cycles (Cycle 1:  Days 1, 8 [± 3 days], and 15 [± 3 days]; Cycle 2 and 
beyond:  Days 1 [± 3 days] and 11 [± 3 days]) 
• Abiraterone:  21-Day Cycles (Cycle 1:  Days 1, 8 [± 3 days], and 15 [± 3 days]; Cycle 2 and 
beyond:  Days 1 [± 3 days] and 11[± 3 days]) 
• Ruxolitinib:  21-Day Cycles (Cycle 1:  Days 1, 8 [± 3 days], and 15 [± 3 days]; Cycle 2 and 
beyond:  Days 1 [± 3 days] and 11 [± 3 days]) 
• Azacitidine:  28-Day Cycles anchored to azacitidine schedule (Days 1, 8 [± 3 days], 15 [± 3 days], 
22 [± 3 days], and 29 to 42) 
If a decision is made that the subject will permanently discontinue study drug, the end of treatment (EOT) 
visit will be conducted.  All subjects will have a safety follow-up visit at 30 to 35 days after the EOT visit 
(or after the last dose of study drug if the EOT visit was not performed).  The end of study (EOS) visit can 
occur at the same time of the safety follow-up visit unless there is an ongoing SAE or clinically 
significant AE.  In this case, EOS visit will occur when the AE is resolved, returned to baseline, or 
deemed irreversible per the investigator. 
Estimated Duration of Participation:   
Subjects will be treated in 21- or 28-day cycle depending on treatment regimens until they meet 
withdrawal criteria.  Treatment duration will vary significantly between subjects, but is expected to 
average approximately 4 to 6 months. 
Estimated Number of Subjects:   
• Part 1:  3 to 10 subjects per cohort per treatment group (3 treatment groups/approximately 60 subjects). 
• Part 2:  225 subjects across 3 treatment groups. 
• Part 3:  Approximately 3 to 10 subjects per cohort per treatment group (6 treatment groups/ 
approximately 60 subjects). 
• Part 4:  Approximately 71 subjects across 4 treatment groups. 
Statistical Methods: 
Part 1 of the study is a standard dose-escalation design, and the sample size depends on the occurrence of 
DLTs.  Approximately 3 to 6 subjects will be enrolled in each dose level.   
Part 2/TGA will enroll up to approximately 165 subjects with specified solid tumors or lymphoma.  
Approximately 5 to 15 subjects will be enrolled in the pancreatic adenocarcinoma, breast cancer, 
glioblastoma multiforme, Ewing's sarcoma, and NHL groups.  The high-grade serous ovarian cancer and 
mCRPC groups will include approximately 20 subjects.  The group of any other solid tumor or lymphoma 
(except the specified) with any pathway alteration relevant to BET protein signaling, 
 
, will enroll up to 20 subjects as well. 
Part 2/TGB will enroll up to 45 subjects with AML, HR- MDS, MDS/MPN, or MF; and Part 2/TGC will 
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enroll up to 15 subjects with MM.  This will provide > 80% chance of detecting at least 1 responder if the 
underlying response rate is 30%. 
Part 3 will use a 3 + 3 design to evaluate different doses of INCB057643 in combination with 
gemcitabine, paclitaxel, rucaparib, abiraterone, ruxolitinib, or azacitidine in 6 treatment groups.  Dose 
escalation for 6 treatment groups will proceed independently.  Approximately 3 to 6 subjects will be 
enrolled in each dose level for each treatment group.  The total number of subjects will depend on the 
frequency of DLTs and the number of dose levels tested before the MTD and RP2D are reached. 
In Part 4, approximately 71 subjects will be enrolled across 4 possible expansion treatment groups to 
further evaluate the safety, tolerability, efficacy, PK, and PD of the RP2Ds selected from Part 3.  The 
high-grade serous ovarian cancer and mCRPC cohorts will include approximately 20 subjects.  The MF 
group will enroll approximately 16 subjects.  The AML/HR-MDS cohort will enroll approximately 
15 subjects. 
Descriptive statistics will be provided where appropriate.  Continuous endpoints will be summarized with 
number of subjects, mean, standard deviation, minimum, median, and maximum for each cohort.  
Categorical endpoints will be summarized with frequency and percentages for each category by cohort.  
The clinical safety data (vital signs, ECGs, routine laboratory tests, and AEs) will be summarized 
descriptively. 
Objective response rate will be estimated with a 95% exact confidence interval (CI). 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................25 
1. 
INTRODUCTION ......................................................................................................30 
1.1. 
Background .................................................................................................................30 
1.2. 
Overview of INCB057643 ..........................................................................................32 
1.2.1. 
Nonclinical Pharmacology of INCB057643 ...............................................................32 
1.2.2. 
Nonclinical Drug Metabolism and Pharmacokinetics of INCB057643 .....................33 
1.3. 
Overview of Standard-of-Care Agents Selected For Combination Therapies ...........34 
1.3.1. 
Overview of Gemcitabine in Solid Tumors Including Ovarian Cancer .....................34 
1.3.2. 
Overview of Paclitaxel in Solid Tumors Including Ovarian Cancer ..........................35 
1.3.3. 
Overview of Rucaparib in Ovarian Cancer ................................................................36 
1.3.4. 
Overview of Abiraterone in Metastatic Castration-Resistant Prostate Cancer ...........36 
1.3.5. 
Overview of Azacitidine in Acute Myeloid Leukemia and Myelodysplastic 
Syndrome ....................................................................................................................37 
1.3.6. 
Overview of Ruxolitinib in Myelofibrosis .................................................................37 
1.4. 
Study Rationale ...........................................................................................................38 
1.4.1. 
Rationale for Combining INCB57643 With Gemcitabine and Paclitaxel in 
Ovarian Cancer ...........................................................................................................38 
1.4.2. 
Rationale for Combining INCB57643 With Rucaparib in Ovarian Cancer ...............39 
1.4.3. 
Rationale for Combining INCB57643 With Abiraterone in Castration-
Resistant Prostate Cancer ...........................................................................................39 
1.4.4. 
Rationale for Combining INCB57643 With Ruxolitinib in Myelofibrosis ................40 
1.4.5. 
Rationale for Combining INCB57643 With Azacitidine in Acute Myeloid 
Leukemia/High-Risk Myelodysplastic Syndrome ......................................................40 
1.5. 
INCB057643 Safety and Potential Risks ....................................................................41 
1.5.1. 
Preclinical Safety and Risks .......................................................................................41 
1.5.2. 
Potential Risks of Gemcitabine ..................................................................................42 
1.5.3. 
Potential Risks of Paclitaxel .......................................................................................42 
1.5.4. 
Potential Risks of Rucaparib ......................................................................................43 
1.5.5. 
Potentials Risks of Abiraterone ..................................................................................43 
1.5.6. 
Potential Risks of Ruxolitinib .....................................................................................43 
1.5.7. 
Potential Risks of Azacitidine ....................................................................................43 
1.5.8. 
Potential Risks of Combination Therapy ....................................................................44 
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1.6. 
Clinical Experience With INCB057643 in Study INCB 57643-101 ..........................44 
1.6.1. 
Clinical Pharmacokinetics and Pharmacodynamics ...................................................44 
1.6.2. 
Clinical Trial Experience ............................................................................................47 
1.6.2.1. 
Dose-Escalation and Expansion, Safety, and Tolerability Study of 
INCB057643 in Subjects With Advanced Malignancies ...........................................47 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................53 
2.1. 
Study Objectives .........................................................................................................53 
2.1.1. 
Primary Objectives .....................................................................................................53 
2.1.2. 
Secondary Objectives .................................................................................................53 
 
53 
2.2. 
Study Endpoints ..........................................................................................................53 
2.2.1. 
Primary Endpoints ......................................................................................................53 
2.2.2. 
Secondary Endpoints ..................................................................................................53 
 
54 
3. 
SUBJECT ELIGIBILITY ...........................................................................................54 
3.1. 
Subject Inclusion Criteria ...........................................................................................54 
3.2. 
Subject Exclusion Criteria ..........................................................................................58 
4. 
INVESTIGATIONAL PLAN .....................................................................................61 
4.1. 
Overall Study Design ..................................................................................................61 
4.1.1. 
Part 1 − Monotherapy Dose Escalation ......................................................................62 
4.1.2. 
Part 2 − Monotherapy Dose Expansion ......................................................................63 
4.1.3. 
Part 3 − Combination Dose Escalation (C-ES) ...........................................................65 
4.1.4. 
Part 4 − Combination Dose Expansion (C-EX) ..........................................................66 
4.2. 
Number of Subjects ....................................................................................................66 
4.2.1. 
Planned Number of Subjects ......................................................................................66 
4.2.2. 
Replacement of Subjects .............................................................................................67 
4.3. 
Measures Taken to Avoid Bias ...................................................................................67 
4.4. 
Duration of Treatment and Subject Participation .......................................................67 
4.5. 
Overall Study Duration ...............................................................................................67 
4.6. 
Study Termination ......................................................................................................67 
5. 
TREATMENT ............................................................................................................68 
5.1. 
Treatment Assignment ................................................................................................68 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................68 
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5.1.2. 
Randomization and Blinding ......................................................................................68 
5.2. 
Study Drugs ................................................................................................................68 
5.2.1. 
INCB057643 ...............................................................................................................68 
5.2.1.1. 
Description and Administration ..................................................................................68 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................69 
5.2.1.3. 
Storage ........................................................................................................................69 
5.2.1.4. 
Dispensing Study Drug ...............................................................................................69 
5.2.1.5. 
Instruction to Subjects for Handling Study Drug .......................................................69 
5.2.2. 
Standard of Care Agents .............................................................................................70 
5.2.2.1. 
Gemcitabine Administration .......................................................................................70 
5.2.2.2. 
Paclitaxel Administration ...........................................................................................70 
5.2.2.3. 
Rucaparib Administration ...........................................................................................70 
5.2.2.4. 
Abiraterone Administration ........................................................................................70 
5.2.2.5. 
Ruxolitinib Administration .........................................................................................70 
5.2.2.6. 
Azacitidine Administration .........................................................................................71 
5.2.2.7. 
Supply, Packaging, and Labeling ...............................................................................71 
5.3. 
Treatment Compliance ................................................................................................71 
5.4. 
Dose Modifications .....................................................................................................72 
5.4.1. 
Study Drug – Part 1 and Part 3 ...................................................................................72 
5.4.1.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ................72 
5.4.1.2. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................73 
5.4.1.3. 
Follow-Up of Dose-Limiting Toxicities .....................................................................73 
5.4.1.4. 
Procedures for Cohort Review and Dose Escalation ..................................................73 
5.4.2. 
INCB057643 Dose Interruptions and Reductions ......................................................74 
5.4.3. 
Standard of Care Agent Dose Interruptions and Reductions ......................................78 
5.4.3.1. 
Specific Guidelines for Gemcitabine and Paclitaxel in Solid Tumors .......................78 
5.4.4. 
Criteria for Permanent Discontinuation of INCB057643 ...........................................79 
5.4.5. 
Criteria and Procedures for Dose Escalations of INCB057643 ..................................79 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................80 
5.5.1. 
Withdrawal Criteria ....................................................................................................80 
5.5.2. 
Withdrawal Procedures ...............................................................................................80 
5.6. 
Concomitant Medications ...........................................................................................81 
5.6.1. 
Restricted Medications ...............................................................................................81 
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5.6.2. 
Prohibited Medications ...............................................................................................82 
6. 
STUDY ASSESSMENTS ..........................................................................................82 
6.1. 
Screening ..................................................................................................................110 
6.2. 
Treatment ..................................................................................................................111 
6.2.1. 
Day 1 .........................................................................................................................111 
6.2.2. 
Visit Scheduling ........................................................................................................111 
6.3. 
End of Treatment ......................................................................................................111 
6.4. 
Follow-Up .................................................................................................................112 
6.4.1. 
Safety Follow-Up ......................................................................................................112 
6.4.2. 
Unscheduled Visits ...................................................................................................112 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES .........................112 
7.1. 
Administration of Informed Consent Form ..............................................................112 
7.2. 
Interactive Response Technology Procedure ............................................................112 
7.3. 
Demography and Medical History ............................................................................112 
7.3.1. 
Transfusion History Status (Myelofibrosis Combination Cohorts Only) .................113 
7.3.2. 
Screening Symptom Form (Myelofibrosis Combination Cohorts Only) .................113 
7.4. 
Prior and Concomitant Medications and Procedures ................................................113 
7.5. 
Safety Assessments ...................................................................................................113 
7.5.1. 
Adverse Events .........................................................................................................113 
7.5.2. 
Physical Examinations ..............................................................................................113 
7.5.2.1. 
Comprehensive Physical Examination .....................................................................114 
7.5.2.2. 
Targeted Physical Examination ................................................................................114 
7.5.3. 
Vital Signs and Weight .............................................................................................114 
7.5.4. 
Cardiac Monitoring ...................................................................................................114 
7.5.4.1. 
Twelve-Lead Electrocardiograms .............................................................................114 
7.5.4.2. 
Electrocardiogram Procedures ..................................................................................114 
7.5.4.3. 
Additional Instructions for Timed Electrocardiograms (Part 1 and Part 2 
Only) .........................................................................................................................114 
7.5.4.4. 
Echocardiogram or MUGA ......................................................................................115 
7.5.5. 
Laboratory Assessments ...........................................................................................115 
7.5.5.1. 
Chemistry, Hematology, Urinalysis, Coagulation Panel, Factor VII, 
Serology, and Endocrine Function Testing ..............................................................115 
7.5.5.2. 
Pregnancy Testing ....................................................................................................115 
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7.5.5.3. 
Hepatitis Screening Tests .........................................................................................115 
7.5.5.4. 
Cardiac Troponin (Either T or I) Testing .................................................................116 
7.6. 
Performance and Health-Related Quality of Life Assessments ...............................116 
7.6.1. 
ECOG Performance Status .......................................................................................116 
7.7. 
Efficacy Assessments ...............................................................................................116 
7.7.1. 
Lymphoma, Chronic Lymphocytic Leukemia, and Myelofibrosis:  CT Scan 
or MRI ......................................................................................................................117 
7.7.1.1. 
MRI or CT Scan in Myelofibrosis Combination Cohort Subjects ...........................117 
7.7.2. 
Lymphoma:  FDG-PET or Combined PET-CT ........................................................118 
7.7.3. 
Solid Tumors and Lymphoma:  Tumor Biopsy ........................................................118 
7.7.4. 
Leukemia, High-Risk Myelodysplastic Syndrome, Myelodysplastic 
Syndrome/Myeloproliferative Neoplasm, Myelofibrosis, and Multiple 
Myeloma:  Bone Marrow Biopsy .............................................................................118 
7.7.5. 
Leukemia and Lymphoma:  Immunophenotyping ...................................................119 
7.7.6. 
Leukemia, HR-MDS, and MDS/MPN:  Peripheral Blood Blast Counts ..................119 
7.7.7. 
Multiple Myeloma:  Disease Assessment .................................................................119 
7.7.8. 
Multiple Myeloma:  Skeletal Survey ........................................................................119 
7.7.9. 
Myelofibrosis:  Spleen Palpitation (Myelofibrosis Combination Cohorts 
Only) .........................................................................................................................119 
7.7.10. 
Castrate Resistant Prostate Cancer:  Prostate Cancer Clinical Trials Work 
Group 3 .....................................................................................................................120 
7.8. 
Pharmacokinetic Assessments ..................................................................................120 
7.8.1. 
Blood Sample Collection ..........................................................................................120 
7.8.2. 
Urine Sample Collection ...........................................................................................120 
7.8.3. 
Bioanalytical Methodology and Analysis .................................................................121 
7.8.4. 
Food-Effect Pharmacokinetic Testing ......................................................................121 
 
121 
 
121 
 
122 
 
122 
 
122 
 
 
.................................................122 
 
122 
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.123 
 
123 
 
124 
7.10. 
Other Study Procedures ............................................................................................124 
7.10.1. 
Distribution of Subject Reminder Cards ...................................................................124 
8. 
SAFETY MONITORING AND REPORTING .......................................................124 
8.1. 
Adverse Events .........................................................................................................124 
8.1.1. 
Definitions ................................................................................................................124 
8.1.2. 
Reporting ..................................................................................................................124 
8.2. 
Laboratory Test Abnormalities .................................................................................126 
8.3. 
Serious Adverse Events ............................................................................................126 
8.3.1. 
Definitions ................................................................................................................126 
8.3.2. 
Reporting ..................................................................................................................127 
8.4. 
Emergency Unblinding of Treatment Assignment ...................................................128 
8.5. 
Pregnancy .................................................................................................................128 
8.6. 
Warnings and Precautions ........................................................................................128 
8.7. 
Data Monitoring Committee .....................................................................................128 
8.8. 
Product Complaints ..................................................................................................128 
9. 
STATISTICS ............................................................................................................129 
9.1. 
Study Populations .....................................................................................................129 
9.2. 
Selection of Sample Size ..........................................................................................129 
9.3. 
Level of Significance ................................................................................................130 
9.4. 
Statistical Analyses ...................................................................................................130 
9.4.1. 
Efficacy Analyses .....................................................................................................130 
9.4.1.1. 
Primary Efficacy Analyses .......................................................................................130 
9.4.1.2. 
Secondary Efficacy Analyses ...................................................................................130 
 
130 
9.4.2. 
Safety Analyses ........................................................................................................131 
9.4.2.1. 
Adverse Events .........................................................................................................131 
9.4.2.2. 
Clinical Laboratory Tests .........................................................................................131 
9.4.2.3. 
Vital Signs ................................................................................................................131 
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9.4.2.4. 
Electrocardiograms ...................................................................................................132 
9.4.3. 
Pharmacokinetic Analysis ........................................................................................132 
9.4.4. 
Pharmacodynamic Analysis......................................................................................132 
9.5. 
Analyses for the Data Monitoring Committee ..........................................................133 
9.6. 
Interim Analysis ........................................................................................................133 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................133 
10.1. 
Investigator Responsibilities .....................................................................................133 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................135 
10.3. 
Data Management .....................................................................................................135 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................136 
10.5. 
Financial Disclosure .................................................................................................136 
10.6. 
Publication Policy .....................................................................................................137 
11. 
REFERENCES .........................................................................................................138 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................144 
APPENDIX B. PHARMACOKINETIC ANALYTICAL PARAMETERS ............................145 
APPENDIX C. EASTERN COOPERATIVE ONCOLOGYGROUP PEFORMANCE 
STATUS ...................................................................................................................146 
APPENDIX D. INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR ACUTE MYELOID LEUKEMIA ...................................................................147 
APPENDIX E. RESPONSE CRITERIA FOR GLIOBLASTOMA .........................................148 
APPENDIX F. INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR MYELODYSPLASTIC SYNDROME ............................................................151 
APPENDIX G. INTERNATIONAL CONSORTIUM PROPOSAL OF UNIFORM 
RESPONSE CRITERIA FOR 
MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS IN 
ADULTS ...................................................................................................................152 
APPENDIX H. REVISED RESPONSE CRITERIA FOR MYELOFIBROSIS:  
INTERNATIONAL WORKING GROUP-MYELOPROLIFERATIVE 
NEOPLASMS RESEARCH AND EUROPEAN LEUKEMIANET 
CONSENSUS REPORT ...........................................................................................155 
APPENDIX I. INTERNATIONAL UNIFORM RESPONSE CRITERIA FOR 
MULTIPLE MYELOMA .........................................................................................157 
APPENDIX J. CRITERIA FOR EVALUATING DISEASE RESPONSE AND 
PROGRESSION IN SUBJECTS WITH MULTIPLE MYELOMA 
TREATED BY HIGH-DOSE THERAPY AND HAEMOPOIETIC STEM 
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CELL TRANSPLANTATION:  MYELOMA SUBCOMMITTEE OF THE 
EUROPEAN SOCIETY FOR BLOOD AND MARROW 
TRANSPLANTATION ............................................................................................158 
APPENDIX K. RESPONSE CRITERIA FOR LYMPHOMA – THE LUGANO 
CLASSIFICATION ..................................................................................................159 
APPENDIX L. RESPONSE ASSESSMENT IN WALDENSTRÖM 
MACROGLOBULINEMIA .....................................................................................161 
APPENDIX M. RESPONSE ASSESSMENT IN CHRONIC LYMPHOCYTIC 
LEUKEMIA .............................................................................................................162 
APPENDIX N. PROSTATE CANCER WORKING GROUP 3 GUIDELINES .....................164 
APPENDIX O. CYP3A4 INHIBITORS AND INDUCERS ....................................................170 
APPENDIX P. SCREENING SYMPTOM FORM ..................................................................177 
APPENDIX Q. MANAGEMENT OF POTENTIAL HY'S LAW CASES ..............................179 
APPENDIX R. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................183 
 
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LIST OF TABLES 
Table 1: 
INCB057643 (Parent) and INCB057228 (M2) Steady-State (Cycle 1 Day 8) 
Pharmacokinetic Parameters .......................................................................................45 
Table 2: 
The Effect of a High-Fat Meal on the Pharmacokinetics of INCB057643 
(12 mg) and INCB057228 (M2) .................................................................................46 
Table 3: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 2 Subjects 
in Study INCB 57643-101 Part 1 Treatment Group A by MedDRA Preferred 
Term in Decreasing Order of Frequency (Safety Evaluable Population) ...................48 
Table 4: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 2 Subjects 
in Study INCB 57643-101 Part 1 Treatment Group B by MedDRA Preferred 
Term in Decreasing Order of Frequency (Safety Evaluable Population) ...................50 
Table 5: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 10% of 
Subjects in Study INCB 57643-101 Part 2/Treatment Group A by MedDRA 
Preferred Term in Decreasing Order of Frequency (Safety Evaluable 
Population) ..................................................................................................................51 
Table 6: 
Standard of Care Agent Administration .....................................................................71 
Table 7: 
Definition of Dose-Limiting Toxicity ........................................................................73 
Table 8: 
Guidelines for Interruption and Restarting of INCB057643 ......................................74 
Table 9: 
Schedule of Assessments – Monotherapy INCB057643 (Part 1 and Part 2; 
All Treatment Groups) ................................................................................................83 
Table 10: Schedule of Laboratory Assessments – Monotherapy INCB057643 (Part 1 
and Part 2; All Treatment Groups) .............................................................................85 
Table 11: Schedule of Assessments – Combination INCB057643 and Gemcitabine 
(Part 3 C-ES-TGA) .....................................................................................................87 
Table 12: Schedule of Laboratory Assessments – Combination INCB057643 and 
Gemcitabine (Part 3 C-ES-TGA) ................................................................................88 
Table 13: Schedule of Timed Pharmacokinetic Assessments – Combination 
INCB057643 and Gemcitabine (Part 3 C-ES-TGA) ..................................................89 
Table 14: Schedule of Assessments – Combination INCB057643 and Paclitaxel (Part 3 
C-ES-TGB) .................................................................................................................90 
Table 15: Schedule of Laboratory Assessments – Combination INCB057643 and 
Paclitaxel (Part 3 C-ES-TGB) ....................................................................................91 
Table 16: Schedule of Timed Pharmacokinetic Assessments – Combination 
INCB057643 and Paclitaxel (Part 3 C-ES-TGB) .......................................................92 
Table 17: Schedule of Assessments – Combination INCB057643 and Rucaparib 
(Part 3 C-ES-TGC and Part 4 C-EX-TGA) ................................................................93 
Table 18: Schedule of Laboratory Assessments – Combination INCB057643 and 
Rucaparib (Part 3 C-ES-TGC and Part 4 C-EX-TGA) ...............................................94 
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Table 19: Schedule of Timed Pharmacokinetic Assessments – Combination 
INCB057643 and Rucaparib (Part 3 C-ES-TGC and Part 4 C-EX-TGA) .................95 
Table 20: Schedule of Assessments – Combination INCB057643 and Abiraterone 
(Part 3 C-ES-TGD and Part 4 C-EX-TGB) ................................................................96 
Table 21: Schedule of Laboratory Assessments – Combination INCB057643 and 
Abiraterone (Part 3 C-ES-TGD and Part 4 C-EX-TGB) ............................................98 
Table 22: Schedule of Timed Pharmacokinetic Assessments – Combination 
INCB057643 and Abiraterone (Part 3 C-ES-TGD and Part 4 C-EX-TGB) ...............99 
Table 23: Schedule of Assessments – Combination INCB057643 and Ruxolitinib 
(Part 3 C-ES-TGE and Part 4 C-EX-TGC) ...............................................................100 
Table 24: Schedule of Laboratory Assessments – Combination INCB057643 and 
Ruxolitinib (Part 3 C-ES-TGE and Part 4 C-EX-TGC) ...........................................102 
Table 25: Schedule of Timed Pharmacokinetic Assessments – Combination 
INCB057643 and Ruxolitinib (Part 3 C-ES-TGE and Part 4 C-EX-TGC) ..............104 
Table 26: Schedule of Assessments – Combination INCB057643 and Azacitidine 
(Part 3 C-ES-TGF and Part 4 C-EX-TGD) ...............................................................105 
Table 27: Schedule of Laboratory Assessments – Combination INCB057643 and 
Azacitidine (Part 3 C-ES-TGF and Part 4 C-EX-TGD) ...........................................107 
Table 28: Schedule of Timed Pharmacokinetic Assessments – Combination 
INCB057643 and Azacitidine (Part 3 C-ES-TGF and Part 4 C-EX-TGD) ..............108 
Table 29: Schedule of Timed Translational/Pharmacodynamic Assessments – 
Combination INCB057643 and Azacitidine (Part 3 C-ES-TGF and Part 4 
C-EX-TGD) ..............................................................................................................109 
Table 30: Local Laboratory Tests:  Required Analytes ............................................................110 
Table 31: Required Analytes for Multiple Myeloma Subjects .................................................119 
Table 32: Probability of Dose Escalation by DLT Rate ...........................................................129 
Table 33: Criteria for Clinically Notable Vital Sign Abnormalities .........................................131 
Table 34: Criteria for Clinically Notable Electrocardiogram Abnormalities ...........................132 
 
LIST OF FIGURES 
Figure 1: 
Composite PK-PD Curve for Subjects in Study INCB 57643-101 (N = 67) .............47 
Figure 2: 
Part 1 and Part 2 Monotherapy Dose Escalation and Expansion Study Design .........64 
Figure 3: 
Part 3 Combination Dose Escalation Study Design ...................................................65 
Figure 4: 
Part 4 Combination Dose Expansion Study Design ...................................................66 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Explanation 
ADT 
androgen deprivation therapy 
AE 
adverse event 
Ae 
amount of drug excreted in urine over sampling interval 
AIDS 
acquired immunodeficiency syndrome 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AR 
androgen receptor 
AR-V7 
androgen receptor splice variant 7 
AST 
aspartate aminotransferase 
AUC 
area under the plasma or serum concentration-time curve 
AUC0-τ 
area under the steady-state plasma or serum 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) 
AUC0-t 
area under the single-dose plasma or serum concentration-time curve from 
Hour 0 to the last quantifiable measurable plasma concentration 
BCLU 
B-cell lymphoma, unclassifiable 
BD 
bromodomain 
BET 
bromodomain and extra-terminal 
BID 
twice daily 
BOR 
best overall response 
BRD 
bromodomain-containing protein 
BRDT 
bromodomain testis-specific protein 
Cave 
average steady-state plasma concentration 
CBC 
complete blood count 
C-ES 
combination dose escalation 
C-EX 
combination dose expansion 
CI 
confidence interval 
Cl/F 
oral dose clearance 
CLL 
chronic lymphocytic leukemia 
Clr 
renal clearance 
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Abbreviation 
Explanation 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
c-MYC 
cellular form of a regulator gene that can act as an oncogene (MYC) 
c-Myc 
transcription factor encoded by the c-MYC gene 
CNS 
central nervous system 
CR 
complete response/remission 
CRi 
complete response with incomplete recovery 
CRPC 
castration-resistant prostate cancer 
CT 
computed tomography 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CYP 
cytochrome P450 
CYP17 
17 α-hydroxylase/C17, 20-lyase 
DHEA 
dehydroepiandrosterone 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EBMT 
European Society for Blood and Marrow Transplantation 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EDC 
electronic data capture 
ELN 
European LeukemiaNet 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG 
[18F] fluorodeoxyglucose 
fe 
percent excreted in urine 
FISH 
fluorescence in situ hybridization 
FLAIR 
fluid-attenuated inversion recovery 
FLC 
free light chain 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
GLP 
Good Laboratory Practices 
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Abbreviation 
Explanation 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
Hgb 
hemoglobin 
HI 
hematological improvement 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HR-MDS 
high-risk myelodysplastic syndrome 
IB 
Investigator's Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL 
interleukin 
IN 
Investigator Notification 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IV 
intravenous 
IWG 
International Working Group 
IWG-MRT 
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment 
JAK 
Janus kinase 
L-DAC 
low-dose cytarabine 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LFT 
liver function test 
LOH 
loss of heterozygosity 
MCP 
methyl-accepting chemotaxis protein 
mCRPC 
metastatic castration-resistant prostate cancer 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MM 
multiple myeloma 
mOS 
median overall survival 
mPFS 
median progression-free survival 
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Abbreviation 
Explanation 
MPN 
myeloproliferative neoplasm 
MPN-SAF TSS 
Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom 
Score 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NF-ĸB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NHL 
non-Hodgkin's lymphoma 
NMC 
nuclear protein in testis midline carcinoma 
NSCLC 
non–small-cell lung cancer 
NTD 
nontolerated dose 
NUT 
nuclear protein in testis (gene) 
OAT 
organic anion transporter 
OATP 
organic anion transporter polypeptide 
OCT 
organic cation transporter 
ORR 
objective response rate 
OS 
overall survival 
PAD 
pharmacologically active dose 
PARP 
Poly (adenosine diphosphate-ribose) polymerase 
PCR 
polymerase chain reaction 
PCWG3 
Prostate Cancer Working Group 3 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PFS 
progression-free survival 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response/remission 
PRBC 
packed red blood cell 
PSA 
prostate-specific antigen 
PT 
prothrombin time 
QD 
once daily 
RANO 
Response Assessment in Neuro-Oncology 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria In Solid Tumors  
RNA 
ribonucleic acid 
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Abbreviation 
Explanation 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SC 
subcutaneous 
sCR 
stringent complete response 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
SOC 
standard of care 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
apparent plasma terminal phase disposition half-life 
TEAE 
treatment-emergent adverse event 
TGA 
Treatment Group A 
TGB 
Treatment Group B 
TGC 
Treatment Group C 
TGD 
Treatment Group D 
TGE 
Treatment Group E 
TGF 
Treatment Group F 
Tmax 
time to maximum plasma concentration 
ULN 
upper limit of normal  
USPI 
United States Prescribing Information 
VGPR 
very good partial response 
Vz/F 
apparent oral dose volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
λz 
apparent terminal-phase disposition rate constant 
 
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1. 
INTRODUCTION 
INCB 57643-101 is a 2-part, open-label, dose-escalation/dose-expansion study evaluating 
INCB057643 in subjects with advanced malignancies.  Part 1 of the study will determine the 
maximum tolerated dose (MTD) of INCB057643 in 3 disease-specific treatment groups.  Part 2 
will evaluate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics 
(PD) of the treatment group−specific dose selected in Part 1 in tumor types postulated to be 
particularly susceptible to inhibition of bromodomain and extra-terminal (BET) proteins.  Part 3 
will determine the MTD and recommended Phase 2 dose (RP2D) of INCB057643 in 
combination with select standard of care (SOC) agents across 6 disease-specific treatment 
groups.  Part 4 will further evaluate the safety, preliminary efficacy, and PK of the treatment 
group combination of the RP2D identified in Part 3 for select tumor types. 
1.1. 
Background 
Central to the evolution of neoplastic cells is a changing pattern of gene expression that 
distinguishes cancer cells from their normal counterparts.  Activation of transcription factors that 
regulate oncogenic processes, including c-Myc and nuclear factor κB (NF-κB), is frequently 
observed in human cancers; however, direct targeting of these proteins has remained elusive.  
Gene expression is also regulated at the level of chromatin by covalent modifications, including 
histone acetylation and methylation, which specify an "epigenetic code" that regulates the 
interactions of DNA-binding proteins, nucleosome remodeling complexes, and transcriptional 
regulators with chromatin (Portela et al 2010).  In malignant cells, aberrant changes in epigenetic 
patterns translate to altered transcriptional profiles.  In many cases, these altered epigenetic 
patterns arise from mutations in genes encoding epigenetic regulator proteins, and mutant 
epigenetic proteins can be bona fide oncogenes (You and Jones 2012).  Thus genetic and 
epigenetic mechanisms cooperate to promote the development and progression of cancer.  A key 
step in translating the epigenetic code is the recognition of modified histone residues by effector 
proteins that harbor specific interaction domains. 
The BET family of proteins consists of 4 members (bromodomain-containing protein [BRD]2, 
BRD3, BRD4, and bromodomain testis-specific protein [BRDT]) that each have 2 bromodomain 
(BD) modules (BD1 and BD2).  These BDs exhibit high selectivity for acetylated lysine residues 
in histones and other proteins.  The human genome encodes 61 distinct BDs, but the BET protein 
modules BD1 and BD2 are distinguishable from other BDs by their higher affinity for 
di-acetylated lysine motifs (Filippakopoulos and Knapp 2014).  Bromodomain testis-specific 
protein is restricted to germ cells; however, BRD2, BRD3, and BRD4 are ubiquitously 
expressed.  The BET proteins function as transcriptional regulators by binding to acetylation 
marks in chromatin at gene promoter and enhancer elements and recruiting transcription 
initiation and elongation complexes such as Mediator, polymerase-associated factor complex, 
and super elongation complex (Wu and Chiang 2007, Dawson et al 2011).  Thus, for many gene 
promoters and enhancers, BET proteins play a crucial role in linking acetylated chromatin marks 
to transcriptional activation. 
Although BET proteins are found to be associated with thousands of gene promoters and 
enhancers in the genome, functional studies have revealed that only a subset of these genes are 
significantly regulated by BET proteins.  These genes are transcriptionally controlled by "super 
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enhancers" that are notable for a high density of BRD4 binding.  Many super-enhancer–regulated 
genes contribute to the development of neoplastic behavior either directly or as a result of 
chromosomal translocation that leads to dysregulated expression of oncogenes from these 
elements, such as in the case of the t(8,14) translocation in multiple myeloma (MM) and Burkitt's 
lymphoma where c-MYC is fused to the immunoglobin heavy chain enhancer.  Transcriptional 
profiling data show that BRD4-dependent genes include many highly regulated genes involved 
in cell proliferation, differentiation, and survival; however, BRD4 does not regulate expression 
of constitutively expressed housekeeping genes (Mochizuki et al 2008, Delmore et al 2011).  In 
view of the critical role of BET in regulating expression of cell fate-determining and cell 
cycle-associated genes, targeted inhibition of BET proteins may have selective pharmacological 
effects on cancer cells. 
The carcinogenic role of the BET protein family is exemplified by a highly malignant, but rare, 
form of epithelial neoplasia called nuclear protein in testis (NUT) midline carcinoma (NMC) in 
which a recurrent translocation of BRD3 or BRD4 with NUT creates a novel fusion oncogene, 
BRD-NUT (French et al 2008).  NUT midline carcinoma is characterized by proliferation of 
undifferentiated epithelial cells resulting from aberrant transcriptional regulation by the mutant 
oncoprotein (Yan et al 2011).  Treatment with the BET-selective inhibitor JQ-1 displaces 
BRD-NUT from chromatin in patient-derived NMC cells, restores terminal squamous cell 
differentiation in vitro, and provides tumor growth suppression in vivo (Filippakopoulos 
et al 2010).  These data support the idea that altered gene transcription associated with BET 
activity in cancer cells is reversible and provide validation that BET protein inhibition can be 
efficacious against malignant cells. 
In preclinical studies, BET inhibitors have demonstrated efficacy across a wide range of 
hematologic cancer and solid tumor models.  Tumor types associated with dysregulation of 
transcription factors appear to be highly responsive to BET inhibition.  For example, androgen 
receptor (AR)–dependent prostate cancer cells are highly sensitive to JQ-1 treatment compared 
with prostate cell lines without androgen dependence (Wyce et al 2013, Asangani et al 2014).  
Bromodomain-containing protein 4 was shown to directly regulate transcriptional activity of AR, 
and JQ-1 treatment dissociated AR binding from chromatin leading to downregulation of AR 
target genes and inhibition of cell growth.  These data suggest that combining BET inhibitors 
with anti-androgens has the potential to suppress AR dependent activity by distinct mechanisms 
and can counteract mutants such as androgen receptor splice variant 7 (AR-V7) that are resistant 
to AR blockade (Asangani et al 2014).  Furthermore, experiments using patient-derived cells 
from tumors associated with activation of the Hedgehog-GLI1 pathway shows that BET 
inhibition reduces growth and downregulates GLI target genes (Tang et al 2014).  Finally, the 
c-MYC oncogene is upregulated in many cancers secondarily (such as in carcinomas of the 
breast, colon, cervix, and lung) or directly through chromosomal translocations (such as in MM 
and double-hit and Burkitt's lymphomas).  In preclinical models of MYC-dependent neoplasms 
including KRAS-mutant lung, aggressive lymphoma, acute myeloid leukemia (AML), and 
t(8;14) MM, BET inhibition was shown to be efficacious in vivo (Shimamura et al 2013, 
Delmore et al 2011).  In a model of AML, combination of a BET inhibitor with the epigenetic 
cancer agent 5-azacytidine was shown to suppress tumor growth greater than individual agents.  
Another example is Ewing's sarcoma, where expression of fusion transcription factors caused by 
the translocation of EWS and ETS genes results in global epigenetic reprogramming.  These 
changes are associated with the expression of an oncogenic program that characterizes Ewing's 
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sarcoma.  Treatment of Ewing cell lines with BET inhibitors was shown to block EWS-ETS 
dependent transcription and to reduce the growth of these cells and tumors in vitro and in vivo 
(Hensel et al 2016).  These data suggest a therapeutic role for BET inhibitors across a wide range 
of cancers and demonstrate that neoplasms derived from aberrant activity of lineage-determining 
transcription factors may be particularly responsive.  
Preclinical studies also showed that BET inhibitors acted synergistically with poly (adenosine 
diphosphate-ribose) polymerase (PARP) inhibitor in homologous recombination–proficient 
cancer cells through BET inhibitor–induced reduction of homologous recombination function 
and enhanced PARP inhibitor–induced DNA damage in cancer cells (Yang et al 2017).  
Bromodomain and extra-terminal inhibitors were shown to impair the transcription of BRCA1 
and RAD51, which are essential for the homologous recombination function, and to sensitize 
homologous recombination–proficient tumors, such as breast and ovarian cancers, to poly 
(adenosine diphosphate-ribose) polymerase (PARP) inhibition.  
Finally, targeting BET proteins may have effects beyond direct inhibition of malignant cell 
growth.  Bromodomain-containing protein 2, BRD3, and BRD4 have been shown to be critical 
for regulating the inflammatory response in several model systems (Belkina et al 2013).  
Bromodomain and extra-terminal inhibitors exhibited a protective effect in vivo against 
endotoxic shock by reducing the global inflammatory response (Nicodeme et al 2010).  
Mechanistically, BRD4 has been shown to facilitate transcription by the NF-κB complex 
(Huang et al 2009).  In lymphoma cells characterized by NF-κB pathway activation, BET 
inhibition reduces the NF-κB transcriptional signature, including proinflammatory genes 
interleukin (IL)-6 and IL-10 (Ceribelli et al 2014).  These studies demonstrate the potential for 
BET inhibition in reducing the inflammatory response.  Tumor-associated inflammation is a 
hallmark of cancer, and elevated levels of proinflammatory proteins, including IL-6, have been 
shown to promote multiple aspects of tumorigenesis (Landskron et al 2014).  Thus, antitumor 
activity of BET inhibitors may result from modulation of inflammation in addition to direct 
effects on the tumor cell.  These data warrant evaluation of BET inhibitors in malignancies 
characterized by underlying inflammation, such as myeloproliferative neoplasms (MPNs), 
including primary myelofibrosis (MF).  Combination of the Janus kinase (JAK) inhibitor 
ruxolitinib with BET inhibitors is synergistic in models of JAK2V617F positive post-MPN 
secondary AML, in part, through greater suppression of signal transducer and activator of 
transcription (STAT)-dependent signaling pathways. 
In summary, inhibition of BET protein activity either alone or in combination with SOC agents 
may have therapeutic utility in diseases such as cancer, where altered expression of growth-
promoting, proinflammatory, and survival genes contributes to the establishment and persistence 
of the oncogenic phenotype. 
1.2. 
Overview of INCB057643 
1.2.1. 
Nonclinical Pharmacology of INCB057643 
In vitro, INCB057643 inhibited binding of BET proteins to acetylated histone H4 peptide.  The 
IC50 values for BRD4BD1 and BRD4BD2 are 39 ± 6 and 6 ± 1 nM (mean ± SD), respectively.  
INCB057643 also inhibited BRD2, BRD3, and with lower potency, BRDT, in biochemical 
assays.  When evaluated against 32 distinct BDs from 25 human proteins, INCB057643 
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exhibited selectivity for BET family BDs.  In cellular assays, INCB057643 suppressed the 
c-MYC protein, a BRD4 target, in KMS12BM MM cells, with an IC50 value of 111 ± 41 nM.  
Many cancer cells derived from hematologic malignancies showed sensitivity to INCB057643 in 
viability assays, and cells treated with INCB057643 exhibited G1 cell cycle arrest and, in some 
examples, apoptotic cell death.  Multiple myeloma and AML cell lines showed the greatest 
sensitivity, in general, with IC50 values for growth inhibition generally < 200 nM.  In contrast, 
INCB057643 inhibited the proliferation of IL-2–stimulated T cells from normal donors with a 
potency of 494 ± 118 nM (mean ± SD).  The growth of a number of solid tumor cell lines from 
colon, lung, and breast cancer were also inhibited by INCB057643.  In an assay to estimate 
potency in the presence of human serum proteins, INCB057643 suppressed c-Myc protein levels 
in myeloma cells spiked into human whole blood, with an IC50 value of 55 nM.  INCB057643 
also suppressed the induction of endogenous methyl-accepting chemotaxis protein (MCP)-1 and 
MCP-3 from human whole blood that was stimulated ex vivo with lipopolysaccharide.  The IC50 
values of 40 nM and 39 nM for MCP-1 and MCP-3, respectively, are similar to the c-Myc whole 
blood IC50 value.  These data demonstrate that INCB057643 inhibits BET proteins in vitro and in 
cellular assays, and that inhibition of BET proteins results in the arrest and, in some models, 
death of cancer cells. 
In vivo, INCB057643 inhibited the growth of several tumor models in mice at tolerated, oral 
doses.  In the MM1.S model of MM, a single dose of INCB057643 suppressed c-Myc protein 
levels in tumor cells in a dose-dependent manner.  Tumor PK-PD analysis revealed an in vivo 
IC50 value of 367 nM for c-Myc suppression in the MM1.S MM model.  The growth of 
established human tumors was suppressed significantly by INCB057643 when administered as a 
single agent in the MM1.S MM, MOLM-16 AML, WILL2 lymphoma, H526 SCLC, and RKO 
colon cancer subcutaneous (SC) xenograft models in immunocompromised mice at 3 mg/kg to 
20 mg/kg administered once daily (QD) or 1 mg/kg to 3 mg/kg administered twice daily (BID) 
orally.  Pharmacokinetic-efficacy analyses suggested that maximum tumor growth inhibition was 
observed when plasma levels of INCB057643 exceeded the in vivo IC50 for nearly 12 hours.  
Refer to the Investigator's Brochure (IB) for additional details. 
1.2.2. 
Nonclinical Drug Metabolism and Pharmacokinetics of INCB057643 
The absorption, distribution, metabolism, and excretion of INCB057643 have been characterized 
in rats, dogs, and monkeys.  Following intravenous (IV) administration, the systemic clearance 
was moderate in rats (36% hepatic blood flow) and low in dogs and monkeys (4.1% and 13% of 
hepatic blood flow, respectively).  The steady-state volume of distribution was moderate in rats 
and monkeys (2.6 and 2.8 L/kg, respectively), but low in dogs (0.66 L/kg).  The terminal 
elimination half-life was moderate, estimated to be approximately 4.3 hours in rats, 7.1 hours in 
dogs, and 7.0 hours in monkeys.  INCB057643 has low to moderate renal excretion; the 
administered dose excreted in urine as parent varied from 12.5% in monkeys, to 17.6% in rats 
and 26.1% in dogs.  After oral administration, oral bioavailability was low in dogs (21%), but 
moderate in rats (58%) and monkeys (39%-78%).  Based on 2-species allometric scaling from 
rats and monkeys, the terminal elimination half-life in humans is projected to be approximately 
17 hours, and the oral bioavailability is projected to be approximately 40%.  At a clinical dose of 
12 mg QD, which is expected to provide plasma concentration exceeding IC50 (55 nM based on 
whole blood c-Myc inhibition) for 12 hours, the total steady-state plasma AUC0-24 and Cmax are 
estimated to be approximately 1.5 μM∙h and 0.1 µM, respectively. 
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INCB057643 exhibits low in vitro permeability across Caco-2 monolayers and low aqueous 
solubility.  In vitro transport studies indicate that INCB057643 is a substrate of both 
P-glycoprotein and breast cancer resistant protein efflux transporters, and neither efflux 
transporter was saturated up to 300 µM.  INCB057643 has limited penetration across the rat 
blood-brain barrier (BBB), with a steady-state brain to plasma concentration ratio of 0.11.  
In vitro human protein binding of INCB057643 was low (unbound fraction of 49.1%), similar to 
that in preclinical species. 
The interactions of INCB057643 with uptake and efflux transporters were evaluated using 
in vitro systems.  Though INCB057643 is a moderate inhibitor of P glycoprotein, organic cation 
transporter (OCT)2, organic anion transporter (OAT)3, organic anion transporter polypeptide 
(OATP)1B3, and OATP1B1, no drug-drug interactions are expected based on the projected 
steady-state human plasma Cmax and concentrations in the gut.  Reaction phenotyping using 
recombinant human cytochrome P450s (CYPs) indicated that INCB057643 was primarily 
metabolized by CYP3A4/5, and therefore, it is possible that the PK of INCB057643 might be 
affected by coadministration of potent CYP3A4 inhibitors or inducers.  INCB057643 is not an 
inhibitor of the major CYPs evaluated.  The metabolism profiles of INCB057643 in rat, monkey, 
and human in vitro liver preparations were qualitatively similar.  Analysis of plasma samples 
identified M3 (INCB070378) to be a major metabolite in rats and M2 (INCB057228) to be a 
major metabolite in monkeys in vivo.  There was no evidence of a human-specific metabolite.  
Metabolite M2 (INCB057228) is an active metabolite with an IC50 of 29 nM (whole blood 
c-MYC inhibition) while M3 (INCB070378) was not active.  The metabolites observed in vitro 
in human liver microsomes were also observed in vivo in preclinical species.  No glutathione 
adducts were detected upon incubation of INCB057643 in human liver microsomes, suggesting 
that INCB057643 does not generate any reactive metabolites.  Refer to the IB for additional 
details. 
1.3. 
Overview of Standard-of-Care Agents Selected For Combination 
Therapies 
1.3.1. 
Overview of Gemcitabine in Solid Tumors Including Ovarian Cancer 
Gemcitabine is a nucleoside metabolic inhibitor that kills cells undergoing DNA synthesis and 
blocks the progression of cells through the G1/S-phase boundary, and it is currently approved in 
the United States and in the European Union to treat breast cancer, non–small-cell lung cancer 
(NSCLC), ovarian cancer, and pancreatic cancer either alone or in combination with other 
chemotherapy agents. 
As a single agent, gemcitabine, as a salvage treatment for platinum refractory ovarian cancer, has 
been extensively evaluated at doses ranging from 800 to 1250 mg/m² administered as a 
30-minute infusion on Days 1, 8, and 15 of a 28-day cycle.  Using this dose and schedule, the 
most frequently occurring dose-limiting toxicities (DLTs) associated with gemcitabine treatment 
are hematologic, with neutropenia occurring more often than thrombocytopenia, are not 
cumulative, and can be managed with dose reductions and/or dose interruptions.  Overall 
response rates varied from 14% to 22%, with an average of 16.5% across the all series with 
gemcitabine as salvage chemotherapy in mostly platinum-resistant or refractory ovarian cancer 
patients (some subjects had prior exposure to paclitaxel; Lorusso et al 2006).  In a randomized 
Phase III study in subjects with platinum-resistant ovarian cancer (who progressed within 
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6 months of platinum-based therapy in the primary setting) comparing gemcitabine 
(1000 mg/m2, Days 1 and 8 every 21 days) with Doxil® (liposomal doxorubicin; 50 mg/m2, 
Day 1 every 28 days), median progression-free survival (mPFS) was 3.6 m versus 3.1 m, median 
overall survival (mOS) was 12.7m versus 13.5m, and objective response rate (ORR; in subjects 
with measurable disease) was 9.2% versus 11.7%, respectively.  There was no statistically 
significant difference between the 2 treatments.  The gemcitabine group experienced 
significantly more constipation, nausea/vomiting, fatigue, and neutropenia, and the doxorubicin 
group experienced significantly more hand-foot syndrome and mucositis (Mutch et al 2007).  
Single-agent gemcitabine has also been studied in lung cancer (Zatloukal et al 1998, 
Pérol et al 2012) and is one of the recommended single agents in the setting of treatment-
refractory or resistant advanced or metastatic diseases (NCCN Guidelines). 
1.3.2. 
Overview of Paclitaxel in Solid Tumors Including Ovarian Cancer 
Paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from tubulin 
dimers and stabilizes microtubules by preventing depolymerization.  This stabilization results in 
the inhibition of the normal dynamic reorganization of the microtubule network that is essential 
for vital interphase and mitotic cellular functions.  Paclitaxel induces abnormal arrays or 
"bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during 
mitosis, and as a result, induced cell death.  It is currently approved in the United States and in 
the European Union to treat ovarian, metastatic breast cancer, locally advanced NSCLC and 
AIDS-related Kaposi's sarcoma. 
Paclitaxel may be administered as single agent for patients who have Stage III/IV ovarian cancer 
with a recurrence within 6 months from initial or subsequent complete response from a platinum-
containing chemotherapy [platinum-resistant] (Grabosch et al 2017, NCCN Guidelines).  In a 
randomized Phase III study (AURELIA) comparing bevacizumab combined with chemotherapy 
versus chemotherapy alone (investigator's choice among pegylated liposomal doxorubicin, 
weekly paclitaxel, or topotecan) in platinum-resistant recurrent ovarian cancer (excluding 
platinum-refractory disease), there was a statistically significant improvement in overall mPFS 
(6.7 m vs 3.4 m, hazard ratio = 0.48 [95% confidence interval (CI), 0.38 to 0.60]), unstratified 
log-rank p < 0.001), in mPFS of the paclitaxel cohort (Avastin® plus paclitaxel vs paclitaxel 
alone; 10.4 m vs 3.9 m, hazard ratio = 0.46), and in Response Evaluation Criteria in Solid 
Tumors (RECIST) ORR (27.3% vs 11.8% [p = 0.001]) and in ORR of the paclitaxel cohort 
(Avastin plus paclitaxel vs paclitaxel alone, 53.3% vs 30.2%) but no statistically significant 
improvement in mOS (16.6 m vs 13.3 m hazard ratio = 0.85 [95% CI, 0.66 to 1.08], p < 0.174; 
the study was not designed to formally compare overall survival [OS]).  The only subgroup to 
approach a statistically significant improvement in OS was Avastin plus weekly paclitaxel in an 
exploratory analysis (unadjusted hazard ratio = 0.65 [95% CI, 0.42 to 1.02]; 22.4 m vs 13.2 m; 
Poveda et al 2015).  Paclitaxel (175-200 mg/m2 on Day 1 of every 3 weeks or 60-80 mg/m2 on 
Day 1 of each week) has been studied in platinum-resistant ovarian cancer (Gynecologic 
Oncology Group et al 2006, Pignata et al 2015, Elit and Hirte 2013), breast (Siedman et al 1995, 
Perez et al 2001), and lung cancers (Lilenbaum et al 2005, Ceresoli et al 2004, 
Yasuda et al 2004), and is one of the recommended single agents in the setting of treatment-
refractory or resistant advanced or metastatic diseases (NCCN Guidelines). 
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1.3.3. 
Overview of Rucaparib in Ovarian Cancer 
Rucaparib is a PARP inhibitor indicated as a monotherapy for the treatment of patients with 
deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who 
have been treated with 2 or more chemotherapies.  It is currently approved in the United States 
under an accelerated approval based on ORR and duration of response (DOR) to treat advanced 
ovarian cancer with BRCA mutation.   
In 2 multicenter, single-arm, open-label clinical studies in advanced ovarian cancer patients with 
BRCA mutation who had progressed after 2 or more prior chemotherapies, 106 subjects received 
rucaparib 600 mg orally BID.  Investigator-assessed ORR was 54% (57/106; 95% CI, 44% to 
64%).  Median DOR for the 57 responders was 9.2 months (95% CI, 6.6 to 11.6 months).  
Objective response rate was 66% (52/79; 95% CI, 54% to 76%) in platinum-sensitive subjects, 
25% (5/20; 95% CI, 9% to 49%) in platinum-resistant subjects, and 0% (0/7; 95% CI, 0% to 
41%) in platinum-refractory subjects.  Objective response rate was similar for subjects with a 
BRCA1 gene mutation or a BRCA2 gene mutation (Rubraca 2017). 
Rucaparib has also been evaluated in platinum-sensitive ovarian cancer patients with BRCA wild 
type but genomic loss of heterozygosity (LOH) that may be a surrogate for homologous repair 
deficiency.  Patients with BRCA wild type but LOH-high tumors showed improved PFS 
compared with BRCA wild type but LOH-low tumors suggesting potential clinical benefit to 
ovarian cancer patients with homologous repair deficiency in the absence of BRCA mutations.  
Rucaparib is also being investigated in the maintenance setting in patients with relapsed ovarian 
cancer with or without mutations in BRCA genes. 
The recommended dose and schedule for rucaparib in patients with ovarian cancer BRCA 
mutation is 600 mg BID PO with or without food.  This oral agent is prepared as 200, 250, and 
300 mg tablets. 
1.3.4. 
Overview of Abiraterone in Metastatic Castration-Resistant Prostate Cancer 
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that 
inhibits 17 α-hydroxylase/C17, 20-lyase (CYP17).  CYP17 is normally expressed in testicular, 
adrenal, and prostatic tissue and is required for androgen biosynthesis, and also expression in 
prostatic tumor tissue and metastatic lesions from castration-resistant prostate cancer (CRPC; 
Efstathiou et al 2012).  CYP17 catalyzes 2 sequential reactions:  1) the conversion of 
pregnenolone and progesterone to their 17α-hydroxyl derivatives by 17αhydroxylase activity and 
2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, 
respectively, by C17, 20 lysate activity.  DHEA and androstenedione are androgens and are 
precursors of testosterone.  CYP17A is a rational target to address persistent androgen synthesis 
and expression of prostate-specific antigen (PSA) and AR in CRPC following androgen 
deprivation therapy (ADT) (Page et al 2006, Mostaghel et al 2008).  Inhibition of CYP17 by 
abiraterone can also result in increased mineralocorticoid production by the adrenals, resulting in 
toxicities such as hypokalemia, hypertension, and fluid retention (Auchus et al 2014).  It is 
currently approved in the United States and in the European Union to treat metastatic castrate 
resistant prostate cancer.   
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1.3.5. 
Overview of Azacitidine in Acute Myeloid Leukemia and Myelodysplastic 
Syndrome 
Azacitidine is a nucleoside metabolic inhibitor that is approved in the United States and in the 
European Union for the treatment of patients with several different subtypes of myelodysplastic 
syndrome (MDS).  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 who 
are ≥ 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 subjects aged ≥ 65 years with 
newly diagnosed AML with > 30% bone marrow blasts.  Median OS was improved (10.4 m vs 
6.5 m, hazard ratio = 0.85, p = 0.10009) but did not reach statistical significance.  Median OS did 
reach statistical significance (12.1 m vs 6.9 m, hazard ratio =0.76, p = 0.019), however, when the 
subjects were censored at the start of subsequent AML therapy by prespecified sensitivity 
analysis.  Also, subjects with poor-risk cytogenetics (hazard ratio = 0.68) and with 
myelodysplasia-related changes (hazard ratio = 0.69) benefited significantly from azacitidine.  
Even though the study was not powered to compare azacitidine with individual conventional 
therapy, the OS of subjects treated with azacitidine or L-DAC (n = 154 vs n = 158, respectively) 
did not differ significantly, and comparable survival rates were also observed comparing 
azacitidine with standard induction therapy (n = 43 vs n = 44, respectively).  Azacitidine is 
superior to best supportive care by post hoc analysis; azacitidine achieved a complete response 
(CR) of 19.5% vs 21.9% when compared with conventional therapies (CR/CRi was 27.8% vs 
25.1%).  The most common treatment-emergent adverse events (TEAEs) ≥ Grade 3 occurring in 
≥ 20% of subjects in the azacitidine arm were febrile neutropenia, neutropenia, 
thrombocytopenia, pneumonia, and anemia.  Although there has been limited investigation into 
the use of azacitidine in relapsed/refractory AML, Al-Ali et al (2012) reported a 10% ORR 
(including hematologic improvement) in subjects who were resistant to primary chemotherapy.   
1.3.6. 
Overview of Ruxolitinib in Myelofibrosis 
Ruxolitinib, a potent and selective inhibitor of JAKs 1 and 2, is approved in the United States 
and in the European Union for use in patients with intermediate- or high-risk MF, including 
primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential 
thrombocythemia myelofibrosis.  Registration studies showed improvement in spleen size, 
symptom burden, and OS with ruxolitinib use in this patient population (Cervantes et al 2013, 
Harrison et al 2012, Mesa et al 2013a, Mesa et al 2013b, Vannucchi et al 2015, Verstovsek 
et al 2012, Verstovsek et al 2013).  
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 to 
17 months).  The majority of subjects (55.8%) were treated for at least 9 months.  The most 
frequently reported adverse events (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 
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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. 
Study Rationale 
INCB057643 is an oral BET protein inhibitor that is being developed for the treatment of 
advanced malignancies.  The BET family of BRDs functions as transcriptional regulators 
binding to acetylation marks in chromatin at gene promoter and enhancer elements and recruiting 
transcription initiation and elongation complexes.  In tumor cells, aberrant patterns of epigenetic 
marks including acetylation underlie abnormal transcriptional regulation of genes involved in 
cellular proliferation, survival, differentiation, and migration, thereby promoting an oncogenic 
program.  Bromodomain and extra-terminal proteins are essential for the transcription of many of 
these genes; thus, inhibition of BET binding to chromatin may suppress oncogenic transcription 
in cancer cells.  Suppression of these oncogenic factors has the potential to inhibit the growth of 
a variety of tumor cell types and may be efficacious in the treatment of advanced malignancies.  
Thus, study subjects with advanced cancer and no proven treatment options are candidates for 
this study to determine preliminary safety and efficacy of INCB057643.  Furthermore, 
biochemical, tumor biomarker, and preclinical pharmacology studies have revealed that 
BET-inhibition may be useful in the treatment of a broad array of cancers, particularly those 
associated with activation of MYC, sonic hedgehog, and RAS pathways, among others.  
Preclinical data using INCB057643 as an inhibitor have demonstrated efficacy in several 
histologic subtypes with activation of these pathways, including lymphomas with c-Myc 
dysfunction, MM, AML, small cell lung cancer, high-grade serous ovarian cancer, and colorectal 
cancer (refer to the IB for additional details).  Part 2 of the study will evaluate the safety, 
tolerability, and activity of INCB057643 administered as a single agent in a subset of solid 
tumors and hematologic malignancies that tend to be associated with these oncogenic profiles.  
1.4.1. 
Rationale for Combining INCB57643 With Gemcitabine and Paclitaxel in 
Ovarian Cancer 
Currently, ovarian cancer patients with Stage III/IV disease who have a recurrence < 6 months 
after first-line platinum-containing chemotherapy are considered platinum resistant and may be 
treated with second-line chemotherapy agents such as liposomal doxorubicin, gemcitabine, and 
paclitaxel, with or without Avastin (NCCN Guidelines).  Approximately 40% of patients are 
currently not being treated/ineligible to receive Avastin in this setting.  After a finite number of 
recurrences, most patients, including those with initial platinum-sensitive diseases, will develop 
platinum-resistant disease with a poor prognosis and die as a result of their disease.  There is an 
urgent unmet medical need to identify additional agents such as INCB057643 to either enhance 
or create a synergistic effect with SOC agents such as gemcitabine and paclitaxel in platinum-
resistant ovarian cancer.  
 
 
 
 
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1.4.2. 
Rationale for Combining INCB57643 With Rucaparib in Ovarian Cancer 
Poly (adenosine diphosphate-ribose) polymerase inhibitors, including rucaparib and olaparib, 
have been approved as monotherapy for treatment of advanced ovarian cancer with BRCA1/2 
mutations (Lord and Ashworth 2017).  Poly (adenosine diphosphate-ribose) polymerase proteins 
are involved in many aspects of gene transcription and DNA repair, including base excision 
repair; inhibition of PARP enzymatic activity by small molecules results in the generation of 
double-stranded DNA breaks that are normally repaired by the homologous recombination 
pathway (Konstantinopoulos et al 2015).  Cells with homologous recombination deficiency, such 
as through BRCA1/2 inactivation, are unable to repair these lesions and undergo cell death in the 
presence of a PARP inhibitor.  Therefore, PARP inhibitors exhibit synthetic lethality in 
homologous recombination–deficient tumors. 
In high-grade serous ovarian cancer, approximately 50% of tumors have genetic defects in 
homologous recombination.  However, a large fraction of patients remain homologous 
recombination–proficient, and treatment-emergent mechanisms of resistance to PARP inhibitors 
include reversion of BRCA1/2 mutations to restore homologous recombination function 
(Konstantinopoulos et al 2015).  Therefore, strategies to block homologous recombination 
function could sensitize de novo or acquired resistant tumors to PARP inhibition.  Bromodomain 
and extra-terminal inhibitors were found to synergize with PARP inhibitors in an unbiased 
chemical library screen (Yang et al 2017).  Ribonucleic acid sequencing analysis revealed that 
the BET inhibitor decreased the expression of BRCA1 and RAD51, 2 essential genes in the 
homologous recombination pathway.  Functional studies showed that the BET inhibition 
decreased homologous recombination–mediated repair of double-stranded DNA breaks upon 
treatment of homologous recombination–proficient cells with a PARP inhibitor, resulting in 
suppressed colony formation in vitro.  The combination of BET inhibitor and PARP inhibitor 
exhibited greater tumor growth inhibition than either single agent in xenograft models of 
homologous recombination–proficient ovarian and breast cancers.  Therefore, BET inhibition 
creates a BRCAness phenotype in homologous recombination–proficient cancer cells and 
sensitizes them to PARP inhibition.  Independent synergy between the Incyte BET inhibitor 
INCB054329 and olaparib was demonstrated in homologous recombination–proficient ovarian 
cancer cell lines and in a xenograft model of SKOV3 ovarian cancer tumors that provides further 
support for this mechanism (Wilson et al 2017).  In addition, the combination of BET inhibitor 
and PARP inhibitor also demonstrated synergy in tumor growth inhibition in homologous 
recombination–deficient ovarian cancer models (Yang et al 2017). 
1.4.3. 
Rationale for Combining INCB57643 With Abiraterone in Castration-Resistant 
Prostate Cancer 
The clinical importance of ongoing AR pathway activity in CRPC progression is reflected in the 
rising serum PSA levels in patients with CRPC following ADT and is confirmed by clinical 
responses to treatment strategies that target residual AR axis activity in CRPC with next 
generation anti-androgen therapies including abiraterone and enzalutamide (Ryan et al 2015).  
However, not all CRPC patients respond to abiraterone or enzalutamide (20%-30% of patients 
are unresponsive to both agents up front), and most responders develop resistance with a widely 
variable DOR (20%-30% have transient responses of 2-3 months).  Several resistance 
mechanisms have been hypothesized, including activated AR signaling axis, such as AR splice 
variants, up-regulation of CYP17A1, up-regulation of full-length AR, AR activation by 
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noncanonical ligands, treatment-emergent neuroendocrine differentiation/small-cell phenotype 
often associated with the N-MYC amplification, and impaired DNA damage repair 
pathway/BRCA2 and ATM mutations (Giacinti et al 2014, Bubley and Balk 2017).  Several of 
these resistant mechanisms have been show to provide cross-resistance, such as up-regulation of 
CYP17, up-regulation of AR, and de novo or treatment-emergent AR splice variants 
(Antonarakis et al 2014).  As a result, the responses to the second-line treatment of CRPC with 
abiraterone following progression on first-line enzalutamide, or vice versa, were usually poor 
(Chandrasekar et al 2015).  Bromodomain and extra-terminal inhibitors, including INCB057643, 
have been shown to inhibit AR signaling pathways through multiple mechanisms and are active 
in enzalutamide- and abiraterone-resistant models (Section 1.1).  Therefore, it is hypothesized 
that INCB057643 in combination with abiraterone will overcome and/or prevent enzalutamide- 
and abiraterone-induced resistance mechanisms.  
1.4.4. 
Rationale for Combining INCB57643 With Ruxolitinib in Myelofibrosis 
Despite statistically significant improvements in signs and symptoms of MF and OS rates, 
ruxolitinib monotherapy, when compared with either placebo or best available therapy 
demonstrated in the registration studies, fails to provide adequate and/or sustained response for 
some subjects.  A subgroup analysis of the Controlled Myelofibrosis Study With Oral JAK 
Inhibitor Treatment I (COMFORT-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 benefitted 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 primary drivers 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.  
Bromodomain and extra-terminal inhibitors including INCB057643 have been shown to inhibit 
the JAK/STAT pathway and the inflammatory pathway (see Section 1.1).  It is hypothesized that 
INCB057643 in combination with ruxolitinib will enhance both disease and symptom control 
compared with ruxolitinib alone. 
1.4.5. 
Rationale for Combining INCB57643 With Azacitidine in Acute Myeloid 
Leukemia/High-Risk Myelodysplastic Syndrome 
For relapsed or refractory AML and HR-MDS, azacitidine is often used as a less aggressive 
salvage therapy option.  For newly diagnosed AML in patients aged ≥ 65 years old, azacitidine is 
recommended as a low-intensity induction therapy, primarily in those who are unfit for high- or 
intermediate-intensity regimens (see Section 1.3.5, NCCN Guidelines).  However, in both 
disease populations, the clinical responses (CR/CRi) and their DORs were limited with the 
CR + CRi rate < 30% and mOS < 10 m, and, as such, new approaches are urgently needed.  
Bromodomain and extra-terminal inhibitors including INCB057643 have been shown to be 
active in de novo and secondary AML and MDS models (see Section 1.1).  It is hypothesized 
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that the combination of INCB57643 with azacitidine will be able to achieve better clinical 
efficacy in order to increase clinical remission rate and duration and OS. 
1.5. 
INCB057643 Safety and Potential Risks 
1.5.1. 
Preclinical Safety and Risks 
The toxicity of INCB057643 was evaluated in 28-day and 3-month GLP studies in 
Sprague Dawley rats and cynomolgus monkeys.  Doses for the pivotal GLP studies were selected 
based on results of range-finding studies and prior experience with other BET inhibitors. 
In rat studies, target organs of toxicity based on microscopic findings included lymphoid organs, 
bone/bone marrow, stomach/gastrointestinal (GI) tract, lungs, and reproductive tract.  All 
findings were reversible.  All of these findings were considered to be related to the 
pharmacologic activity of INCB057643 (ie, there were no off-target toxicities). 
The 28-day monkey study did not result in any adverse effects at any dose level (2.5 mg/kg per 
day was the highest dose tested).  
In the 3-month monkey study, dose levels of 1, 2.5, and 5 mg/kg per day were evaluated.  Dose 
levels of 2.5 and 5 mg/kg per day were not tolerated, and these groups were euthanized early 
(approximately Days 40 and 20, respectively).  Several animals in these groups exhibited signs 
of hemorrhage (bruising, hematoma, dark red areas throughout GI tract at necropsy).  
Histopathology findings in these groups were similar, including mucosal atrophy, 
degeneration/regeneration, inflammation, and hemorrhage in the GI tract; minimal to moderate 
cardiac myopathy characterized by single to multiple foci of myocardiocyte 
atrophy/degeneration in the heart; minimal to severe decrease in bone marrow cellularity in the 
bone marrow; lymphoid depletion in the thymus; and atrophy, degeneration and regeneration in 
the pancreas.  Hypoactivity, liquid feces, and dehydration were observed clinically in some of 
the animals, along with altered electrolytes in calcium, chloride, phosphorous, potassium, and/or 
sodium.  Thrombocytopenia and anemia were also observed in some animals.  Mild cardiac 
myopathy was observed in a single animal administered 1 mg/kg per day.  Based on steady state 
exposure data from the 28-day toxicology study in cynomolgus monkeys, the exposure at 
2.5 mg/kg per day in monkeys is expected to be equivalent to 1.1-fold of the human exposure at 
12 mg QD observed in the INCB 57643-101 study.  This finding of cardiac myopathy met the 
criteria for an Expedited Safety Report, as it was unexpected, related to the drug, and presented a 
potential risk to the subjects in the INCB 57643-101 study, which was submitted to regulatory 
agency on 23 MAR 2018. 
Several findings in the toxicity studies were anticipated based on the pharmacology of BET 
inhibition.  Degeneration, erosion, and/or ulceration of the mucosal epithelium of the stomach 
observed in rats and the GI tract of monkeys are consistent with anticipated effects of BRD4 
inhibition in the GI tract.  Exploratory studies in rats conducted using structurally similar and 
structurally distinct BET protein inhibitors demonstrate that all of these compounds produce 
similar GI toxicity, the onset of which occurs at exposures expected to produce significant 
pharmacologic activity.  The GI findings were reversible.  Effects on the bone, bone marrow, and 
lymphoid organs are also expected based on the mechanism of action of INCB057643 and were 
reversible in the 28-day rat study.  Due to early euthanization of all the monkeys treated at 
2.5 and 5 mg/kg per day in the 3-month monkey study, the reversibility of the toxicities observed 
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is largely unknown.  However, based on its severity, cardiac histopathologic findings would not 
be expected to be reversible. 
The PK of INCB057643 was characterized in rats, dogs, and monkeys.  The urinary excretion of 
INCB057643 was determined to be 12.5% of dose in monkeys, 17.6% in rats, and 26.1% in 
dogs.  Further, in vitro, and in vivo metabolism studies in animals indicate generation of major 
and minor metabolites.  These data indicate that renal clearance is not the major route of 
clearance for INCB057643 and that metabolism is likely the predominant clearance pathway.  
The clearance mechanism of the active metabolite, INCB057228, is less clear; however, 
exposure of this metabolite in patients is only about 10% to 15% of the parent compound. 
Enrollment of subjects with mild to moderate organ impairment (≤ Grade 2 creatinine clearance) 
in the carefully monitored Phase 1 setting would allow us to better understand the impact of such 
organ dysfunction on the disposition of INCB057643 and in turn would inform the 
inclusion/exclusion criteria for Phase 2 studies. 
Subjects in enrolling this study will be informed of the potential risks identified in animal 
studies.  Subjects will be closely monitored for any signs of GI symptoms and will have 
hematologic parameters, as well as blood chemistries, closely monitored during study 
participation.  Subjects will also be regularly monitored by echocardiogram or MUGA, including 
ejection fraction change, and cardiac troponin testing.  The dose of INCB057643 may be 
interrupted or adjusted in subjects experiencing AEs.  Effects on fertility and fetal development 
have not been evaluated.  Men should avoid fathering a child and women of childbearing 
potential should take appropriate contraceptive measures from the time of screening through 
follow-up.  Refer to the IB for additional details. 
1.5.2. 
Potential Risks of Gemcitabine 
Risks associated with use of gemcitabine include myelosuppression, which is the principal DLT.  
Gemcitabine can suppress bone marrow function as manifested by leukopenia, neutropenia, 
thrombocytopenia, and anemia.  Subjects should be monitored for myelosuppression during 
therapy.  Subjects may also experience pulmonary toxicity and respiratory failure, hepatic 
toxicity, and capillary leak syndrome.  The most common adverse reactions as monotherapy are 
nausea; vomiting; anemia; increased ALT, AST, and alkaline phosphatase (ALP); neutropenia; 
leukopenia; proteinuria; fever; hematuria; rash; thrombocytopenia; and dyspnea.  A complete 
discussion of risks associated with gemcitabine can be found in the United States Prescribing 
Information (USPI; Gemzar 2017) or in the Summary of Product Characteristics (SmPC; 
Gemzar 2008). 
1.5.3. 
Potential Risks of Paclitaxel 
Risks associated with the use of paclitaxel include myelosuppression, which is the principal 
DLT.  Paclitaxel can suppress bone marrow function as manifested by neutropenia, leukopenia, 
thrombocytopenia, and anemia.  Subjects should be monitored for myelosuppression during 
therapy.  Subjects may also experience infections, bleeding, hypersensitivity reactions, 
bradycardia, hypotension, abnormal electrocardiograms (ECGs), peripheral neuropathy, myalgia 
and arthralgia, nausea and vomiting, diarrhea, mucositis, alopecia, bilirubin elevation, alkaline 
phosphate increase, AST increase, and injection site reaction.  A complete discussion of risks 
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associated with paclitaxel can be found in the USPI (Taxol 2011) or in the SmPC 
(Abraxane 2016). 
1.5.4. 
Potential Risks of Rucaparib 
There are risks associated with the use of rucaparib, including warnings and precautions for 
MDS/AML.  Monitor subjects for hematological toxicities including anemia, thrombocytopenia, 
neutropenia, and lymphopenia.  The most common AEs (≥ 20%) include nausea, fatigue 
(including asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased 
appetite, diarrhea, thrombocytopenia, and dyspnea.  The most common laboratory abnormalities 
(≥ 35%) are increase in creatinine, increase in ALT, increase in AST, decrease in hemoglobin, 
decrease in lymphocytes, increase in cholesterol, decrease in platelets, and decrease in absolute 
neutrophil count (ANC).  Fetal harm can also occur in patients taking rucaparib; advise females 
of the potential reproductive risk to a fetus and to use effective contraception.  A complete 
discussion of risks associated with rucaparib can be found in the USPI (Rubraca 2017). 
1.5.5. 
Potentials Risks of Abiraterone 
Risks associated with the use of abiraterone include mineralocorticoid excess, adrenocortical 
insufficiency, and hepatotoxicity.  Abiraterone should be used with caution in subjects who have 
a history of cardiovascular disease.  Subjects should be monitored for hypokalemia, 
hypertension, and liver function abnormalities.  The most common AEs as monotherapy are 
fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, 
dyspnea, urinary tract infection, and contusions.  The most common laboratory abnormalities are 
anemia, elevated alkaline phosphate, hypertriglyceridemia, lymphopenia, hypercholesterolemia, 
hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.  A complete 
discussion of risks associated with paclitaxel can be found in the USPI (Zytiga 2017a) or in the 
SmPC (Zytiga 2017b). 
1.5.6. 
Potential Risks of Ruxolitinib 
Risks associated with the use of ruxolitinib include thrombocytopenia, which is the principal 
DLT.  Subjects should be monitored for thrombocytopenia.  The most common AEs as 
monotherapy are thrombocytopenia, anemia, bruising, dizziness and headache, elevated ALT, 
elevated AST, and hypercholesterolemia.  A complete discussion of risks associated with 
ruxolitinib can be found in the USPI (Jakafi 2016) or in the SmPC (Jakavi 2017). 
1.5.7. 
Potential Risks of Azacitidine 
Risks associated with the use of azacitidine include anemia, neutropenia, and thrombocytopenia 
which are the principal DLTs.  The most common adverse reactions > 30% by the SC route are 
nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site 
erythema, constipation, neutropenia and ecchymosis.  The most common adverse reactions by 
the IV route are petechiae, rigors, weakness, and hypokalemia.  A complete discussion of risks 
associated with azacitidine can be found in the USPI (Vidaza 2016) or in the SmPC 
(Vidaza 2017). 
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1.5.8. 
Potential Risks of Combination Therapy 
INCB057643 has not been combined with gemcitabine, paclitaxel, rucaparib, abiraterone, 
ruxolitinib, or azacitidine previously in the clinical setting.  The effects of these combinations are 
being assessed in this protocol.  As described above, the most common AEs associated with 
these SOC agents are neutropenia, anemia, thrombocytopenia, nausea, vomiting, diarrhea, and 
liver function abnormalities.  The most common AEs associated with INCB057643 have been 
thrombocytopenia and GI AEs (see Section 1.6.2).  Adverse events will be monitored to identify 
occurrences of new safety signals or potentiation of any SOC agents and INCB05764-related 
side effects. 
1.6. 
Clinical Experience With INCB057643 in Study INCB 57643-101 
1.6.1. 
Clinical Pharmacokinetics and Pharmacodynamics 
Preliminary PK data are available for 42 subjects who have received INCB057643 8 mg QD, 
12 mg QD, or 16 mg QD in Study INCB 57643-101.  With multiple-dose administration, 
INCB057643 attained peak plasma concentrations with a median Tmax of 1 to 2 hours.  
Subsequently, INCB057643 plasma concentrations declined in a monophasic manner with a 
mean terminal phase half-life ranging from 8.31 to 15.3 hours.  M2 (INCB057228), a major and 
active metabolite, achieved peak plasma concentrations with a median Tmax of 2 to 4 hours.  
INCB057228 plasma concentrations declined in a monophasic manner with a mean terminal 
phase half-life ranging from 12.3 to 14.4 hours.  An approximately linear relationship was 
observed for INCB057643 exposures (Cmax and AUC) over the dose range studied (Table 1).  No 
significant food effect on PK has been observed based on preliminary data (Table 2). 
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Table 1: 
INCB057643 (Parent) and INCB057228 (M2) Steady-State (Cycle 1 Day 8) Pharmacokinetic Parameters 
Analyte 
Treatment 
Group 
Dose 
(mg) 
N 
Cmax 
(nM) 
Tmax 
(h) 
Cmin 
(nM) 
AUC0–τ 
(nM·h) 
CL/F 
(L/h) 
Vz/F 
(L) 
t½ 
(h) 
INCB057643 (Parent) 
Part 1/TGA 
8 
4 
224 ± 149 
(185) 
1.0 
(1.0, 4.0) 
35.7 ± 33.8 
(26.6) 
2060 ± 1240 
(1800) 
12.1 ± 6.89 
(10.7) 
156 ± 55.3 
(149) 
10.3 ± 4.59 
(9.65) 
Part 1/TGA 
12 
3 
233 ± 24.4 
(232) 
2.0 
(2.0, 4.0) 
49.1 ± 8.17 
(48.6) 
2860 ± 321 
(2850) 
10.2 ± 1.1 
(10.2) 
144 ± 23.6 
(142) 
9.47 ± 1.1 
(9.71) 
Part 1/TGA 
16 
7 
340 ± 165 
(310) 
2.0 
(2.0, 4.0) 
101 ± 87.4 
(64.0) 
4330 ± 2860 
(3620) 
12.6 ± 7.48 
(10.7) 
212 ± 73.4 
(198) 
15.3 ± 9.67 
(12.9) 
Part 2/TGA 
12 
22 
295 ± 104 
(279) 
2.0 
(1.0, 6.0) 
39.9 ± 25.7 
(33.0) 
2820 ± 1190 
(2620) 
11.8 ± 4.29 
(11.0) 
138 ± 44.7 
(129) 
8.31 ± 2.56 
(7.95) 
Part 1/TGB 
8 
6 
178 ± 63.8 
(167) 
1.0 
(0.5, 2.0) 
28.4 ± 13.9 
(24.4) 
1850 ± 471 
(1800) 
11.1 ± 3.4 
(10.7) 
134 ± 63.7 
(121) 
8.57 ± 2.62 
(8.12) 
INCB057228 (M2) 
Part 1/TGA 
8 
4 
17.7 ± 8.06 
(16.2) 
2.0 
(2.0, 6.0) 
5.46 ± 4.59 
(4.36) 
250 ± 137 
(225) 
94.5 ± 45.9 
(85.8) 
1390 ± 466 
(1330) 
14.4 ± 7.42 
(13.1) 
Part 1/TGA 
12 
3 
19.2 ± 10.5 
(16.7) 
2.0 
(2.0, 8.0) 
7.32 ± 4.84 
(5.83) 
314 ± 192 
(261) 
141 ± 123 
(111) 
4720, 1290 
11.6, 14.7 
Part 1/TGA 
16 
6 
52.1 ± 30.2 
(44.2) 
4.0 
(2.0, 6.0) 
15.1 ± 9.95 
(12.7) 
717 ± 351 
(643) 
67.2 ± 35.8 
(60) 
1290 ± 927 
(100) 
14.1 ± 5.39 
(13.3) 
Part 2/TGA 
12 
22 
37.3 ± 22.0 
(32.4) 
2.0 
(1.0, 8.0) 
9.15 ± 6.17 
(7.63) 
507 ± 261 
(448) 
73.6 ± 40.4 
(64.6) 
1360 ± 1100 
(1080) 
12.3 ± 5.26 
(11.3) 
Part 1/TGB 
8 
6 
25.9 ± 12.1 
(22.6) 
2.0 
(0, 4.0) 
9.22 ± 5.22 
(7.70) 
390 ± 171 
(355) 
60.8 ± 33.6 
(54.4) 
849 ± 228 
(823) 
13.5 ± 5.67 
(12.3) 
Note:  All values are presented as mean ± SD (geometric mean) with the exception of Tmax, which is presented as median (minimum, maximum). 
Note:  The predose PK samples on Cycle 1 Day 8 were imputed as the 24-hour trough samples. 
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Table 2: 
The Effect of a High-Fat Meal on the Pharmacokinetics of INCB057643 
(12 mg) and INCB057228 (M2) 
Analyte 
N 
Treatment 
Cmax (nM) 
Tmax (h) 
AUCτ 
(h·nM) 
CL/F (L/h) 
V/F (L) 
57643 
11 
Fasted 
(C1D8)
a 
281 ± 87.4 
(268) 
2.0 
(2.0, 6.0) 
2980 ± 1030 
(2820) 
10.9 ± 4.13 
(10.3) 
142 ± 44.5 
(136) 
12 
Fed 
(C2D1) 
253 ± 75.8 
(242) 
6.0 
(4.0, 24.0) 
3500 ± 1220 
(3300) 
9.33 ± 3.48 
(8.77) 
148 ± 35.5 
(145) 
57228 
11 
Fasted 
(C1D8) 
35.2 ± 14.2 
(32.3) 
4.0 
(2.0, 8.0) 
519 ± 243 
(470) 
– 
– 
12 
Fed 
(C2D1) 
38.5 ± 28.8 
(30.4) 
8.0 
(4.0, 24.0) 
630 ± 445 
(511) 
– 
– 
Geometric mean ratio (reference = fasted) 
57643 
 
 
0.89 
(0.78, 1.01) 
 
1.13 
(0.99, 1.29) 
 
 
57228 
 
 
0.95 
(0.74, 1.22) 
 
1.07 
(0.86, 1.33) 
 
 
C1D8 = Cycle 1 Day 8; C2D1 = Cycle 2 Day 1. 
Note:  All values are presented as mean ± SD (geometric mean) with the exception of Tmax, which is presented as median 
(minimum, maximum). 
a The predose PK samples on Cycle 1 Day 8 were imputed as the 24-hour trough samples. 
Pharmacodynamic analysis was performed using an ex vivo assay measuring protein levels of 
c-MYC, a BRD4 target gene, in KMS12BM cells spiked into subject plasma.  In preliminary PD 
analysis after oral administration of 8 mg, 12 mg, and 16 mg, INCB057643 demonstrated 
inhibition of total c-Myc with maximal inhibition occurring between 1 and 4 hours after drug 
administration.  The average c-Myc inhibition at steady state (Day 8, from predose to 8 hours) 
was 30%, 44%, and 65% for doses of 8 mg (n = 11), 12 mg (n = 51), and 16 mg (n = 7), 
respectively.  Maximum peak inhibition of total c-Myc ranged from approximately 16% to 77% 
at 8 mg, 20% to 92% at 12 mg, and 61% to 97% at 16 mg.  Inhibition of c-Myc was reduced to 
< 10% at trough (Cycle 1 Day 8 predose) for subjects receiving INCB057643 8 mg and 12 mg 
and approximately 30% for subjects receiving INCB057643 16 mg.  A composite PK-PD curve 
was plotted for 67 subjects, and an IC50 value of 202.4 nM was determined by nonlinear 
regression curve fitting (see Figure 1). 
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Figure 1: 
Composite PK-PD Curve for Subjects in Study INCB 57643-101 (N = 67) 
 
1.6.2. 
Clinical Trial Experience 
1.6.2.1. 
Dose-Escalation and Expansion, Safety, and Tolerability Study of INCB057643 
in Subjects With Advanced Malignancies 
As of the data cutoff date 19 JAN 2018, 113 subjects with advanced malignancies have received 
at least 1 dose of INCB057643 on Study INCB 57643-101:  17 subjects in Part 1/TGA, 
12 subjects in Part 1/TGB, 1 subject in Part 1/TGC, 80 subjects in Part 2/TGA, 1 subject in 
Part 2/TGB, and 2 subjects in Part 3/TGF.  INCB057643 8 mg QD, 12 mg QD, or 16 mg QD has 
been administered as monotherapy (111 subjects) in Parts 1 and 2.  INCB057643 8 mg QD has 
been administered in combination with azacitidine (2 subjects) in Part 3.  No subjects have been 
enrolled in Part 4.  Part 4 will not be opened for enrollment. 
As of MAR 2018, no further subjects are being enrolled in all the cohorts due to a less favorable 
benefit/risk assessment based on emerging data, mainly the histopathological finding of cardiac 
myopathy observed in the preclinical 3-month toxicology study in monkeys (Section 1.5.1). 
1.6.2.1.1. Part 1 Monotherapy Dose Escalation 
In Part 1/TGA, doses of 8 mg QD, 12 mg QD, and 16 mg QD were evaluated.  All 17 subjects 
(100%) in the clinical database reported at least 1 TEAE.  Frequently reported TEAEs (≥ 25.0% 
incidence) included fatigue, nausea, decreased appetite, diarrhea, and hyperglycemia (see 
Table 3).  Serious AEs occurred in 8 subjects (47.1%); the majority of the SAEs were reported at 
the nontolerated dose of 16 mg QD.  One subject receiving 16 mg QD had an SAE of Grade 3 
increased INR that was resolved with interruption of study drug and supportive care, which was 
deemed a DLT and considered by the investigator to be related to study treatment; the subject 
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was taking warfarin at the time of the event.  The SAEs reported in the 8 mg QD and 12 mg QD 
groups were performance status decreased, sepsis, and tumor pain (8 mg QD) and hepatic failure 
(12 mg QD).  Two fatal SAEs occurred in Part 1/TGA, including hepatic failure (12 mg QD) and 
pneumonia (16 mg QD), both deemed not related to the study drug by the investigators.  Four 
subjects (23.5%) in Part 1/TGA discontinued INCB057643 treatment because of TEAEs:  
3 subjects at 16 mg QD (abdominal pain upper and confusional state, hyperglycemia, and INR 
increased, respectively) and 1 subject at 8 mg QD (performance status decreased).  There were 
no TEAEs leading to discontinuation at 12 mg QD. 
Two subjects (11.8%) in Part 1/TGA (at 8 mg QD and 16 mg QD, respectively) reported TEAEs 
of herpes zoster (Grade 2).  Both events were resolved with SOC measures and without study 
drug interruption. 
The 16 mg QD dose in Part 1/TGA was deemed not tolerated due to DLT and other TEAEs 
leading to dose interruption, reduction, and termination.  The 12 mg QD dose was selected as 
MTD and RP2D for further evaluation in Part 2/TGA monotherapy expansion. 
Table 3: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 2 Subjects 
in Study INCB 57643-101 Part 1 Treatment Group A by MedDRA Preferred 
Term in Decreasing Order of Frequency (Safety Evaluable Population) 
MedDRA Preferred Term, n (%) 
8 mg QD 
(N = 4) 
12 mg QD 
(N = 5) 
16 mg QD 
(N = 8) 
Total 
(N = 17) 
Fatigue 
2 (50.0) 
4 (80.0) 
4 (50.0) 
10 (58.8) 
Nausea 
3 (75.0) 
4 (80.0) 
3 (37.5) 
10 (58.8) 
Decreased appetite 
2 (50.0) 
2 (40.0) 
3 (37.5) 
7 (41.2) 
Diarrhoea 
1 (25.0) 
2 (40.0) 
3 (37.5) 
6 (35.3) 
Hyperglycaemia 
2 (50.0) 
0 
4 (50.0) 
6 (35.3) 
Abdominal pain 
0 
2 (40.0) 
2 (25.0) 
4 (23.5) 
Anemia 
0 
1 (20.0) 
3 (37.5) 
4 (23.5) 
Thrombocytopenia/platelet count decreased
a 
1 (25.0) 
0 
3 (37.5) 
4 (23.5) 
Urinary tract infection 
3 (75.0) 
0 
1 (12.5) 
4 (23.5) 
Vomiting 
2 (50.0) 
2 (40.0) 
0 
4 (23.5) 
Weight decreased 
2 (50.0) 
1 (20.0) 
1 (12.5) 
4 (23.5) 
Back pain 
1 (25.0) 
1 (20.0) 
1 (12.5) 
3 (17.6) 
Constipation 
0 
2 (40.0) 
1 (12.5) 
3 (17.6) 
Dizziness 
1 (25.0) 
1 (20.0) 
1 (12.5) 
3 (17.6) 
Dry mouth 
1 (25.0) 
1 (20.0) 
1 (12.5) 
3 (17.6) 
Dysgeusia 
0 
1 (20.0) 
2 (25.0) 
3 (17.6) 
Hypertension 
0 
1 (20.0) 
2 (25.0) 
3 (17.6) 
Pruritus 
1 (25.0) 
1 (20.0) 
1 (12.5) 
3 (17.6) 
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Table 3: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 2 Subjects 
in Study INCB 57643-101 Part 1 Treatment Group A by MedDRA Preferred 
Term in Decreasing Order of Frequency (Safety Evaluable Population) 
(Continued) 
MedDRA Preferred Term, n (%) 
8 mg QD 
(N = 4) 
12 mg QD 
(N = 5) 
16 mg QD 
(N = 8) 
Total 
(N = 17) 
Cough 
1 (25.0) 
1 (20.0) 
0 
2 (11.8) 
Depression 
2 (50.0) 
0 
0 
2 (11.8) 
Herpes zoster 
1 (25.0) 
0 
1 (12.5) 
2 (11.8) 
Influenza like illness 
1 (25.0) 
0 
1 (12.5) 
2 (11.8) 
Muscle spasms 
1 (25.0) 
0 
1 (12.5) 
2 (11.8) 
Performance status decreased 
1 (25.0) 
0 
1 (12.5) 
2 (11.8) 
a Subjects for whom both preferred terms were reported are counted only once.  Overall, platelet count decreased was reported 
for 3 subjects, and thrombocytopenia was reported for 1 subject. 
In Part 1/TGB, doses of 8 mg QD and 12 mg QD were evaluated.  All 12 subjects (100%) in the 
clinical database reported at least 1 TEAE (see Table 4).  The most frequently reported TEAEs 
(≥ 30% of subjects) in this group were anemia, thrombocytopenia/platelet count decreased, 
diarrhea, epistaxis, fatigue, decreased appetite, dyspnea, and febrile neutropenia.  In the clinical 
database, SAEs were reported for 8 subjects (66.7%) in Part 1/TGB; SAEs reported in more than 
1 subject included febrile neutropenia (3 subjects, 25.0%), acute kidney injury (2 subjects, 
16.7%), and respiratory failure (2 subjects, 16.7%).  Fatal TEAEs were reported for 3 subjects 
(25.0%) in Part 1/TGB and included anemia and thrombocytopenia, sepsis, and acute kidney 
injury, respectively, all deemed not related to study drug by the investigators.  Two subjects in 
Part 1/TGB discontinued INCB057643 treatment because of TEAEs (anemia and 
thrombocytopenia and nausea, respectively). 
Coagulation-related events were reported for 2 subjects in Part 1/TGB.  Events of increased INR 
(G1) and aPTT prolonged (G1) were reported for 1 subject at 12 mg QD, and aPTT prolonged 
(G2) was reported for 1 subject at 8 mg QD. 
The dose of 12 mg QD was selected as MTD and RP2D in Part 1/TGB for further evaluation in 
Part 2/TGB. 
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Table 4: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 2 Subjects 
in Study INCB 57643-101 Part 1 Treatment Group B by MedDRA Preferred 
Term in Decreasing Order of Frequency (Safety Evaluable Population) 
MedDRA Preferred Term, n (%) 
8 mg QD 
(N = 7) 
12 mg QD 
(N = 5) 
Total 
(N = 12) 
Anaemia 
5 (71.4) 
3 (60.0) 
8 (66.7) 
Thrombocytopenia/platelet count decreased
a 
5 (71.4) 
3 (60.0) 
8 (66.7) 
Diarrhoea 
4 (57.1) 
1 (20.0) 
5 (41.7) 
Epistaxis 
2 (28.6) 
3 (60.0) 
5 (41.7) 
Fatigue 
3 (42.9) 
2 (40.0) 
5 (41.7) 
Decreased appetite 
3 (42.9) 
1 (20.0) 
4 (33.3) 
Dyspnoea 
2 (28.6) 
2 (40.0) 
4 (33.3) 
Febrile neutropenia 
2 (28.6) 
2 (40.0) 
4 (33.3) 
Acute kidney injury 
3 (42.9) 
0 
3 (25.0) 
Fall 
2 (28.6) 
1 (20.0) 
3 (25.0) 
Lung infection 
2 (28.6) 
1 (20.0) 
3 (25.0) 
Nausea 
3 (42.9) 
0 
3 (25.0) 
Oropharyngeal pain 
2 (28.6) 
1 (20.0) 
3 (25.0) 
Stomatitis 
2 (28.6) 
1 (20.0) 
3 (25.0) 
Vomiting 
3 (42.9) 
0 
3 (25.0) 
Activated partial thromboplastin time prolonged 
1 (14.3) 
1 (20.0) 
2 (16.7) 
Atrial fibrillation 
1 (14.3) 
1 (20.0) 
2 (16.7) 
Cough 
0 
2 (40.0) 
2 (16.7) 
Dehydration 
2 (28.6) 
0 
2 (16.7) 
Dry mouth 
2 (28.6) 
0 
2 (16.7) 
Dysgeusia 
1 (14.3) 
1 (20.0) 
2 (16.7) 
Hypotension 
1 (14.3) 
1 (20.0) 
2 (16.7) 
Hypoxia 
2 (28.6) 
0 
2 (16.7) 
Non-cardiac chest pain 
1 (14.3) 
1 (20.0) 
2 (16.7) 
Oral pain 
2 (28.6) 
0 
2 (16.7) 
Pyrexia 
2 (28.6) 
0 
2 (16.7) 
Respiratory failure 
2 (28.6) 
0 
2 (16.7) 
Sinus tachycardia 
0 
2 (40.0) 
2 (16.7) 
White blood cell count decreased 
0 
2 (40.0) 
2 (16.7) 
a Subjects for whom both preferred terms were reported are counted only once.  Overall, platelet count decreased was reported 
for 5 subjects, and thrombocytopenia was reported for 3 subjects. 
In Part 1/TGC, TEAEs reported for the single enrolled subject included cough, fatigue, and 
oropharyngeal pain; fatal SAEs while on study drug of sepsis, septic shock, and organ failure 
were also reported and deemed not related to study drug by the investigators. 
1.6.2.1.2. Part 2 Monotherapy Dose Expansion 
In Part 2/TGA, 77 of the 80 subjects (96.3%) in the clinical database reported at least 1 TEAE 
(see Table 5).  The most frequently reported TEAEs (≥ 25% of subjects) included nausea, 
fatigue, thrombocytopenia/platelet count decreased, decreased appetite, and vomiting.  In the 
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clinical database, SAEs were reported for 33 subjects (41.3%) in Part 2/TGA.  Serious AEs 
reported for more than 1 subject included thrombocytopenia/platelet count decreased (6 subjects, 
7.5%), respiratory failure (4 subjects, 5.0%); abdominal pain and sepsis (3 subjects each, 3.8%); 
and anemia, hypotension, muscular weakness, and urosepsis (2 subjects each, 2.5%).  Fatal 
TEAEs were reported for 7 subjects (8.8%) in Part 2/TGA and included respiratory failure 
(4 subjects) and cardiac arrest, cardiac failure, pyuria, sepsis, liver function test increased, fluid 
overload, depressed level of consciousness, death, and disease progression (reported for 1 subject 
each), all of which were deemed not related to study drug by the investigators.  Eleven subjects 
in Part 2/TGA discontinued INCB057643 treatment because of TEAEs (ie, anemia, 
thrombocytopenia/platelet count decreased, nausea, disease progression, fatigue, hepatic failure, 
hyperbilirubinemia, sepsis, weight decreased, spinal cord infarction, and dyspnea). 
In Part 2/TGA, 5 subjects had increased INR (1 Grade 3 and reported as an SAE and 
4 ≤ Grade 2).  The subject who had the Grade 3 SAE of increased INR was taking concomitant 
warfarin.  The 4 subjects who had ≤ Grade 2 increased INR were on alternative anticoagulant 
therapies.  Two additional subjects reported aPTT prolonged (Grade 2), and 1 additional subject 
reported PT prolonged (Grade 2) with an increased INR (Grade 2). 
Five subjects in Part 2/TGA (12 mg QD) reported TEAEs of herpes zoster (≤ Grade 2), 4 of 
which were resolved with SOC measures.  The other was considered “not recovered/not 
resolved” at the time of death due to disease progression. 
Table 5: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 10% of 
Subjects in Study INCB 57643-101 Part 2/Treatment Group A by MedDRA 
Preferred Term in Decreasing Order of Frequency (Safety Evaluable 
Population) 
MedDRA Preferred Term, n (%) 
12 mg QD 
(N = 80) 
Nausea 
39 (48.8) 
Fatigue 
33 (41.3) 
Thrombocytopenia/platelet count decreased
a 
27 (33.8) 
Decreased appetite 
22 (27.5) 
Vomiting 
20 (25.0) 
Diarrhoea 
19 (23.8) 
Constipation 
15 (18.8) 
Anaemia 
14 (17.5) 
Dysgeusia 
13 (16.3) 
Hyperglycaemia 
11 (13.8) 
Blood bilirubin increased 
10 (12.5) 
Dehydration 
9 (11.3) 
Dizziness 
9 (11.3) 
Cough 
8 (10.0) 
a Subjects for whom both preferred terms were reported are counted only once.  Overall, platelet count decreased was reported 
for 15 subjects, and thrombocytopenia was reported for 14 subjects. 
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In Part 2/TGB, there were no TEAEs reported for the single enrolled subject with AML as of the 
data cutoff date. 
1.6.2.1.3. Part 3 Combination Therapy Dose Escalation 
In Part 3/TGF, there were no TEAEs reported for the 2 enrolled subjects with AML as of the 
data cutoff date. 
1.6.2.1.4. Drug-Drug Interaction Study of INCB057643 and Warfarin  
The primary objective of this study was to determine the effect of multiple doses of 
INCB057643 12 mg QD on the PK and PD of warfarin after a 25 mg single oral dose 
administration of warfarin and the effect of warfarin on INCB057643 PK in healthy volunteers. 
In Cohort 1, 17 healthy subjects received a single oral dose of 25 mg (5 × 5 mg tablets) 
Coumadin® (warfarin) on Day 1 and then INCB057643 12 mg QD (3 × 4 mg tablets) on Days 11 
through 19, followed by a single oral dose of warfarin (5 × 5 mg tablets) on Day 13.  In Cohort 2, 
20 healthy subjects received INCB057643 12 mg QD (3 × 4 mg tablets) on Days 1 to 7. 
With the concomitant administration of INCB057643, the geometric mean Cmax and AUC of 
S- or R-warfarin increased by 9%, 1%, 9%, and 10%, respectively, and the 90% CI of geometric 
mean ratio (GMR) for Cmax and AUC was within (0.8, 1.25).  With the concomitant 
administration of warfarin, the geometric mean Cmax and AUC of INCB057643 changed by 
-3.3% and +3%, respectively, and the 90% CI of GMR for Cmax and AUC were  between 0.8 and 
1.25.  Administration of INCB057643 alone caused approximately 35% maximal Factor VII 
serum concentration decrease at steady state and minimal increase of INR.  Administration of 
warfarin alone caused approximately 50% maximal Factor VII serum concentration decrease and 
approximately 74% INR increase.  Coadministration of INCB057643 and warfarin decreased 
maximal Factor VII serum concentration by approximately 70%.  Comparing coadministration of 
INCB057643 and warfarin to warfarin alone, the geometric mean INRmax and AUCINR, 0-168h 
changed by -9.6% and -0.7%, respectively, and the 90% CI of GMR for INRmax and 
AUCINR,0-168h were between 0.8 and 1.25.  The data from this study indicate that there is no effect 
on the PK of INCB057643 and warfarin, PD markers, or INR after coadministration of 
INCB057643 and warfarin.   
In Cohort 1 Period 2, 2 subjects withdrew from study on Day 13 and Day 11, respectively.  In 
Cohort 2, 2 subjects withdrew from study on Day 6.  There were no deaths, SAEs, TEAEs of 
Grade 3 or higher, or TEAEs leading to treatment discontinuation in this study. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
• To assess the safety and tolerability of INCB057643 as monotherapy and in 
combination with SOC agents in subjects with advanced malignancies. 
2.1.2. 
Secondary Objectives 
• To evaluate the PK of INCB057643 when administered as monotherapy in the fasted 
state and in the fed state (food effect; Part 2 only) and when administered in 
combination with SOC agents in the fasted state. 
• To assess the PD of INCB057643 when administered as monotherapy in subjects with 
advanced malignancies. 
• To evaluate the preliminary efficacy of INCB057643 when administered as 
monotherapy and in combination with SOC agents based on the investigator 
assessment of response using criteria appropriate for each disease in subjects with 
advanced malignancies. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoints 
• Safety and tolerability of INCB057643 as monotherapy and in combination with SOC 
agents as assessed by clinical laboratory assessments, physical examinations, 12-lead 
ECGs, and AEs. 
2.2.2. 
Secondary Endpoints 
• Cmax, Tmax, Cmin, AUC0-t, and AUC0-τ of INCB057643 at Cycle 1 Day 1, Cycle 1 
Day 8, and Cycle 2 Day 1 (food effect; Part 2 only).  
• Pharmacodynamic profile of INCB057643 using a plasma PD assay. 
• Objective response rate in subjects with measurable or evaluable disease as 
determined by the investigator assessment of response using the criteria appropriate 
for each disease. 
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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. 
Subject Inclusion Criteria 
Subjects with relapsed or refractory advanced or metastatic malignancies (see Section 4.1 for 
detailed study population) who meet all of the following criteria may be included in the study: 
1. Men and women aged 18 years or older. 
2. Histologically or cytologically confirmed diagnosis of advanced malignancy: 
a. Part 1 – Monotherapy Dose Escalation: 
− TGA:  Advanced solid tumor or lymphoma 
− TGB:  Acute leukemia (any), HR-MDS, MDS/MPN, or MF  
− TGC:  MM 
b. Part 2 – Monotherapy Dose Expansion: 
− TGA:  Presence of measureable disease in one of the following tumor types:  
pancreatic adenocarcinoma, mCRPC, breast cancer, high-grade serous ovarian 
cancer, glioblastoma multiforme, NHL, Ewing's sarcoma, or any solid tumor or 
lymphoma (except specified above) with any pathway alteration relevant to BET 
protein signaling, such as MYC pathway activation, which is hypothesized to be 
susceptible to INCB057643 monotherapy (requires approval by medical monitor). 
− TGB:  AML, HR-MDS, MDS/MPN, or MF 
− TGC:  Measureable/evaluable MM, defined as one or more of the following: 
 Serum M-protein ≥ 0.5 g/dL 
 Urine M-protein ≥ 200 mg/24 h 
 Serum free light chain (FLC):  Involved FLC level ≥ 10 mg/dL provided 
serum FLC ratio is abnormal 
c. Part 3 – Combination Dose Escalation (C-ES):  
− C-ES-TGA:  any solid tumor for which treatment with gemcitabine is relevant.  
− C-ES-TGB:  any solid tumor for which treatment with paclitaxel is relevant.  
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− C-ES-TGC (conducted in the United States only):  any solid tumor for which 
treatment with rucaparib is relevant. 
− C-ES-TGD:  any mCRPC subjects eligible to receive abiraterone plus prednisone.  
 mCRPC subjects must maintain a castrate level of testosterone documented 
(< 50 ng/dL) during the screening period and while on study. 
− C-ES-TGE (conducted in the United States only):  any MF subjects currently 
receiving ruxolitinib with an inadequate response, as defined below: 
 Palpable spleen of > 10 cm below the left subcostal margin on physical 
examination at screening OR 
 Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical 
examination AND active symptoms of MF at screening as demonstrated by 
presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening 
Symptom Form (see Appendix P).  
 Subjects must be receiving ruxolitinib for ≥ 6 months with a stable dose for 
≥ 8 weeks (acceptable doses are 5 to 25 mg BID).  
− C-ES-TGF:  any AML and HR-MDS subjects eligible to receive azacitidine. 
d. Part 4 – Combination Dose Expansion (C-EX):  
− C-EX-TGA (conducted in the United States only):  any BRCA wild type platinum-
resistant mHGSOC (epithelial ovarian/fallopian tube/primary peritoneal cancer) 
subjects eligible to receive rucaparib. 
 Platinum-resistant disease is defined by disease progression within 6 months 
of completing platinum-based therapy.   
 Known BRCA wild type by a validated assay before consenting. 
 Subjects must be PARP inhibitor naive or have had a clinical response (CR or 
partial response [PR]) to a prior PARP inhibitor and progressed and have a 
BRCA status that was shown to be BRCA wild type at the time of consent.  
− C-EX-TGB:  any mCRPC subjects who have progressed on first-line 
enzalutamide for metastatic disease and who are eligible to receive abiraterone 
plus prednisone (chemotherapy treatment naive); OR any mCRPC subjects who 
have demonstrated PSA progression with or without radiologic progression while 
being treated with abiraterone plus prednisone and who are clinically stable and 
will remain on abiraterone plus prednisone (prior chemotherapy is allowed). 
 Progression is defined by the Prostate Cancer Working Group 3 (PCWG3) 
guidelines (blood-based PSA or imaging [nodes, viscera, and bone] at study 
entry).  
 mCRPC subjects must maintain a castrate level of testosterone documented 
(< 50 ng/dL) during the screening period and while on study. 
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− C-EX-TGC (conducted in the United States only):  any MF subjects currently 
receiving ruxolitinib with an inadequate response, as defined below: 
 Palpable spleen of > 10 cm below the left subcostal margin on physical 
examination at screening OR 
 Palpable splenomegaly of 5 to 10 cm below left subcostal margin on physical 
examination AND active symptoms of MF at screening as demonstrated by 
presence of 1 symptom score ≥ 5 or 2 symptom scores ≥ 3 using the Screening 
Symptom Form (see Appendix P).  
 MF subjects must be receiving ruxolitinib for ≥ 6 months with a stable dose 
for ≥ 8 weeks (acceptable doses are 5 to 25 mg BID).  
− C-EX-TGD:  any AML and HR-MDS subjects eligible to receive azacitidine. 
 Confirmed AML or HR-MDS (International Prognostic Scoring System -2 or 
high risk) in accordance with WHO diagnostic criteria. 
 Failure of prior therapy with HMA, defined as at least 1 of the following:  
o Progression to AML 
o % increase in bone marrow blasts  
o Relapsed disease after response 
o At least 4 cycles of treatment without clinical benefit (hematological 
improvement or better) 
3. Prior therapy, as follows: 
a. For Parts 1 and 2/TGA and TGB, subjects must have progressed following at least 
1 line of prior therapy, and there is no further established therapy that is known to 
provide clinical benefit (including subjects who are intolerant to, not eligible for, or 
refuse the established therapy).   
− Subjects with AML are eligible if they have relapsed and/or refractory disease, if 
they are ≥ 65 years of age and are not candidates for or have refused standard 
chemotherapy, or if they have no established standard of care that is known to 
provide clinical benefit in the judgement of the investigator. 
− Subjects with MF must be resistant, refractory, or intolerant to ruxolitinib therapy. 
b. For Parts 1 and 2/TGC, MM subjects must have relapsed from or have been 
refractory to ≥ 2 prior treatment regimens, including a proteasome inhibitor and an 
immunomodulatory drug, and have no current standard options available. 
c. For Parts 3 and 4, subjects must have progressed following at least 1 line of prior 
therapy, and treatment with the select SOC must be relevant for the specific disease 
cohort. 
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4. For subjects with solid tumors and lymphoma in all parts of the study (where applicable),  
willingness to undergo a pretreatment core or excisional tumor biopsy (except for 
glioblastoma) or availability of a tumor block or 25 unstained slides from biopsy or 
resection of primary tumor or metastasis that is preferably ≤ 1 year old and obtained after 
completion of last treatment.  For subjects with hematologic malignancies in which bone 
marrow biopsy and/or aspirate is part of the disease assessment, willingness to undergo a 
pretreatment bone marrow biopsy and/or aspirate (as appropriate to disease).  If a biopsy 
is not possible or contraindicated, or the tissue requirement cannot be satisfied, this may 
be omitted with approval from the medical monitor.  In all cases, preferably, biopsies will 
be confirmed to contain adequate tumor tissue by a local pathology review.  
5. Life expectancy > 12 weeks; for MF subjects in Parts 3 and 4, life expectancy 
≥ 24 weeks. 
6. ECOG performance status score:  
a. Parts 1 and 3:  0 or 1 
b. Parts 2 and 4:  0, 1, or 2 
7. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Women of childbearing potential must have a negative serum pregnancy test at 
screening and immediately before the first dose (within 24 hours) of study drug.  
b. Women of nonchildbearing potential are defined as surgically sterile with a 
hysterectomy and/or bilateral oophorectomy OR ≥ 24 months of amenorrhea and at 
least 50 years of age. 
c. Men and women of childbearing potential must agree to take appropriate precautions 
(ie, use at least 2 forms of contraception) to avoid pregnancy or fathering children 
from screening through follow-up (at least 28 days after the last dose of all study 
medications).  Permitted methods that are at least 99% effective in preventing 
pregnancy should be communicated to the subjects and their understanding 
confirmed. 
Note:  While double-barrier methods (a combination of male condom with either cap, 
diaphragm, or sponge with spermicide) are not considered highly effective per the 
CTFG guidance (see Appendix A), for the purposes of this study they are considered 
acceptable birth control methods.  The treating physician is responsible for discussing 
acceptable methods of contraception with the subject for the purposes of this study in 
subjects with advanced cancer. 
8. Females must agree to abstain from breastfeeding during study participation and for 
28 days after study drug discontinuation.  
9. Males must also agree to refrain from donating semen or sperm during treatment and for 
28 days after discontinuation from this study. 
10. Ability to comprehend and willingness to sign an informed consent form (ICF). 
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3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Inadequate bone marrow function demonstrated by any of the following:  
Laboratory Parameter 
Part 1/ 
TGA 
Part 2/ 
TGA 
Parts 1 and 2/ 
TGC
a 
Part 3/C-ES-TGA/TGB/ 
TGC/TGD and  
Part 4/C-EX-TGA/TGB 
Part 3/C-ES-TGE and 
Part 4/C-EX-TGC 
Hemoglobin (g/dL) 
< 10.0 
< 8.0 
< 8.0 
< 9.0 
Subjects unwilling to receive 
red blood cell transfusion to 
treat low hemoglobin levels 
are excluded. 
Platelet count (× 109/L) 
< 100 
< 100 
< 75 
< 100 
< 50 in 4 weeks before 
screening or platelet 
transfusions within 8 weeks of 
screening. 
ANC (× 109/L) 
< 1.5 
< 1.0 
< 1.0 
< 1.5 
< 0.5 in the 4 weeks before 
screening. 
Note:  No specific hematologic exclusion criteria apply for subjects with AML/HR-MDS in Parts 1 and 2/TGB, Part 3 
C-ES-TGF, or Part 4 C-EX-TGD.  The medical monitor will review all CBC parameters before approving enrollment into the 
study. 
a Multiple myeloma subjects in Part 2 only:  < 50 × 109/L if 50% of bone marrow nucleated cells are plasma cells. 
2. Inadequate organ function demonstrated by any of the following, unless due to the 
underlying disease and approved by the medical monitor: 
a. All Parts:  Total bilirubin > 1.5 × upper limit of normal (ULN).  Total bilirubin 
> 1.5 × ULN is acceptable if direct bilirubin ≤ 1.2 × ULN or with a diagnosis of 
Gilbert's syndrome. 
b. Parts 1 and 3:  AST or ALT > 1.5 × ULN. 
c. Parts 2 and 4:  AST and ALT > 2.5 × ULN or > 5 × ULN for subjects with liver 
metastases.  
d. All Parts:  Creatinine clearance < 50 mL/min based on Cockroft-Gault formula or 
24-hour urinalysis (< 30 mL/min for MM). 
e. All Parts:  ALP ≥ 2.5 × ULN. 
− Subjects with 1) bone metastases AND 2) no hepatic parenchymal metastases on 
screening radiographic examinations may enroll if ALP is ≤ 5 × ULN.  Subjects 
with 1) bone metastases AND 2) hepatic parenchymal metastases on screening 
radiographic examination may enroll if ALP is ≤ 5 × ULN only with medical 
monitor approval. 
3. Receipt of anticancer medications or investigational drugs within the following intervals 
before the first administration of study drug, unless with medical monitor approval: 
a. < 5 half-lives or 14 days, whichever is longer, for any investigational agent. 
b. < 5 half-lives for all other chemotherapy or targeted small molecule anticancer 
medications. 
c. < 6 weeks for mitomycin-C or nitrosoureas. 
d. < 4 weeks for immunotherapy or antibody therapy. 
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e. The following concurrent medications are allowed: 
− Subjects with mCRPC may be maintained on androgen deprivation, chemical or 
surgical, at the discretion of the investigator, with a castrate level of testosterone 
documented (< 50 ng/dL) during the screening period and while on study.  
− Low-dose corticosteroids (prednisone or the equivalent ≤ 10 mg per day) may be 
administered.  Use of inhaled or topical steroids and prophylactic corticosteroids 
for radiographic procedures is permitted. 
− For hematologic malignancies:  Hydroxyurea for controlling proliferative disease 
may be administered.  Hydroxyurea should not be used within at least 48 hours 
before and on the day of the 
 sample collection (bone marrow and 
blood) or during or 72 hours before or after azacitidine administration. 
− For Parts 1 and 2/TGC:  Receipt of less than 160 mg dexamethasone within 
14 days before receiving the first dose of study drug is allowed. 
− Denosumab and zoledronic acid are permitted to treat cancer-related bone 
diseases. 
4. Prior receipt of any BET inhibitor.  
5. 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 following allogeneic transplant within 2 weeks of Cycle 1 
Day 1. 
6. Unless approved by the medical monitor, may not have received autologous 
hematopoietic stem cell transplant within 3 months before treatment. 
7. Any unresolved toxicity ≥ Grade 2 (except stable Grade 2 peripheral neuropathy or 
alopecia) from previous anticancer therapy. 
8. 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.  For Part 3/C-ES-TGE and 
Part 4/C-EX-TGC, MF subjects may not have splenic irradiation within 6 months of the 
first dose of INCB057643. 
9. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
10. Type 1 diabetes or uncontrolled Type 2 diabetes.   
a. All Parts:  HbA1c of ≥ 8% (all subjects will have HbA1c test at screening). 
b. For Parts 1 and 3 only:  Fasting blood glucose > 160 mg/dL (> 8.9 mmol/L) 
11. Known human immunodeficiency virus infection (HIV; HIV 1/2 antibodies). 
12. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection as defined in 
Section 7.5.5.3. 
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13. Currently active and uncontrolled infectious disease requiring systemic antibiotic, 
antifungal, or antiviral treatment. 
14. Untreated brain or CNS metastases or brain/CNS metastases that have progressed 
(eg, evidence of new or enlarging brain metastasis or new neurological symptoms 
attributable to brain/CNS metastases).  Subjects with previously treated and clinically 
stable brain/CNS metastases and off all corticosteroids for ≥ 2 weeks before Cycle 1 
Day 1 are eligible.  Primary CNS lymphoma will only be permitted in Part 2/TGA.  
Subjects with glioblastoma are not subjected to this criterion with medical monitor 
approval. 
15. History or presence of abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  A screening QTc interval of > 470 msec 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.  Subjects with QTc prolongation due to a pacemaker may enroll if the JT is 
normal or with medical monitor approval.  In the event that a single QTc is > 470 msec, 
the subject may enroll if the average QTc for the 3 ECGs is < 470 msec.  QTcF is 
preferred QT correction formula. 
16. History (≤ 1 year) of clinically significant or uncontrolled cardiac disease, acute 
myocardial infarction, New York Heart Association Class III or IV congestive heart 
failure, or clinical significant arrhythmia not controlled by standard-of-care therapy.  
Subjects with a pacemaker and well-controlled rhythm for at least 1 month before first 
dose of study drug will be allowed. 
17. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy. 
18. Unless approved by the medical monitor, current use of prohibited medication as 
described in Section 5.6.2.  
19. Unless approved by the medical monitor, use of any potent CYP3A4 inhibitors or 
inducers (Appendix N) within 14 days or 5 half-lives (whichever is longer) before the 
first dose of study drug. 
20. Known hypersensitivity or severe reaction to INCB057643, similar compounds, or 
excipients of INCB057643 (refer to the IB). 
21. Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the 
dose schedule and study evaluations. 
22. Unable to swallow and retain oral medication. 
23. Currently breastfeeding. 
24. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug or any of the SOC agents and 
attending required study visits; pose a significant risk to the subject; or interfere with 
interpretation of study data. 
25. Inability to comprehend or unwilling to sign the ICF. 
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26. Any sign of clinically significant bleeding within 14 days of Cycle 1 Day 1. 
27. International normalized ratio, prothrombin time (PT), and activated partial 
thromboplastin time (aPTT) > 1.5 × ULN (unless the subject is receiving anticoagulant 
therapy, in which case, the subject may be included as long as the INR, PT, and aPTT are 
within therapeutic range of intended use of anticoagulants). 
Note:  Partial thromboplastin time may be used in place of aPTT per institutional 
standards. 
28. All parts of the study (where applicable) for solid tumors and lymphomas:  Subjects with 
a history of bleeding related to cancer under study requiring a medical intervention 
(eg, embolization procedure, red blood cell transfusion, or hospitalization) within 30 days 
of study enrollment. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an open-label, dose-escalation/dose-expansion study of INCB057643 as monotherapy or 
in combination with SOC agents in subjects with relapsing or refractory advanced malignancies.  
Subjects will receive INCB057643 continuously administered orally in 21- or 28-day cycles, as 
applicable to regimen schedules in combination (see Section 5.2 for details).  Alternative 
administration schedules may be assessed if indicated by emerging safety, PK, or PD data.  The 
study consists of 4 parts.  Parts 1 and 2 will evaluate INCB057643 as monotherapy, and Parts 3 
and 4 will evaluate INCB057643 in combination with SOC agents. 
The study began with Part 1, Monotherapy Dose Escalation, which will determine the MTD of 
INCB057643 and/or a tolerated dose that reaches the desired target inhibition (ie, a 
pharmacologically active dose [PAD]; plasma concentration exceeding ex vivo or projected 
c-Myc IC50 for approximately 6-12 hours or achieves clinical response).  Part 1 will be 
conducted in 3 disease-specific treatment groups. 
Part 2, Monotherapy Dose Expansion, will further evaluate the safety, preliminary efficacy, PK, 
and PD of the treatment group−specific dose selected in Part 1 (at ≤ the MTD) in select tumor 
types postulated to be particularly susceptible to inhibition of BET proteins.  See Figure 2 for the 
study design of Parts 1 and 2.  
Part 3, Combination Dose-Escalation (C-ES), will determine the MTD and/or a tolerated dose 
(the RP2D) of the combination of INCB057643 with one of the SOC agents.  Part 3 will be 
conducted in 6 disease-specific treatment groups.  
Part 4, Combination Dose-Expansion (C-EX), after identification of the RP2D in combination 
regimens in Part 3, will further determine safety, tolerability, efficacy, PK, and PD.  Part 4 will 
be conducted in 4 treatment groups.  The sponsor may decide not to expand any or some cohorts. 
As a follow-up to the data cutoff date of 19 JAN 2018, screening and enrollment was placed on 
hold by the sponsor in MAR 2018, due to a less favorable benefit/risk assessment based on 
emerging data, which was mainly histopathological finding of cardiac myopathy observed in the 
preclinical 3-month toxicology study in monkeys (Section 1.5.1).  Furthermore, all subjects were 
asked to reconsent if they were opting to continue receiving study treatment at the discretion of 
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the investigators and receive INCB057643 ≤ 8 mg QD.  Therefore, as of MAR 2018, no further 
subjects are being enrolled in Parts 1, 2, and 3, and Part 4 will not be opened for enrollment. 
4.1.1. 
Part 1 − Monotherapy Dose Escalation 
The study began with dose escalation in Part 1.  Part 1 comprises 3 disease-specific treatment 
groups.  Each treatment group will use a 3 + 3 design to determine the tolerated dose over a 
21-day cycle.  See Figure 2 for the study design of Parts 1 and 2. 
• Treatment Group A (TGA) will include subjects with any advanced solid tumor or 
lymphoma. 
• Treatment Group B (TGB) will include subjects with acute leukemia, HR-MDS, 
MDS/MPN, or MF.  
• Treatment Group C (TGC) will include subjects with MM. 
Enrollment into the study began in TGA.  The initial dose level was 8 mg QD.  Once a PAD has 
been identified in TGA, TGB and TGC will begin parallel enrollment at that PAD.  
Subsequently, dose escalation will proceed independently in the 3 treatment groups to an MTD 
(or a tolerated PAD if an MTD is not reached), each using a 3 + 3 design.  If there is a distinct 
discrepancy in tolerability among different disease types within the same treatment group, 
additional disease-specific dose-escalation schedules may be initiated. 
Each dose-escalation cohort will initially enroll at least 3 subjects.  If no DLTs are observed in 
the initial 3 subjects, another cohort will begin enrollment at the next highest dose level.  Dose 
escalations between cohorts may be up to 100% until a DLT is observed, after which dose 
escalations in the relevant treatment group will be limited to no more than 50% above the 
previous level.  Dose escalations 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.  Subjects will continue to receive 
INCB057643 in 21-day cycles until withdrawal criteria are met (eg, toxicity, disease 
progression). 
If 1 DLT is observed in the first 3 subjects, at least 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 tolerated dose.  Thus, the MTD will be defined as 1 dose level below the nontolerated dose 
(NTD) 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 sponsor, in consultation with participating investigators, may elect to investigate 1 or more 
dose levels less than the NTD or expand a dose cohort(s) deemed tolerable up to 12 subjects in 
order to obtain additional PK, PD, and safety data before determining the MTD.  At the end of 
Cycle 1, subjects who took ≥ 80% of planned doses of INCB057643 (eg, 17 of 21 doses) during 
the study observation period or experience a DLT will be included in the evaluation cohort.  
See Section 5.4.1.1 for DLT criteria. 
Individual subjects within each cohort will undergo reductions/interruptions in INCB057643 
administration according to prescribed safety parameters.  Subjects tolerating INCB057643 at the 
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assigned dose for at least 4 cycles may be considered for a dose increase if a higher dose has 
been found to be tolerated in a subsequent cohort (see Section 5.4.5 for details). 
4.1.2. 
Part 2 − Monotherapy Dose Expansion 
Part 2 of the study will evaluate the treatment group−specific dose selected in Part 1 in specific 
tumor types postulated to be particularly susceptible to inhibition of BET proteins.  See Figure 2 
for the study design of Parts 1 and 2.  A dose up to the MTD may be selected for use in each 
expansion cohort by the sponsor and investigators.  More than 1 dose of INCB057643 and/or 
schedule may be assessed, pending emerging safety, PK, and PD data.  Part 2/TGA will enroll up 
to approximately 165 subjects with specified solid tumors or lymphoma (see Section 3.1).  The 
high-grade serous ovarian cancer cohort will include approximately 20 subjects.  At least 5 of 
these subjects will have BRD4 amplification, and at least another 5 will have MYC 
amplification/ overexpression/translocation.  The BRD4 and MYC molecular signature will be 
identified for enrollment eligibility by known status before subjects sign the ICF.  The mCRPC 
cohort will include approximately 20 subjects.  At least 5 of these will have AR-V7 identified for 
enrollment eligibility by known status before subjects sign the ICF, and another 5 will have 
poorly differentiated neuroendocrine phenotype identified by local investigators and pathologists 
before subjects sign the ICF.  An NHL cohort will include approximately 45 subjects, 5 to 15 of 
those having a diagnosis of "double-hit" or "triple-hit" (overexpression and/or translocation of 
MYC and BCL2 and/or BCL6) diffuse large B-cell lymphoma (DLBCL), 5 to 15 of those having 
a diagnosis of follicular lymphoma, and 5 to 15 of those to enroll other NHLs such as DLBCL, 
Burkitt's lymphoma, or B-cell lymphoma, unclassifiable (BCLU; with features intermediate 
between DLBCL and Burkitt's lymphoma).  The other disease-specific and molecularly defined 
groups in TGA, (pancreatic adenocarcinoma, breast cancer, glioblastoma multiforme, and 
Ewing's sarcoma; see Section 3.1) will enroll approximately 5 to 15 subjects each.  Efforts 
should be made to identify subjects with a pathway alteration relevant to BET signaling such as 
MYC or BRD amplification in these tumor types.  An additional group of up to approximately 
20 subjects with any other tumor (except those specified previously) known to have pathway 
alteration relevant to BET protein signaling will also be enrolled.  Part 2/TGB will enroll 
approximately 45 subjects (5 to 15 in each tumor type) with AML, HR-MDS, MDS/MPN, and 
MF.  Part 2/TGC will enroll initially 5 to 15 subjects with MM.   
If ≥ 33% of subjects in a Part 2 expansion cohort experience DLTs during Cycle 1, then further 
enrollment to the cohort will be stopped, and a lower dose level may be explored. 
During dose escalation and expansion, the small number of subjects in each group and 
heterogeneity of dose and subject characteristics within the groups is the reason for not having 
predefined efficacy stopping criteria.   
Individual dose titration will be permitted according to Protocol-defined safety parameters.  
Subjects will continue to receive INCB057643 in 21-day cycles until withdrawal criteria are met 
(eg, toxicity, disease progression).  Additional PK assessments for food effect on drug exposure 
will be performed in the first 12 subjects enrolled into Part 2/TGA.  Additional subjects may be 
enrolled if there are data quality issues among the initial 12 subjects. 
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Figure 2: 
Part 1 and Part 2 Monotherapy Dose Escalation and Expansion Study Design 
 
a Increments up to 100% until DLT occurs within a given treatment group, then up to 50% thereafter. 
b Defined as plasma concentration exceeding ex vivo or projected c-Myc IC50 for 8 to 12 hours or achieves clinical 
response. 
c Part 2/TGA Expansion:  The high-grade serous ovarian cancer group will include approximately 20 subjects; at 
least 5 of which will have BRD4 amplification and another 5 will have MYC amplification/overexpression/ 
translocation.  The BRD4 and MYC molecular signature will be identified by known status before subject 
screening.  The mCRPC cohort will include approximately 20 subjects; at least 5 of which will have AR-V7 and at 
least another 5 of which will have poorly differentiated neuroendocrine phenotype.  The AR molecular signature 
will be identified by known status before subject screening.  The NHL cohort will include approximately 
45 subjects; 5 to 15 of which will have a diagnosis of "double-hit" or "triple-hit" DLBCL, 5 to 15 of which will 
have follicular lymphoma, and 5 to 15 of which to enroll other NHLs such as Burkitt's lymphoma or BCLU (with 
features intermediate between DLBCL and Burkitt's lymphoma).  The other tumor type cohorts in the Part 2/TGA 
expansion will enroll approximately 5 to 15 subjects each.  An additional group of up to approximately 20 subjects 
with any tumor (except separately listed) known to have pathway alteration relevant to BET protein signaling will 
also be enrolled.  Part 2/TGA expansion may enroll up to approximately 165 subjects. 
d Part 2/TGB Expansion will enroll 5 to 15 (each tumor type) subjects with AML, HR-MDS, MDS/MPN or MF for 
a possible total of up to 45 subjects; Part 2/TGC Expansion will enroll 5 to 15 subjects with MM for a possible 
total of up to 15 subjects. 
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4.1.3. 
Part 3 − Combination Dose Escalation (C-ES) 
Part 3 will determine the MTD and/or a tolerated dose (the RP2D) of the combination of 
INCB057643 and one of the SOC agents in relapsed or refractory advanced or metastatic solid 
tumor and hematologic malignancies.  See Figure 3.  The starting dose of INCB057643 in the 
combination treatment groups will be the PAD or 1 dose level below the MTD of INCB057643 
monotherapy identified in Part 1 of this study.  Pending emerging data in Part 1 and Part 2, a 
lower starting dose of INCB057643 could be selected for all or several combinations in Part 3 
(eg, 2 dose levels below the MTD of INCB057643 in Part 1).  Starting doses of the SOC 
combination agents will be selected from conventional dose regimens for the first dose cohort 
and can be modified for the subsequent cohorts, pending emerging safety data.  INCB057643 
doses will not exceed the monotherapy MTD identified in Part 1.  
Combination treatment groups will escalate independently and in parallel until the MTD and/or a 
tolerated dose (the RP2D) of the combinations is identified and will be followed by independent 
expansion cohorts at the selected dose(s) in Part 4.  Pending emerging data, more than 1 RP2D 
dose could be explored in each expansion cohort in Part 4. 
Dose escalation will follow the 3 + 3 design.  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.  See Section 3 for subject eligibility. 
Figure 3: 
Part 3 Combination Dose Escalation Study Design 
 
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4.1.4. 
Part 4 − Combination Dose Expansion (C-EX) 
After identification of the RP2D in combination regimens in Part 3, Part 4 will enroll subjects 
with select relapsed or refractory advanced or metastatic solid tumor and hematologic 
malignancies to further determine safety, tolerability, efficacy, PK, and PD in the treatment 
groups presented in Figure 4.  The sponsor may decide not to expand any or some cohorts 
pending emerging data.  See Section 3 for subject eligibility.  
Figure 4: 
Part 4 Combination Dose Expansion Study Design 
 
4.2. 
Number of Subjects 
4.2.1. 
Planned Number of Subjects 
• Part 1:  3 to 10 subjects may be enrolled per cohort per treatment group (3 treatment 
groups/approximately 60 subjects).  See Figure 2. 
• Part 2:  225 subjects may be enrolled across 3 treatment groups.  See Figure 2. 
• Part 3:  3 to 10 subjects may be enrolled per cohort per treatment group (6 treatment 
groups/approximately 60 subjects).  See Figure 3. 
• Part 4:  Approximately 71 subjects may be enrolled across 4 treatment groups.  
See Figure 4. 
• Approximately 19 centers are planned to participate in this study in the United States 
and in the European Union. 
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4.2.2. 
Replacement of Subjects 
During Part 1 and Part 3, subjects will be replaced for any of the following reasons:  
• Subjects who have not received at least 80% of planned INCB057643 doses during 
the 21- or 28-day DLT observation period.  For INCB057643 QD dosing, a 21-day 
cycle would require at least 17 doses; a 28-day cycle would require at least 23 doses.  
• Subjects who do not meet the eligibility requirements of the study (see Section 3). 
4.3. 
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. 
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.  When the subject discontinues INCB057643, the treatment period will end and 
the subject will enter the follow-up period (see Section 6.2).  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 ICF.  The end of the study will occur when all 
subjects have discontinued study drug and have completed applicable follow-up assessments.  
The overall duration of the study is expected to be approximately 24 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 institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or the 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. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Study sites will enter subject demographic and baseline data into the interactive voice/web 
response technology (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 withdraw consent or discontinue from the study after being 
assigned a subject number will retain their initial number. 
Site staff will contact the IRT to enter the quantities of study drug that are received from the 
sponsor and what has been dispensed to the subjects.  Refer to the IRT manual for detailed 
information. 
For subjects who signed an ICF but are not allocated and for subjects who are allocated but were 
not treated, refer to the electronic case report form (eCRF) Completion Guidelines for instruction 
on which eCRFs to complete. 
5.1.2. 
Randomization and Blinding 
Not applicable. 
5.2. 
Study Drugs 
5.2.1. 
INCB057643 
5.2.1.1. 
Description and Administration 
Physical and chemical properties of INCB057643 are summarized in the IB.  INCB057643 is 
formulated as 4 mg immediate-release tablets.  The tablet is round and white to off-white and 
contains the active drug substance along with compendial grade excipients lactose monohydrate, 
sodium starch glycolate, and magnesium stearate. 
Subjects will self-administer INCB057643 orally QD, as instructed by the investigator.  It will be 
administered in the clinic on the schedule outlined in Section 6.  INCB057643 doses should be 
taken in the morning on an empty stomach when possible.  Subjects will fast for approximately 
2 hours before and 1 hour after INCB057643 administration, except on days when serial PK and 
PD sampling is conducted, then subjects will fast at least 8 hours before the study drugs or as 
indicated in Section 7.8.  If a dose is missed by more than 8 hours, then the subject should skip 
that dose and take next scheduled dose at the usual time.  The sponsor may implement alternate 
administration, such as intermediate doses, alternate dosing schedules, or alternate formulations, 
depending on PK, PD, and safety results.  Subjects will continue to receive combination therapy 
as long as they are deriving benefit and have not met any of the Protocol-defined conditions for 
discontinuation of treatment.  Intra-subject dose escalation is not permitted in combination 
therapy treatment groups. 
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The starting dose in Part 1/TGA was 8 mg QD.  The starting dose of INCB057643 in Part 2 will 
be the PAD or 1 dose level below the MTD of INCB057643 monotherapy identified in Part 1 of 
the study.  The starting dose of INCB057643 in Part 3 C-ES-TGA/TGB/TGC/TGD will be 8 mg 
QD, identified as the PAD, and 1 dose level below the MTD of 12 mg QD identified in 
Part 1/TGA of the study (Section 1.6) in a 21- or 28-day continuous treatment cycle, depending 
on the SOC agent being administered in combination.  Pending emerging data in Part 1 and 
Part 2, a lower starting dose of INCB057643 could be selected for all or several combinations in 
Part 3 (eg, 2 dose levels below the MTD of INCB057643 in Part 1).  The starting dose of 
INCB057643 in Part 4 will be the treatment group–specific RP2D identified in Part 3. 
5.2.1.2. 
Supply, Packaging, and Labeling 
INCB057643 will be provided as 4 mg tablets packaged in high-density polyethylene bottles.  
No preparation is required.  All Incyte investigational product labels will be in the local language 
and will comply with the legal requirements of each country and will state "Caution: New 
Drug—Limited by Federal (or United States) law to investigational use." 
5.2.1.3. 
Storage 
INCB057643 drug product should be stored at ambient conditions (15°C-30°C or 59°F-86°F). 
5.2.1.4. 
Dispensing Study Drug 
An initial bulk supply of INCB057643 will be provided to investigative sites by Incyte before 
enrollment of the first subject.  When dispensing to subjects, the investigator or designee will 
contact the IRT system, remove the appropriate quantity of study drug from their stock, dispense 
the medication, and enter the amount dispensed into the eCRF and drug accountability log.  Full 
details will be provided in the Study Manual. 
5.2.1.5. 
Instruction to Subjects for Handling Study Drug 
The subject must be instructed in the handling of study drug as follows: 
• To store the study drug at room temperature. 
• To only remove from the study drug bottle the number of tablets needed at the time of 
administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses on schedule. 
• To fast for approximately 2 hours before and 1 hour after INCB057643 
administration. 
• If a dose is missed by more than 8 hours, then the subject should skip that dose and 
take next scheduled dose at the usual time. 
• To report any missed doses. 
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• If the subject vomits after taking study drug, the subject should not take another dose; 
dosing should be resumed at the next scheduled dose. 
• To keep study drug in a safe place and out of reach of children. 
To bring all used and unused study drug kits to the site at each visit. 
5.2.2. 
Standard of Care Agents 
Conventional regimens of the SOC agents will be used throughout Part 3 and Part 4 of the study 
(see Table 6).  Subjects will continue to receive combination therapy as long as they are deriving 
benefit and have not met any of the Protocol-defined conditions for discontinuation of treatment.  
Dosing adjustment (dosing delay and/or dose reduction) during treatment is allowed.  
Intra-subject dose-escalation is not permitted. 
5.2.2.1. 
Gemcitabine Administration 
Gemcitabine will be administered as 1000 mg/m2 by a 30-minute IV infusion (± 5 min), on 
Days 1 and 8 of each 21-day cycle.  Subjects may receive prophylactic granulocyte colony-
stimulating factor (G-CSF) support with filgrastim (Neupogen®) per institutional guidelines, 
however, it should not be given in the first cycle unless discussed with the medical monitor. 
5.2.2.2. 
Paclitaxel Administration 
Paclitaxel will be administered as 80 mg/m2 by a 1-hour IV infusion (± 15 min) on Days 1, 8, 
and 15 of each 21-day cycle.  Treatment continuation following clinical response will be at the 
discretion of the investigator.  Subjects must receive premedications (IV or PO) with 
corticosteroids, H1- and H2-antagonists, antihistamines, and antiemetics based on institutional 
guidelines, investigator practice, or local prescribing information or standards of care.  Subjects 
may receive prophylactic G-CSF support with filgrastim (Neupogen) per institutional guidelines, 
however, it should not be given in the first cycle unless discussed with the medical monitor. 
5.2.2.3. 
Rucaparib Administration 
Rucaparib will be administered as 600 mg (two 300 mg tablets) PO BID in a continuous dosing 
regimen with or without food.  This oral agent is prepared as 200, 250, and 300 mg tablets. 
5.2.2.4. 
Abiraterone Administration 
Abiraterone will be administered as 1000 mg (two 500 mg tablets or four 250 mg tablets) PO QD 
in a continuous dosing regimen in combination with prednisone 5 mg PO BID.  Abiraterone 
should be taken on an empty stomach; no food should be consumed for at least 2 hours before 
the dose is taken and for at least 1 hour after the dose is taken. 
5.2.2.5. 
Ruxolitinib Administration 
Ruxolitinib will be administered as a dose of 5 to 25 mg PO BID in a continuous dosing regimen 
using the dose designated as the stable dose at the time of screening for each subject.  Doses of 
ruxolitinib should be self-administered approximately 12 hours apart without regard to food. 
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5.2.2.6. 
Azacitidine Administration 
Azacitidine will be administered as a dose of 75 mg/m2 IV or SC for 7 days during a 9-day or 
less period (ie, a 2-day break allowed on weekend, if needed) of each 28-day treatment cycle. 
5.2.2.7. 
Supply, Packaging, and Labeling 
In countries where reference therapies (or their generic equivalents) are commercially available, 
investigators are responsible for ensuring that subjects receive commercially available supplies 
of these therapies for the entire duration of study participation.  Incyte may provide certain 
reference therapies where required by applicable law or regulation or under other limited 
circumstances when a subject may not otherwise have access to these therapies.  The contents of 
the labels will be in accordance with all applicable regulatory requirements. 
Table 6: 
Standard of Care Agent Administration 
SOC Agent 
Dose 
Route and 
Administration 
Cycle 
Gemcitabine 
1000 mg/m2 
IV, Days 1 and Day 8 of 
each cycle 
21-day cycle 
Paclitaxel 
80 mg/m2 
IV, Days 1, 8, and 15 of 
each cycle 
21-day cycle 
Rucaparib 
600 mg 
PO, two 300 mg tablets 
BID; continuous with or 
without food 
21-day cycle 
Abiraterone 
1000 mg 
PO, two 500 mg tablets 
QD; continuous plus 
prednisone 5 mg BID on 
empty stomach 
21-day cycle 
Ruxolitinib 
Stable dose at screening 
such as 10-50 mg 
PO, 5-25 mg BID; 
continuous without regard 
to food 
21-day cycle 
Azacitidine 
75 mg/m2 
IV or SC, 7 days during a 
9-day or less period of 
each cycle 
28-day cycle 
5.3. 
Treatment Compliance 
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. 
INCB057643, rucaparib, abiraterone + prednisone, and ruxolitinib are oral medications, and 
compliance will be calculated by the sponsor based on the drug accountability documented by 
the site staff and monitored by the sponsor or the sponsor's designee (tablet counts).  Subjects 
will be instructed to bring all study drugs with them to the study visits in order for site personnel 
to conduct tablet counts to assess study drug accountability.  The drug accountability 
documentation will be used by the sponsor to calculate treatment compliance.  Drug 
accountability will not be captured in InForm for standard-of-care agents used in this study. 
Gemcitabine, paclitaxel, and azacitidine are administered as either IV or SC infusions by the site 
personnel.  Receipt of infusions will be documented by the site staff and monitored by the 
sponsor or the sponsor's designee. 
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5.4. 
Dose Modifications 
5.4.1. 
Study Drug – Part 1 and Part 3 
Selections and modifications to the study drug regimen are planned for dose-escalation cohorts 
(Part 1 and Part 3).  Dose interruptions and modifications also may occur for individual study 
subjects.  The identification of DLTs will define the doses used in planned cohorts.  Further, for 
both INCB057643 and any of the other chemotherapy regimens, the occurrence of DLTs and 
other toxicities (related or unrelated to study drug) will guide decisions for treatment 
interruptions and discontinuation for individual subjects. 
Subjects enrolled in the dose-escalation portion of the study will have the option of escalating to 
a dose found to be tolerated in a subsequent cohort, as per Section 5.4.5.  
5.4.1.1. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
Specific toxicities occurring during Cycle 1 of Part 1 and Part 3 will be considered to be DLTs if 
they meet the definition of a DLT, as defined below (see Table 7).  All DLTs will be assessed by 
the investigator using CTCAE v4.03. 
In Part 1 and Part 3, subjects who took at least 17 of 21 (≥ 80%) prescribed doses (21-day cycle) 
or 23 of 28 (≥80%) prescribed doses (28-day cycle) of INCB057643 during Cycle 1 or had a 
DLT will be included in the evaluation cohort.  Additional subjects will be enrolled to achieve a 
minimum of 3 evaluable subjects in the cohort if there are discontinuations or dose interruptions 
that result in a subject being nonevaluable for dose evaluation. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of determining the tolerated dose of 
INCB057643 in Part 1 and Part 3, 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. 
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Table 7: 
Definition of Dose-Limiting Toxicity 
Nonhematologic toxicity 
• Any ≥ Grade 3 nonhematologic toxicity EXCEPT: 
− Nausea, vomiting, and diarrhea adequately controlled with medical therapy within 48 hours 
− Any nonhematologic toxicity clearly and incontrovertibly related to the underlying disease or its progression 
− Alopecia 
− Grade 3 fatigue, asthenia, fever, anorexia, or constipation 
− Singular or nonfasting elevations in blood glucose (ie, blood glucose excursions will be considered DLTs if 
fasting blood glucose is elevated [≥ Grade 3] on 2 separate occasions 3 days apart). 
Hematologic toxicity 
Parameter 
Treatment Group/Cohort 
Toxicity 
Anemia 
All 
Any Grade 4, unexplained by underlying disease. 
Neutropenia 
Part 1/TGA; Part 3/ 
C-ES-TGA/TGB/TGC/TGD 
Any Grade 4. 
Part 1/TGB; Part 3/ 
C-ES-TGE/TGF 
Grade 4 with a hypocellular bone marrow lasting ≥ 6 weeks 
after the start of a course in the absence of residual disease. 
Part 1/TGC 
Any Grade 4 lasting > 7 days. 
Febrile neutropenia 
Part 1/TGA and TGC; 
Part 3/C-ES-TGA/TGB/ 
TGC/TGD 
Febrile neutropenia of any duration (ANC < 1.0 × 109/L and 
fever ≥ 38.5°C) 
Thrombocytopenia 
Part 1/TGA and TGC; 
Part 3/C-ES-TGA/TGB/ 
TGC/TGD 
Grade 3 or higher with clinically significant bleeding or any 
requirement for platelet transfusion outside of institutional 
practice. 
Other toxicities not meeting DLT criteria 
• While the rules for adjudicating DLTs in the context of dose escalation are specified above, an AE not listed 
above may be defined as a DLT after a consultation with the sponsor and investigators, based on the emerging 
safety profile. 
5.4.1.2. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications, after 
discussion with the sponsor (whenever possible), necessary to optimally treat the subject. 
5.4.1.3. 
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. 
5.4.1.4. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, to agree on dose escalation, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
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5.4.2. 
INCB057643 Dose Interruptions and Reductions 
Treatment with INCB057643 may be delayed up to 2 weeks (14 days) to allow for resolution of 
toxicity.  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 INCB057643. 
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 8).  In general, these guidelines should be followed for all the AEs unless the event can 
clearly be determined to be UNRELATED to the study drug.  ALT/AST elevations should be 
managed as described in Table 8.  Thrombocytopenia, neutropenia, and anemia should be 
managed according to the guidelines (Table 8).  In general, study drug should be interrupted for 
Grade 3 AEs and not resumed until the event improves to ≤ Grade 1, at which point it may be 
resumed at the next lower dose level.  In general, study drug should be permanently discontinued 
for Grade 4 AEs.  Exceptions can be made for the hematologic toxicities (thrombocytopenia, 
neutropenia, and anemia) without clinical consequence (eg, no fever, infection, bleeding).  Other 
transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs 
or symptoms may also be exempt from dose-reduction rules.  Hematologic events (eg, 
thrombocytopenia, anemia, neutropenia) occurring in Part 1 precipitating dose interruptions 
during Cycle 1 of treatment will be evaluated as potential DLTs (Table 7)  Hematologic AEs that 
precipitate dose interruptions should be monitored for recovery at least every 3 days, if feasible.  
Other AEs should follow the guidelines for their management according to the section of 
"GENERAL TOXICITIES" in Table 8. 
Table 8: 
Guidelines for Interruption and Restarting of INCB057643 
GENERAL TOXICITIES 
Adverse Event 
Action Taken 
• Any Grade 1 or Grade 2 toxicity 
Continue INCB057643 and treat the toxicity; monitor as 
clinically indicated. 
• Any Grade 3 toxicity, if clinically significant and not 
manageable by supportive care 
1. Interrupt INCB057643 up to 2 weeks (14 days), until 
toxicity resolves to ≤ Grade 1. 
2. Restart INCB057643 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 INCB057643 and follow-up per Protocol.  
(Exceptions require approval of sponsor.) 
• Any other Grade 4 toxicity 
Discontinue INCB057643 and follow-up per Protocol. 
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Table 8: 
Guidelines for Interruption and Restarting of INCB057643 (Continued) 
CHEMISTRY 
Adverse Event 
Action Taken 
• Grade 3 AST and/or ALT is > 5.0 and < 20.0 × ULN 
In subjects with liver metastasis-related elevations at 
baseline, contact sponsor to discuss clinical 
management. 
• Interrupt INCB057643 up to 2 weeks (14 days) until 
the toxicity has resolved to ≤ Grade 1. 
• Monitor LFTs at least weekly until the toxicity has 
resolved to ≤ Grade 1. 
• If resolved within 14 days after INCB057643 
interruption, restart INCB057643 at next lower dose 
(or at 25% reduction, rounded down to the nearest pill 
strength); monitor as clinically indicated. 
• If not resolved to ≤ Grade 1 or baseline within 
14 days after INCB057643 interruption, discuss with 
medical monitor. 
• Complete a coagulation panel on the subject. 
• Evaluate for potential Hy's law case (Appendix Q). 
• 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.   
• Grade 4 AST and/or ALT is ≥ 20.0 × ULN 
In subjects with liver metastasis-related elevations at 
baseline, contact sponsor to discuss clinical 
management. 
Discontinue INCB057643. 
• Total bilirubin > 2 × ULN 
In subjects with Gilbert's syndrome, contact sponsor to 
discuss clinical management. 
Evaluate for potential Hy's Law case (Appendix Q): 
• If < 3 × ULN, monitor at least weekly until resolved 
to ≤ Grade 1. 
• If > 3 × ULN, interrupt treatment, when resolved to 
≤ Grade 1, restart INCB057643 at the next lower 
dose. 
• If >10 × ULN, discontinue INCB057643. 
• ALT > 3.0 × ULN, ALP < 2 × ULN, and bilirubin 
≥ 2.0 × ULN (Hy's Law), and no other immediately 
apparent possible cause of aminotransferase elevation 
and hyperbilirubinemia, including, but not limited to, 
viral hepatitis, pre-existing chronic or acute liver 
disease, or the administration of other drug(s) known 
to be hepatotoxic. 
Discontinue INCB057643. 
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Table 8: 
Guidelines for Interruption and Restarting of INCB057643 (Continued) 
HEMATOLOGY 
Parameter 
Treatment Group/ 
Expansion Cohort 
Adverse 
Event 
Action Taken 
* Platelet 
count 
(× 109/L) 
Part 1/TGA; 
Part 1/TGC; 
Part 3/C-ES-TGA/ 
TGB/TGC/TGD 
25 to < 50 
• Hold until resolved to ≥ 75 if baseline was > 100; or 
hold until resolved to ≥ 50, if baseline was > 75; 
monitor CBC approximately every 3 days. 
• Restart INCB057643 at same dose and monitor. 
• At second occurrence, restart INCB057643 at next 
lower dose and monitor.   
< 25 
• Discontinue INCB057643 if symptomatic.  
• If asymptomatic: 
− Hold until resolved to ≥ 75, if baseline was > 100; 
or hold until resolved to > 50, if baseline was > 75; 
monitor CBC approximately every 3 days. 
− Restart INCB057643 at a reduced dose; consult 
medical monitor if needed.  
− At second occurrence, discontinue INCB057643. 
Parts 1 and 2/TGB; 
Part 3/C-ES-TGF; 
Part 4/C-EX-TGD 
N/A 
Thrombocytopenia should be managed as per 
institutional standard, relevant to the underlying disease.  
Consult with the medical monitor for management 
outside of the institutional standard. 
Part 3/C-ES-TGE; Part  
4/C-EX-TGC 
≥ 50% 
decrease from 
baseline 
platelet count 
• Evaluate underlying disease 
• Consider dose interruption if cytopenias are NOT due 
to underlying disease or treatment with SOC agents. 
• Restart INCB057643 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 8: 
Guidelines for Interruption and Restarting of INCB057643 (Continued) 
HEMATOLOGY 
Parameter 
Treatment Group/ 
Expansion Cohort 
Adverse 
Event 
Action Taken 
* ANC 
(× 109/L) 
Part 1/TGA; 
Part 3/C-ES-TGA/ 
TGB/TGC/TGD; 
Part 4/C-EX-TGA/ 
TGB 
< 1.0 
• Hold until resolved to ≥ 1.0; monitor CBC 
approximately every 3 days. 
• Restart INCB057643 at same dose and monitor; at 
second occurrence, restart INCB057643 at next lower 
dose and monitor. 
< 0.5 
Discontinue INCB057643; consult medical monitor if 
needed. 
Parts 3/C-ES-TGE; 
Part 4/C-EX-TGC 
≥ 50% 
decrease from 
baseline ANC 
count 
• Evaluate underlying disease. 
• Consider dose interruption if cytopenias are NOT due 
to underlying disease or treatment with SOC agents.  
• Restart INCB057643 at next lower dose (or 25% 
reduction if in expansion cohort, rounded down to the 
nearest tablet strength); monitor as clinically 
indicated. 
Parts 1 and 2/TGB; 
Parts 3/C-ES-TGF; 
Part 4/C-EX-TGD 
N/A 
Neutropenia should be managed as per institutional 
standard, relevant to the underlying disease.  Consult 
with the medical monitor for management outside of the 
institutional standard. 
* Hgb 
(g/dL) 
Part 1/TGA, 
Part 2/TGA; 
Part 1/TGC; 
Part 2/TGC; 
Part3 C-ES-TGA/ 
TGB/TGC/TGD; 
Part 4/C- EX-TGA/ 
TGB 
< 8.0 
• Hold until resolved to ≥ 8.0; monitor CBC 
approximately every 3 days; provide supportive care 
if needed. 
• Restart INCB057643 at same dose and monitor per 
Protocol. 
• At second occurrence, restart INCB057643 at next 
loser dose and monitor. 
• If recovery to > 8.0 does not occur within 14 days of 
dose interruption and/or is refractory to transfusion 
support, permanently discontinue INCB057643 and 
follow-up per protocol. 
< 6.5 
Discontinue INCB057643; consult medical monitor if 
needed. 
Parts 1 and 2/TGB; 
Part 3/C-ES-TGE/ 
TGF; 
Part 4/C-EX-TGC/ 
TGD 
N/A 
Anemia should be managed as per institutional standard, 
relevant to the underlying disease.  Consult with the 
medical monitor for management outside of institutional 
standard. 
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Table 8: 
Guidelines for Interruption and Restarting of INCB057643 (Continued) 
CARDIAC MONITORING 
Event 
Grade 
Action Taken 
Ejection fraction decreased 
(measured by either 
echocardiogram or MUGA) 
Grade 2 
• Mandatory hold of study treatment; may resume 
treatment at a reduced dose at the discretion of the 
investigator when ejection fraction recovered to > 50%;  
or discontinue treatment at the discretion of the 
investigator. 
• Mandatory discontinuation of treatment when recurred 
after resuming study treatment. 
Grade 3/4 
• Mandatory discontinuation of treatment. 
Cardiac troponin (either T or I) 
Grade 1 
• Mandatory hold of study treatment; may resume 
treatment at a reduced dose at the discretion of the 
investigator when cardiac troponin recovered within 
normal reference range; or discontinue treatment at the 
discretion of the investigator. 
• Mandatory discontinuation of treatment when recurred 
after resuming study treatment. 
 
Grade 3 
• Mandatory discontinuation of treatment. 
* Exceptions can be made for these hematologic toxicities without clinical consequence (eg, no fever, infection, bleeding). 
5.4.3. 
Standard of Care Agent Dose Interruptions and Reductions 
Action taken with any of the SOC combination agents in response to AEs should be in 
accordance with the respective agent's prescribing information and will be made at the discretion 
of the investigator; if needed, the sponsor's medical monitor should be consulted.  Standard of 
care treatment cycles may be delayed, or the dose may be reduced for laboratory parameters or 
AEs that are judged by the investigator to be related to the SOC agent.  If study drug needs to be 
permanently discontinued due to an AE clearly associated with the study drug, the SOC agent 
may be continued at the discretion of the investigator and with approval of the medical monitor. 
5.4.3.1. 
Specific Guidelines for Gemcitabine and Paclitaxel in Solid Tumors 
Specific guidelines for gemcitabine and paclitaxel dose interruptions, reductions, and 
modifications in the treatment of solid tumors is as follows: 
1. Gemcitabine: 
a. Follow the label or institutional guidelines for dose interruption, restarting, and 
modification regarding hematologic toxicities. 
b. Generally, no dose modification is required for ≤ Grade 3 liver function test (LFT) 
abnormalities; discontinuation is required for Grade 4 LFT toxicity or Hy's Law 
cases. 
c. Generally, no dose modification is required for ≤ Grade 2 nonhematologic toxicities; 
dose reduction is recommended for Grade 3 AEs, and discontinuation is required for 
Grade 4 AEs. 
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2. Paclitaxel: 
a. Follow the label or institutional guidelines for dose interruption, restarting, and 
modification regarding hematologic toxicities. 
b. Dose interruption and reduction may be needed for ≥ Grade 2 neuropathy; 
discontinuation may be needed for persistent ≥ Grade 3 neuropathy. 
c. Generally, no dose modification is required for ≤ Grade 2 LFT abnormalities; 1-level 
dose reduction is recommended for concomitant Grade 2 ALT/AST elevation and 
Grade 1 total bilirubin increased, and 2-level dose reduction is recommended for 
Grade 3 LFT elevations.  Discontinuation is required for Grade 4 LFT toxicity or Hy's 
Law cases. 
5.4.4. 
Criteria for Permanent Discontinuation of INCB057643 
The occurrence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study drug treatment and will require that the study drug be 
permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that, 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. 
• A persistent treatment-related AE requiring a delay of therapy for more than 2 weeks 
(14 days), unless a greater delay has been approved by the sponsor. 
• An AE requiring more than 2 dose reductions of INCB057643, if below the PAD of 
INCB057643. 
5.4.5. 
Criteria and Procedures for Dose Escalations of INCB057643 
Intrasubject dose escalation of INCB057643 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. 
• The subject has received ≥ 4 cycles of study drug without drug-related toxicity 
≥ Grade 2. 
• The dose level to which the subject will be escalating has been determined to be safe 
based on the MTD criteria. 
• The subject is willing to submit to the PK, PD, and ECG schedule as required in 
Cycle 1 (other Cycle 1−specific assessments do not need to be repeated). 
• In the opinion of the investigator, the subject does not have any concurrent condition 
or circumstance that would complicate the dose escalation or PK/PD sampling, or 
pose increased risk to the subject. 
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5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study drug for the following reasons: 
• The subject becomes pregnant. 
• Consent is withdrawn.  Note:  Consent withdrawn means that the subject can no 
longer be followed.  Subjects may choose to discontinue study treatment and remain 
in the study to be followed for progression and survival (as applicable). 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
• Unacceptable toxicity has occurred to the subject. 
• Disease progression has occurred except in the circumstance where, in the setting of 
otherwise stable disease, a medical procedure or radiation therapy is required to a 
single lesion, with medical monitor approval. 
A subject may be discontinued from study treatment as follows: 
• If, during the course of the study, a subject is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, the sponsor should be consulted for instruction on handling the 
subject. 
5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the last date of 
the last dose of study drug and the reason for subject withdrawal will be recorded in the eCRF.  
In addition, the following steps should be followed (Note:  These visits are described in 
Section 6): 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The end of treatment (EOT) visit should be performed. 
• The end of study (EOS) visit should be performed following the 30-day safety 
follow-up visit unless there is a going SAE or clinically significant AE.  In this case, 
EOS visit will occur when the AE is resolved, returned to baseline, or deemed 
irreversible per the investigator. 
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• The date of the EOT visit should be recorded in the IRT. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, are deemed irreversible, or 
initiation of a new anticancer treatment, whichever occurs first. 
5.6. 
Concomitant Medications 
5.6.1. 
Restricted Medications 
Restricted medications are as follows: 
• Use of chronic systemic corticosteroid doses > 10 mg/day prednisone (or equivalent) 
is not permitted from screening through EOT, except for transient use of < 3 days.  
Short courses [≤ 3 days] of systemic corticosteroids > 10 mg/day prednisone (or 
equivalent) are permitted (eg, for transfusion reaction prophylaxis).  Subjects with 
glioblastoma may be treated with corticosteroids (prednisone or equivalent) 
> 10 mg/day with approval from the medical monitor.  Subjects receiving abiraterone 
may be treated with prednisone as per label instructions. 
• Use of moderate inducers or inhibitors of CYP3A4 (see Appendix O) should be used 
with caution, and investigators should seek other options where possible. 
− Additional timed PK testing following the schedule for Cycle 1 Day 15 may be 
required if subjects initiate or require a dose adjustment of inhibitors or inducers 
of CYP3A4 during the study. 
• Use of anticoagulants that will increase INR, such as coumarin-based anticoagulants 
(eg, warfarin), is discouraged, but not prohibited.  Investigators are encouraged to 
switch subjects to alternate anticoagulation therapies which does not directly target 
Factor VII and increase INR.  Coagulation panel should be monitored more closely 
while a subject is on any anticoagulant.   
• Hydroxyurea for controlling proliferative disease is permitted with medical monitor 
approval, but 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.  
• For subjects taking INCB057643 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 GI 
toxicity. 
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5.6.2. 
Prohibited Medications 
Prohibited medications are as follows: 
• Use of any anticancer drugs during study other than any Protocol-required agents.  
Denosumab and zoledronic acid are permitted to treat cancer-related bone diseases. 
• Use of potent inducers and inhibitors of CYP3A4 (see Appendix O), with the 
exception of certain topical medications such as ketoconazole, based on its low 
overall bioavailability. 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in Table 9, Table 11, Table 14, Table 17, 
Table 20, Table 23, and Table 26.  All laboratory assessments will be performed as indicated in 
Table 10, Table 12, Table 15, Table 18, Table 21, Table 24, and Table 27.  All timed PK 
assessments will be performed as indicated in Table 13, Table 16, Table 19, Table 22, Table 25, 
and Table 28.  Table 30 described the laboratory analytes to be assessed.  Section 7 describes the 
instructions on each assessment.  Further details of study procedures and assessments can be 
found in the study reference manual. 
For combination therapy treatment groups, Day 1 of each study cycle will correspond with the 
first day of SOC agent administration in that cycle; thus study cycles may become out of sync 
with the originally planned disease assessment schedule.  In this event, disease assessments 
will remain on the original schedule for that treatment group and will be measured from 
the baseline (screening) disease assessment.  All other assessments will shift to coincide with 
the revised treatment (cycle) schedule.  For example, if one of the SOC agents has a delay in 
beginning therapy on Cycle 2 Day 1, the next scheduled visit when the SOC agent is 
administered will be Cycle 2 Day 1, and all other assessments will coincide with that Cycle 2 
Day 1. 
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Table 9: 
Schedule of Assessments – Monotherapy INCB057643 (Part 1 and Part 2; All Treatment Groups) 
Visit Day 
Section 
Screening 
Treatment 
EOT 
Disease Assessment 
Safety 
Follow-Up 
C1 
C2 and Beyond 
D-28 to D-1 
D1 
D2 
D8 
D15 
D1 
D2
a 
D11
b 
Evaluation/Window 
 
 
 
± 3 D 
± 3 D 
± 3 D 
 
± 3 D 
+ 3 D 
Per Investigator 
Discretion 
30 to 35 D 
After EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3 
X 
X
c 
 
 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
 
X 
 
 
X 
 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
d 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AE assessment 
7.5.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete/targeted physical examination
e 
7.5.2 
Xe 
X 
 
X 
X 
X 
 
X 
Xe 
 
Xe 
ECOG performance status 
7.6.1 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Vital signs/weight 
7.5.3 
X 
X 
X
f 
Xf 
Xf 
X 
Xf 
Xf 
X 
 
X 
12-Lead ECG  
7.5.4 
X 
 
 
 
 
X 
 
 
 
 
X 
Timed triplicate 12-lead ECG
g 
7.5.4.3 
 
X 
 
X 
 
 
 
 
 
 
 
Immunophenotyping
h 
7.7.5 
X 
When confirming CR 
 
 
Tumor biopsy (TGA)
i 
7.7.4 
X 
Optional tumor biopsy during study, as clinically indicated 
 
 
Bone marrow examination (TGB and TGC)
j 
7.7.4 
X 
 
 
 
 
Xj 
 
 
 
 
 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
 
 
 
Efficacy/disease assessments
k 
 
 
 
 
 
 
 
 
 
 
X 
 
Skeletal survey
l 
7.7.8 
X 
At investigator discretion 
 
 
Administer INCB057643 in clinic 
5.2.1.1 
 
X 
X 
X 
 
X
m 
Xm 
 
 
 
 
Drug dispense/compliance check 
5.2.1.4, 5.3 
 
X 
 
 
 
X 
 
 
X
n 
 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
7.5.4.4 
 
X 
 
 
 
X 
 
 
X 
 
X 
a Applicable to Part 2/TGA subjects in the food-effect study at Cycle 2 only.  See Section 7.8.4 for details. 
b After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
c On C1D1 only, review inclusion/exclusion criteria before dose administration. 
d Prior medications documented only at screening. 
e Comprehensive physical examination required at screening, EOT, and safety follow-up.  Targeted physical examination will be conducted at other visits.  Height will be measured at screening only. 
f Weight not required. 
g Triplicate ECGs will be performed predose and 0.5, 1, 2, 4, 6, and 8 hours postdose and within 15 minutes of the PK sampling on C1D1 and C1D8.  Note that triplicate ECGs will be performed with a 
1- to 3-minute break between evaluations.   
h Immunophenotyping appropriate to the underlying pathology will be conducted by flow cytometry at screening and when confirming CR on subjects with lymphoma, leukemia, and MPNs 
(MDS/MPN and MF). 
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i All subjects in TGA (solid tumors and lymphoma) will have a tumor biopsy at screening (unless adequate archival tissue is available as per Section 7.9.9).  This is not required for glioblastoma.  
Biopsy during treatment and/or at disease progression are strongly recommended, but not mandatory.  For example, if a biopsy is performed during the treatment period to assess disease status, to 
confirm response or progression, or if otherwise clinically indicated, a sample of the biopsy will be provided to the sponsor.  The subject will need to sign ICF for optional biopsy.  See Section 7.9.9 
for additional details. 
j Investigators will perform disease and efficacy assessments per their own discretion.  All subjects in TGB and TGC will have a bone marrow biopsy and/or aspirate (as appropriate to underlying 
pathology) at screening.  For TGB, follow-up bone marrow biopsy and/or aspirates performed will be performed at Months 3, 6, 12, and yearly thereafter when required for response assessment, or as 
clinically indicated.  For TGC, follow-up bone marrow biopsy for MM subjects will be performed if confirming a CR unless otherwise clinically indicated.  For MDS/MPN and MF, follow-up bone 
marrow biopsy and/or aspirates performed will be performed at Months 3, 6, 12, and yearly thereafter when required for response assessment, or as clinically indicated.  For AML subjects, bone 
marrow disease assessment during Cycle 2 is strongly recommended unless contraindicated.  See Section 7.7.4 for additional details. 
k Investigators will perform disease and efficacy assessments per their own discretion.  Subjects in TGA will have efficacy/disease assessments performed every 9 weeks (± 1 week) during the treatment 
period.  Subjects in TGB will have peripheral blood disease status assessments at screening, C1D1, C1D15, D1 of each subsequent cycle, and EOT.  If screening assessments are performed within 
7 days of treatment initiation, they do not need to be repeated at C1D1.  Subjects with solid tumors, lymphoma, and MF will have imaging assessments every 9 weeks using the appropriate imaging 
modality (eg, MRI or CT for spleen/liver size assessment in MF).  Bone marrow biopsy and/or aspirates performed as clinically indicated or at Months 3, 6, 12, and yearly thereafter when required for 
response assessment.  See Section 7.7.4 for additional details.  AML disease assessments will be performed on Day 1 of each cycle.  Bone marrow biopsy and/or aspirates for response is to be 
performed at C4D1 or earlier as clinically indicated, followed by every other month as clinically indicated, or upon circulating blood cell recovery, to assess anti-leukemic activity (cytogenetic testing 
is not required if CR is not present).  Note:  For subjects who have a significant blast count reduction (as determined by the investigator) but have not completely cleared circulating blasts, the C4D1 
bone marrow is still strongly encouraged to be performed to assess the impact of treatment on the bone marrow blast content.  See Section 7.7.4 for additional details. 
l TGC only. 
m Applicable to Part 2/TGA subjects in the food-effect study at Cycle 2 only.  See Section 7.8.4 for details. 
n EOT visit – compliance check only. 
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Table 10: 
Schedule of Laboratory Assessments – Monotherapy INCB057643 (Part 1 and Part 2; All Treatment Groups) 
Visit Day 
Section 
Screening
a 
Treatment 
Disease Assessment 
EOT 
Safety 
Follow-Up 
D-28 to D-1 
C1 
C2 and Beyond 
D1 
D2 
D8 
D15 
D1 
D2
b 
D11
c 
Evaluation/Window 
 
 
 
± 3 D 
± 3 D 
± 3 D 
 
± 3 D 
Per Investigator 
Discretion 
+ 3 D 
30 to 35 D 
After EOT 
Overnight fast before visit 
7.8 
 
X 
 
X 
 
Xb 
 
 
 
 
 
Serum chemistry 
7.5.5.1 
X 
X
d 
X 
X 
X 
X 
 
X 
 
X 
X 
Hematology with differential 
7.5.5.1 
X 
Xd 
X 
X 
X 
X 
 
X 
 
X 
X 
Coagulation panel
e 
7.5.5.1 
Xe 
Xd 
X 
Xe 
Xe 
Xe 
 
Xe 
 
X 
X 
Factor VII protein antigen assaye 
7.5.5.1 
Xe 
Xd 
 
Xe 
Xe 
Xe 
 
Xe 
 
X 
X 
Urinalysis  
7.5.5.1 
X 
 
 
 
 
X
f 
 
 
 
X 
X 
Lipid panel 
7.5.5.1 
X 
 
 
 
 
Xf 
 
 
 
X 
 
Hepatitis testing 
7.5.5.3 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test  
7.5.5.2 
X 
X
g 
 
 
 
 
 
 
 
X 
X 
Timed PK – plasma
h 
7.8.1 
 
X 
X 
X 
 
Xb 
Xb 
 
 
 
 
Timed PK – urine
i 
7.8.2 
 
 
 
X 
 
 
 
 
 
 
 
Timed PD – plasma
j 
7.9.2 
 
X 
X 
X 
 
 
 
 
 
 
 
Cardiac troponin (T and/or I) 
 7.5.5.4  
 
X 
 
 
 
X 
 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1.  
b Applicable to Part 2/TGA subjects in the food-effect study at Cycle 2 only.  See Section 7.8.4 for details. 
c After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
d If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
e All subjects will have coagulation panel conducted as indicated in the table and as needed.  Extrinsic pathway coagulation factor profile, at minimum Factor VII protein/antigen assay concentration, 
will be obtained at screening or C1D1, C1D8, C1D15, C2D1, C2D11, and C3D1(sampling does not need to be repeated on Day 11 of Cycle 3 or any subsequent cycles).  However, it should be 
performed any time there is a Grade 2 increased INR.  If the last Factor VII result before the EOT visit is within normal range, Factor VII does not need to be tested EOT.  If the Factor VII result at the 
EOT visit is within normal range, Factor VII does not need to be tested at the safety follow-up visit.  Study visits do not need to be delayed waiting on the Factor VII protein/antigen assay results as 
long as INR/PT results are within normal limits. 
f Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles thereafter (eg, Cycle 10, Cycle 13, etc) during the treatment period. 
g If the screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
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h Collect timed PK samples predose (any time within 30 min of drug administration) and at 0.5 (± 5 min), 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 8 (± 30 min) hours after 
administration on C1D1 and C1D8; C1D2 is predose only (any time within 30 min of drug administration). 
i Predose void will be collected and time recorded from each subject.  Total urine will be collected over an 8-hour interval after study drug administration.  Two 10 mL aliquots will be collected.  
See Section 7.8.2 for details. 
j Timed plasma PD will follow the same schedule as timed PK samples (predose [any time within 30 min of drug administration] and at 0.5 [± 5 min], 1 [± 15 min], 2 [± 15 min], 4 [± 15 min], 
6 [± 30 min], and 8 [± 30 min] hours after administration on C1D1 and C1D8; C1D2 is predose only [any time within 30 min of drug administration]). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 11: 
Schedule of Assessments – Combination INCB057643 and Gemcitabine (Part 3 C-ES-TGA) 
Visit Day 
Section 
Screening 
Treatment 
Disease Assessment 
EOT 
Safety Follow-Up 
C1 and C2 
C3 and Beyond 
D-28 to D-1 
D1 
D8 
D15 
D1 
D8 
Evaluation/Window 
 
± 3 D 
(C2D1 only) 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per Investigator 
Discretion 
+ 3 D 
30 to 35 D After 
EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3 
X 
X
a 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
X 
 
 
X 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
b 
X 
X 
X 
X 
X 
 
X 
X 
AE assessment 
7.5 
X 
X 
X 
X 
X 
X 
 
X 
X 
Complete/targeted physical examination
c 
7.5.2 
Xc 
X 
X 
X 
X 
X 
 
Xc 
X 
ECOG performance status 
7.6.1 
X 
X 
 
 
X 
 
 
X 
X 
Vital signs/weight 
7.5.3 
X 
X
d 
X 
X 
Xd 
X 
 
X 
X 
12-Lead ECG
e 
7.5.4.1 
X 
X 
 
 
X 
 
 
X 
 
Tumor biopsy
f 
7.7.3 
X 
Optional tumor biopsy during the treatment period and/or at EOT/disease progression, or as 
clinically indicated. 
 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
 
Disease assessments
g 
7.7 
X 
 
 
 
 
 
X 
X 
 
Administer INCB057643 in clinic
h 
5.2.1.1 
 
X 
X 
 
X 
 
 
 
 
Administer gemcitabine in clinic
i 
5.2.2.1 
 
X 
X 
 
X 
X 
 
 
 
Drug dispense/compliance check
j 
5.2.1.4, 
5.3 
 
X 
X 
X 
X 
X 
 
X 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
 
X 
X 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
 7.5.4.4  
 
X 
 
 
X 
 
 
X 
X 
a On C1D1 only, review inclusion/exclusion criteria before dose administration. 
b Prior medications documented only at screening. 
c Complete physical examination at screening and EOT only.  Height at screening only.  Targeted physical examination all other visits.   
d Weight is measured on Day 1 of each cycle only. 
e All 12-lead ECGs will be performed with the subject in a recumbent or semi-recumbent position after 5 minutes of rest and will not be performed within 15 minutes after a blood collection.  
Electrocardiograms may be performed throughout treatment as clinically indicated. 
f Tumor biopsy at screening is required; tumor biopsy during the treatment period and/or at disease progression is strongly recommended but not mandatory.   
g The same imaging technique will be used in a subject throughout the study. 
h INCB057643 will be administered in the clinic for any study visit where a PK sample is drawn and on Day 1 of each cycle.  INCB057643 will be administered before chemotherapy. 
i Gemcitabine will be administered on Days 1 and 8 of each 21-day cycle.  Subjects may receive prophylactic G-CSF support with filgrastim (Neupogen) per institutional guidelines, however, it will not 
be given in the first cycle unless discussed with the medical monitor.  Dosing delay, interruption, reduction, or termination is allowed for AE management. 
j Dispense study drug on Day 1 of each cycle; on all other days, compliance check is required. 
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Page 88 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 12: 
Schedule of Laboratory Assessments – Combination INCB057643 and Gemcitabine (Part 3 C-ES-TGA) 
Visit Day 
Section 
Screening
a 
Treatment 
Disease Assessment 
EOT 
Safety Follow-Up 
C1 and C2 
C3 and Beyond 
D-28 to D-1 
D1 
D8 
D15 
D1 
D8 
Evaluation Window 
 
± 3 D 
(C2D1 
only) 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per Investigator 
Discretion  
+ 3 D 
30 to 35 D After 
EOT 
Overnight fast before visit 
7.8 
 
X
b 
Xb 
 
 
 
 
 
 
Serum chemistry 
7.5.5.1 
X 
X
c 
X 
X 
X 
X 
 
X 
X 
Hematology with differential 
7.5.5.1 
X 
Xc 
X 
X 
X 
X 
 
X 
X 
Coagulation panel
d 
7.5.5.1 
X 
Xc 
X 
X 
X 
 
 
X 
X 
Factor VII protein/antigen assayd 
7.5.5.1 
X 
Xc 
X 
X 
X 
 
 
X 
X 
Urinalysis
e 
7.5.5.1 
X 
Xe 
 
 
Xe 
 
 
X 
X 
Lipid panele 
7.5.5.1 
X 
Xe 
 
 
Xe 
 
 
X 
 
Hepatitis testing 
7.5.5.3 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
7.5.5.2 
X 
X
f 
 
 
 
 
 
X 
X 
Cardiac troponin (either T or I) 
7.5.5.4  
 
X 
 
 
X 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1. 
b Only required during Cycle 1. 
c If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
d All subjects will have coagulation panel conducted at screening, C1D1, C1D8, C1D15, C2D1, C2D8, Day 1 of each subsequent cycle, and when clinically indicated.  If a subject is on a coumarin-
based anticoagulant, such as warfarin, in addition to required testing per Protocol, coagulation panel may be tested as per standard of care or at the investigator's discretion.  Extrinsic pathway 
coagulation factor profile, at minimum Factor VII protein/antigen assay concentration, will be obtained at screening or C1D1, C1D8, C1D15, C2D1, C2D8, C3D1, and any time there is a Grade 2 
increased INR along with the coagulation panel.  If the last Factor VII result before the EOT visit is within normal range, Factor VII does not need to be tested at EOT.  If the Factor VII result at the 
EOT visit is within normal range, Factor VII does not need to be tested at the safety follow-up visit.  Study visits do not need to be delayed waiting on the Factor VII results as long as INR/PT results 
are eligible according to enrollment eligibility.  Factor VII does not need to extend beyond C3D1.   
e Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles thereafter (eg, Cycle 10, Cycle 13, etc) during the treatment period. 
f If the screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
g Correlative plasma will be collected predose C1D1, C2D1, at each disease assessment, and at EOT.  Refer to the Laboratory Manual for collection methods.  May be drawn after the subject signs the 
ICF, is approved for enrollment, and within 7 days before dose administration on C1D1. 
 
 
. 
 
 
 
 
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Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 13: 
Schedule of Timed Pharmacokinetic Assessments – Combination INCB057643 and Gemcitabine (Part 3 
C-ES-TGA) 
Visit 
Fasting 
Requirement 
HOLD 
AM Dose 
Predose
a 
INCB057643 
Dose
b 
Gemcitabine 
Dose 
Time Postdosea 
1 h ± 
15 min 
Snack or 
Meal 
2 h ± 15 min 4 h ± 15 min 6 h ± 15 min 8 h ± 30 min 
C1D1 
At least 8 h before 
study drugs 
N/A 
X 
♦ 
♦ 
X 
X 
X 
X 
X 
X 
C1D8 
At least 8 h before 
study drugs 
X 
X 
♦  
♦ 
X 
X 
X 
X 
X 
X 
a Collect timed PK samples predose (any time within 30 min of INCB057643 administration) and at 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 8 (± 30 min) hours after INCB057643 
administration on C1D1 and C1D8. 
b INCB057643 dose will be administered just before the dose of gemcitabine. 
CONFIDENTIAL 

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Page 90 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 14: 
Schedule of Assessments – Combination INCB057643 and Paclitaxel (Part 3 C-ES-TGB) 
Visit Day 
Section 
Screening 
Treatment 
Disease 
Assessment 
EOT 
Safety 
Follow-Up 
D-28 to D-1 
C1 and C2 
C3 and Beyond 
D1 
D8 
D15 
D1 
D8 
D15 
Evaluation Window 
 
± 3 D 
(C2D1 
only) 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per 
Investigator 
Discretion 
+ 3 D 
30 to 35 D 
After EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3 
X 
X
a 
 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
X 
 
 
 
X 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
b 
X 
X 
X 
X 
X 
X 
 
X 
X 
AE assessment 
7.5 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Complete/targeted physical examination
c 
7.5.2 
Xc 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECOG performance status 
7.6.1 
X 
X 
 
 
X 
 
 
 
X 
X 
Vital signs/weight 
7.5.3 
X 
X
d 
X 
X 
Xd 
X 
X 
 
X 
X 
12-Lead ECG
e 
7.5.4.1 
X 
X 
 
 
X 
 
 
 
X 
 
Tumor biopsy
f 
7.7.3 
X 
Optional tumor biopsy during the treatment period and/or at EOT/disease progression, or as clinically 
indicated. 
 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
 
 
Disease assessments
g 
7.7 
X 
 
 
 
 
 
 
X 
X 
 
Administer INCB057643 in clinic
h 
5.2.1.1 
 
X 
X 
 
X 
 
 
 
 
 
Administer paclitaxel in clinic
i 
5.2.2.2  
 
X 
X 
X 
X 
X 
X 
 
 
 
Drug dispense/compliance check
j 
5.2.1.4, 5.3 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
   7.5.4.4  
 
X 
 
 
X 
 
 
 
X 
X 
a On C1D1 only, review inclusion/exclusion criteria before dose administration. 
b Prior medications documented only at screening. 
c Complete physical examination at screening only.  Height at screening only.  Targeted physical examination at all other visits. 
d Weight is measured on Day 1 of each cycle only. 
e All 12-lead ECGs will be performed with the subject in a recumbent or semi-recumbent position after 5 minutes of rest and will not be performed within 15 minutes after a blood collection.  
Electrocardiograms may be performed throughout treatment as clinically indicated. 
f Tumor biopsy at screening is required; tumor biopsy during treatment and/or at disease progression is strongly recommended but not mandatory. 
g The same imaging technique will be used in a subject throughout the study. 
h INCB057643 will be administered in the clinic for any study visit where a PK sample is drawn and on Day 1 of each cycle.  INCB057643 will be administered before chemotherapy. 
i Paclitaxel will be administered on Days 1, 8, and 15 of each 21-day cycle.  Subjects must receive premedications (IV or PO) with corticosteroids, H1- and H2-antagonists, antihistamine, and 
antiemetics based on institutional guidelines, investigator practice, or local prescribing information or standards of care.  Subjects may receive prophylactic G-CSF support with filgrastim (Neupogen) 
per institutional guidelines.  Prophylactic G-CSF will not be given in the first cycle unless discussed with the medical monitor.  Dosing delay, interruption, reduction, or termination is allowed for AE 
management. 
j Dispense study drug on Day 1 of each cycle; on all other days, compliance check is required. 
CONFIDENTIAL 

Incyte Corporation 
Page 91 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 15: 
Schedule of Laboratory Assessments – Combination INCB057643 and Paclitaxel (Part 3 C-ES-TGB) 
Visit Day 
Section 
Screening
a 
Treatment 
Disease 
Assessment 
EOT 
Safety 
Follow-Up 
C1 and C2 
C3 and Beyond 
D-28 to D-1 
D1 
D8 
D15 
D1 
D8 
D15 
Evaluation Window 
 
± 3 D 
(C2D1 
only) 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per 
Investigator 
Discretion 
+3 D 
30 to 35 D 
After EOT 
Overnight fast before visit
b 
7.8 
 
X 
X 
 
 
 
 
 
 
 
Serum chemistry 
7.5.5.1 
X 
X
c 
X 
X 
X 
X 
X 
 
X 
X 
Hematology with differential 
7.5.5.1 
X 
Xc 
X 
X 
X 
X 
X 
 
X 
X 
Coagulation panel
d 
7.5.5.1 
X 
Xc 
X 
X 
X 
 
 
 
X 
X 
Factor VII protein/antigen assayd 
7.5.5.1 
X 
Xc 
X 
X 
X 
 
 
 
X 
X 
Urinalysis
e 
7.5.5.1 
X 
Xe 
 
 
Xe 
 
 
 
X 
X 
Lipid panele 
7.5.5.1 
X 
Xe 
 
 
Xe 
 
 
 
X 
 
Hepatitis testing 
7.5.5.3 
X 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
7.5.5.2 
X 
X
f 
 
 
 
 
 
 
X 
X 
Cardiac troponin (either T or I) 
7.5.5.4  
 
X 
 
 
X 
 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1. 
b Only required during Cycle 1. 
c If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
d All subjects will have coagulation panel including Factor VII protein/antigen assay concentration conducted at screening, C1D1, C1D8, C1D15, C2D1, C2D8, C2D15, C3D1, and any time there is a 
Grade 2 increased INR.  If the last Factor VII result before the EOT visit is within normal range, Factor VII does not need to be tested at EOT.  If the Factor VII result at the EOT visit is within normal 
range, Factor VII does not need to be tested at the safety follow-up visit.  If a subject is on a coumarin-based anticoagulant, such as warfarin, in addition to required testing per Protocol, coagulation 
panel may be tested as per standard of care or at the investigator's discretion.  Study visits do not need to be delayed waiting on the Factor VII results as long as INR/PT results are eligible according to 
enrollment eligibility.  Factor VII does not need to extend beyond C3D1.  Coagulation panel is conducted on Day 1 of each subsequent cycle beginning with Cycle 3. 
e Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles there after (eg, Cycle 10, Cycle 13, etc) during the treatment period. 
f If the screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
 
 
 
 
 
 
 
CONFIDENTIAL 

Incyte Corporation 
Page 92 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 16: 
Schedule of Timed Pharmacokinetic Assessments – Combination INCB057643 and Paclitaxel (Part 3 
C-ES-TGB) 
Visit 
Fasting 
Requirement 
HOLD 
AM Dose 
Predose
a 
INCB057643 
Dose
b 
Paclitaxel Dose 
Time Postdosea 
1 h ± 
15 min 
Snack or 
Meal 
2 h ± 15 min 4 h ± 15 min 6 h ± 15 min 8 h ± 30 min 
C1D1 
At least 8 h before 
the study drugs 
N/A 
X 
♦ 
♦ 
X 
X 
X 
X 
X 
X 
C1D8 
At least 8 h before 
the study drugs 
X 
X 
♦  
♦ 
X 
X 
X 
X 
X 
X 
a Collect timed PK samples predose (any time within 30 min of INCB057643 administration) and at 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 8 (± 30 min) hours after INCB057643 
administration on C1D1 and C1D8. 
b INCB057643 dose will be administered just before the daily dose of paclitaxel. 
CONFIDENTIAL 

Incyte Corporation 
Page 93 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 17: 
Schedule of Assessments – Combination INCB057643 and Rucaparib (Part 3 C-ES-TGC and Part 4 
C-EX-TGA) 
Visit Day 
Section 
Screening 
Treatment 
Disease 
Assessment 
EOT 
Safety 
Follow-Up 
D-28 to D-1 
C1 
C2 and Beyond 
D1 
D8 
D15 
D1 
D11
a 
Evaluation Window 
 
 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per Investigator 
Discretion 
+ 3 D 
30 to 35 D 
After EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3 
X 
X
b 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
X 
 
 
X 
X 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
c 
X 
X 
X 
X 
X 
 
X 
X 
AE assessment 
7.5 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECOG performance status 
7.6.1 
X 
X 
 
 
X 
 
 
X 
X 
Comprehensive/targeted physical 
examination
d 
7.5.2 
Xd 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs/weight
e 
7.5.3 
X 
Xe 
X 
X 
Xe 
X 
 
X 
X 
12-Lead ECG
f 
7.5.4.1 
X 
X 
 
 
X 
 
 
X 
X 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
 
Tumor biopsy
g 
7.7.3 
X 
 
 
 
Optional tumor biopsy during the treatment period and/or at 
EOT/disease progression, or as clinically indicated. 
 
Disease assessments
h 
7.7 
X 
 
 
 
 
 
X 
X 
 
Administer INCB057643 in clinic
i 
5.2.1.1 
 
X 
X 
 
X 
 
 
 
 
Administer rucaparib in clinic
j 
5.2.2.3 
 
X 
X 
 
X 
 
 
 
 
Drug dispense/compliance check
k 
5.2.1.4, 5.3 
 
Xk 
X 
X 
Xk 
X 
 
X 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
 
X 
 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
7.5.4.4  
 
X 
 
 
X 
 
 
X 
X 
a After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
b On C1D1 only, review inclusion/exclusion criteria before dose administration. 
c Prior medications documented only at screening. 
d Complete physical examination at screening only.  Height at screening only.  Targeted physical examination at all other visits. 
e Weight is measured on Day 1 of each cycle. 
f All 12-lead ECGs will be performed with the subject in a recumbent or semi-recumbent position after 5 minutes of rest and will not be performed within 15 minutes after a blood collection.  
Electrocardiograms may be performed throughout treatment as clinically indicated. 
g Tumor biopsy at screening is required; tumor biopsy during treatment and/or at disease progression are strongly recommended but not mandatory. 
h The same imaging technique will be used in a subject throughout the study. 
i INCB057643 will be administered in the clinic for any study visit where a PK sample is drawn and on Day 1 of each cycle.  INCB057643 will be administered before rucaparib. 
j Rucaparib will be administered in the clinic for any study visit where a PK sample is drawn and on Day 1 of each cycle. 
k Dispense drug on Day 1 of each cycle; on all other days, compliance check is required. 
CONFIDENTIAL 

Incyte Corporation 
Page 94 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 18: 
Schedule of Laboratory Assessments – Combination INCB057643 and Rucaparib (Part 3 C-ES-TGC and Part 4 
C-EX-TGA) 
Visit Day 
Section 
Screening
a 
Treatment 
Disease Assessment 
EOT 
Safety Follow-Up 
C1 
C2 and Beyond 
D-28 to D-1 
D1 
D8 
D15 
D1 
D11
b 
Evaluation Window 
 
 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per Investigator 
Discretion 
+ 3 D 
30 to 35 D After 
EOT 
Overnight fast before visit
c 
7.8 
 
X 
X 
 
 
 
 
 
 
Serum chemistry 
7.5.5.1 
X 
X
d 
X 
X 
X 
X 
 
X 
X 
Hematology with differential 
7.5.5.1 
X 
Xd 
X 
X 
X 
X 
 
X 
X 
Coagulation panel
e 
7.5.5.1 
X 
Xd 
X 
X 
X 
 
 
X 
X 
Factor VII protein/antigen assaye 
7.5.5.1 
X 
Xd 
X 
X 
X 
 
 
X 
X 
Urinalysis
f 
7.5.5.1 
X 
 
 
 
Xf 
 
 
X 
X 
Lipid panelf 
7.5.5.1 
X 
 
 
 
Xf 
 
 
X 
 
Hepatitis testing 
7.5.5.3 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
7.5.5.2 
X 
X
g 
 
 
 
 
 
X 
X 
Cardiac troponin (either T or I) 
7.5.5.4 
 
X 
 
 
X 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1. 
b After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
c Only required for Cycle 1. 
d If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
e All subjects will have coagulation panel including Factor VII protein/antigen assay concentration conducted at screening, C1D1, C1D8, and C1D15.  Subsequently, Factor VII only needs to be 
collected on Day 1 of Cycle 2 and Cycle 3; coagulation panel is conducted on Day 1 of each subsequent cycle beginning with Cycle 2.  Factor VII protein/antigen assay will also be collected upon a 
Grade 2 increased INR.  If the last Factor VII result before the EOT visit is within normal ranger, Factor VII does not need to be tested at EOT.  If the Factor VII result at the EOT visit is within 
normal range, Factor VII does not need to be tested at the safety follow-up visit.  If a subject is on a coumarin-based anticoagulant, such as warfarin, in addition to required testing per Protocol, 
coagulation panel may be tested as per standard of care or at the investigator's discretion.  Study visits do not need to be delayed waiting on the Factor VII results as long as INR/PT results are eligible 
according to enrollment eligibility. 
f Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles there after (eg, Cycle 10, Cycle 13, etc) during the treatment period. 
g If the screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 

Incyte Corporation 
Page 95 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 19: 
Schedule of Timed Pharmacokinetic Assessments – Combination INCB057643 and Rucaparib (Part 3 
C-ES-TGC and Part 4 C-EX-TGA) 
Visit 
Fasting 
Requirement 
HOLD 
AM Dose 
Predose
a 
INCB057643 
Dose
b 
Rucaparib 
Dose 
Time Postdosea 
0.5 h ± 
15 min 
1 h ± 
15 min 
Snack or 
Meal 
2 h ± 
15 min 
4 h ± 
15 min 
6 h ± 
15 min 
8 h ± 
30 min 
C1D1 
At least 8 h 
before the study 
drugs 
N/A 
X 
♦ 
♦ 
X 
X 
X 
X 
X 
X 
X 
C1D8 
At least 8 h 
before the study 
drugs 
X 
X 
♦  
♦ 
X 
X 
X 
X 
X 
X 
X 
a Collect timed PK samples predose (any time within 30 min of INCB057643 administration) and at 0.5 (± 5 min), 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 8 (± 30 min) hours after 
INCB057643 administration on C1D1 and C1D8. 
b INCB057643 dose will be administered just before the dose of rucaparib. 
CONFIDENTIAL 

Incyte Corporation 
Page 96 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
Table 20: 
Schedule of Assessments – Combination INCB057643 and Abiraterone (Part 3 C-ES-TGD and Part 4 
C-EX-TGB) 
Visit Day 
Section 
Screening 
Treatment 
Disease 
Assessment 
EOT 
Safety 
Follow-Up 
D-28 to D-1 
C1 
C2 and Beyond 
D1 
D8 
D15 
D1 
D11
a 
Evaluation Window 
 
 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per 
Investigator 
Discretion 
+ 3 D 
30 to 35 D 
After EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
X 
Inclusion/exclusion criteria 
3 
X 
X
b 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
X 
 
 
X 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
c 
X 
X 
X 
X 
X 
 
X 
X 
AE assessment 
7.5 
X 
X 
X 
X 
X 
X 
 
X 
X 
Complete/targeted physical examination
d 
7.5.2 
Xd 
X 
X 
X 
X 
X 
 
X 
X 
ECOG performance status 
7.6.1 
X 
X 
 
 
X 
 
 
X 
X 
Vital signs/weight
e 
7.5.3 
X 
Xe 
X 
X 
Xe 
X 
 
X 
X 
12-lead ECG
f 
7.5.4.1 
X 
X 
 
 
X 
 
 
X 
 
Tumor biopsy
g 
7.7.3 
X 
 
 
 
Optional tumor biopsy during the treatment period 
and/or at EOT/disease progression, or as clinically 
indicated. 
 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
 
Disease assessments:  imaging (nodal, visceral, 
and bone)
h 
7.7.10 
X 
 
 
 
 
 
X 
X 
 
Disease assessments:  blood-based PSA
i 
7.7.10 
X 
 
 
 
X 
 
X 
X 
 
Administer INCB057643 in clinic
j 
5.2.1.1 
 
X 
X 
 
X 
 
 
 
 
Administer abiraterone in clinic
k 
5.2.2.4 
 
X 
X 
 
X 
 
 
 
 
Drug dispense/compliance check
l 
5.2.1.4, 5.3 
 
X 
X 
X 
X 
X 
 
X 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
 
X 
X 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
7.5.4.4  
 
X 
 
 
X 
 
 
X 
X 
a After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
b On C1D1 only; review inclusion/exclusion criteria before dosing dose administration. 
c Prior medications are only documented at screening. 
d Complete physical examination at screening only.  Height at screening only.  Targeted physical examination at all other visits. 
e Weight is measured on Day 1 of each cycle. 
f All 12-lead ECGs will be performed with the subject in a recumbent or semi-recumbent position after 5 minutes of rest and will not be performed within 15 minutes after a blood collection.  
Electrocardiograms may be performed throughout treatment as clinically indicated. 
g Tumor biopsy at screening is required; tumor biopsy during treatment and/or at disease progression is strongly recommended but not mandatory. 
h Investigators will perform disease and efficacy assessments per their own discretion.  The same imaging technique will be used in a subject throughout the study. 
i Blood-based PSA will be assessed at screening, C2D1, Day 1 of each subsequent cycle, at the time of imaging disease assessment, and when clinically indicated. 
CONFIDENTIAL 

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Page 97 of 198 
Protocol INCB 57643-101 Am 7 
Version 7 
22 OCT 2018 
j INCB057643 and abiraterone will be administered in the clinic for any study visit where a PK sample is drawn.  INCB057643 will be administered before chemotherapy. 
k Abiraterone will be administered orally QD with two 500 mg tablets or four 250 mg tablets in combination with prednisone 5 mg administered orally BID (continuous dosing).  Abiraterone will be 
taken on an empty stomach.  No food will be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken in a 21-day cycle. 
l Dispense drug on Day1 of each cycle; at all other visits, compliance check is required. 
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Table 21: 
Schedule of Laboratory Assessments – Combination INCB057643 and Abiraterone (Part 3 C-ES-TGD and 
Part 4 C-EX-TGB) 
Visit Day 
Section 
Screening
a 
Treatment 
Disease Assessment 
EOT 
Safety Follow-Up 
C1 
C2 and Beyond 
D-28 to D-1 
D1 
D8 
D15 
D1 
D11
b 
Evaluation Window 
 
 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per Investigator 
Discretion 
+ 3 D 
30 to 35 D After 
EOT 
Overnight fast before visit 
7.8  
 
X 
X 
 
 
 
 
 
 
Serum chemistry 
7.5.5.1  
X 
X
c 
X 
X 
X 
X 
 
X 
X 
Hematology with differential 
7.5.5.1  
X 
Xc 
X 
X 
X 
X 
 
X 
X 
Coagulation panel
d 
7.5.5.1  
X 
Xc 
X 
X 
X 
 
 
X 
X 
Factor VII protein/antigen assayd 
7.5.5.1 
X 
Xc 
X 
X 
X 
 
 
X 
X 
Urinalysis
e 
7.5.5.1  
X 
 
 
 
Xe 
 
 
X 
X 
Lipid panele 
7.5.5.1 
X 
 
 
 
Xe 
 
 
X 
 
Hepatitis testing 
7.5.5.3  
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
7.5.5.2  
X 
X
f 
 
 
 
 
 
X 
X 
Cardiac troponin (either T or I)  
7.5.5.4  
 
X 
 
 
X 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1. 
b After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
c If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
d All subjects will have coagulation panel including Factor VII protein/antigen assay concentration conducted at screening, C1D1, C1D8, C1D15.  Subsequently, Factor VII only needs to be collected 
on Day 1 of Cycle 2 and Cycle 3.  Coagulation panel is conducted on Day 1 of each subsequent cycle beginning with Cycle 2.  Factor VII protein/antigen assay will also be collected upon a Grade 2 
increased INR.  If the last Factor VII result before the EOT visit is within normal range, Factor VII does not need to be tested at EOT.  If the Factor VII result at the EOT visit is within normal range, 
Factor VII does not need to be tested at the safety follow-up visit.  If a subject is on a coumarin-based anticoagulant, such as warfarin, in addition to required testing per protocol, coagulation panel 
may be tested as per standard of care or at the investigator's discretion.  Study visits do not need to be delayed waiting on the Factor VII results as long as INR/PT results are eligible according to 
enrollment eligibility. 
e Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles there after (eg, Cycle 10, Cycle 13, etc) during the treatment period. 
f If the screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
 
 
 
 
 
 
 
 
 
 
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Table 22: 
Schedule of Timed Pharmacokinetic Assessments – Combination INCB057643 and Abiraterone (Part 3 
C-ES-TGD and Part 4 C-EX-TGB) 
Visit 
Fasting 
Requirement 
HOLD 
AM Dose 
Predose
a 
INCB057643 
Dose
b 
Abiraterone 
Dose 
Time Postdosea 
0.5 h ± 
15 min 
1 h ± 
15 min 
Snack or 
Meal 
2 h ± 
15 min 
4 h ± 
15 min 
6 h ± 
15 min 
8 h ± 
30 min 
C1D1 
At least 8 h before 
the study drugs 
N/A 
X 
♦ 
♦ 
X 
X 
X 
X 
X 
X 
X 
C1D8 
At least 8 h before 
the study drugs 
X 
X 
♦  
♦ 
X 
X 
X 
X 
X 
X 
X 
a Collect timed PK samples predose (any time within 30 min of INCB057643 administration) and at 0.5 (± 5 min), 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 8 (± 30 min) hours after 
INCB057643 administration on C1D1 and C1D8. 
b INCB057643 dose will be administered just before the dose of abiraterone. 
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Table 23: 
Schedule of Assessments – Combination INCB057643 and Ruxolitinib (Part 3 C-ES-TGE and Part 4 
C-EX-TGC) 
Visit Day 
Section 
Screening 
Treatment 
Disease 
Assessment 
EOT 
Safety 
Follow-Up 
D-28 to D-1 
C1 
C2 and Beyond 
D1 
D8 
D15 
D1 
D11
a 
Evaluation Window 
 
 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per 
Investigator 
Discretion 
+ 3 D 
30 to 35 D 
After EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
3 
X 
X
b 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
X 
 
 
X 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
c 
X 
X 
X 
X 
X 
 
X 
X 
Transfusion history/status 
7.3.1 
X 
X
d 
 
 
Xd 
 
 
X 
X 
Screening Symptom Form 
7.3.2 
X 
 
 
 
 
 
 
 
 
Administer INCB057643 in clinic 
5.2.1.1 
 
X 
X 
 
X 
 
 
 
 
Administer ruxolitinib in clinic 
5.2.2.5 
 
X 
X 
 
X 
 
 
 
 
Drug dispense/compliance check
e 
5.2.1.4, 5.3 
 
X 
X 
X 
X 
X 
 
X 
 
Complete physical examination 
7.5.2.1 
X
f 
 
 
 
 
 
 
X 
X 
Targeted physical examination 
7.5.2.2 
 
X 
X 
X 
X 
X 
 
 
 
Spleen palpation 
7.7.9 
X 
X
g 
 
 
Xg 
 
 
X 
X 
ECOG performance status 
7.6.1 
X 
Xg 
 
 
Xg 
 
 
X 
X 
Vital signs/weight
h 
7.5.3 
Xh 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
7.5.4.1 
X 
X 
 
 
X
i 
 
 
X 
X 
AE assessment 
7.5 
X 
X 
X 
X 
X 
X 
 
X 
X 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
 
Bone marrow
j 
7.7.4 
X 
 
 
 
 
 
X 
 
 
MRI/CT Scan of abdomen/pelvis 
7.7.1 
X 
 
 
 
 
 
X
k 
 
 
IWG-MRT assessment
l 
7.7.4, 
Appendix H 
 
 
 
 
 
 
X 
X 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
 
X 
 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA  
7.5.4.4  
 
X 
 
 
X 
 
 
X 
X 
a After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
b On C1D1 only, review inclusion/exclusion criteria before dose administration. 
c Prior medications are collected only at screening. 
d Transfusion history/status will be conducted on Day 1 of each cycle through Cycle 8; then Day 1 of every 4th cycle thereafter.  
e Drug will be dispensed on Day 1 of each cycle.  Drug compliance will be checked at each visit. 
f Height at screening only. 
g Spleen palpation and ECOG assessment will be conducted on Day 1 of each cycle through Cycle 8; then Day 1 of every 4th cycle thereafter. 
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h Weight will be checked at each visit along with vital signs. 
i Starting at Cycle 4 and continuing every 12 weeks thereafter. 
j Investigators will perform disease and efficacy assessments per their own discretion.  Bone marrow biopsy must be completed at screening, unless biopsy and data from previous 2 months are 
available.  Additional biopsies will be performed at Week 24, Week 48, and every 24 weeks thereafter.  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. 
k Through Week 108. 
l The first IWG-MRT assessment will be conducted at Week 24 and then every 12 weeks thereafter.Error! Reference source not found. 
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Table 24: 
Schedule of Laboratory Assessments – Combination INCB057643 and Ruxolitinib (Part 3 C-ES-TGE and 
Part 4 C-EX-TGC) 
Visit Day 
Section 
Screening
a 
Treatment 
Disease Assessment 
EOT 
Safety Follow-Up 
C1 
C2 and Beyond 
D-28 to D-1 
D1 
D8 
D15 
D1 
D11
b 
Evaluation Window 
 
 
± 3 D 
± 3 D 
± 3 D 
± 3 D 
Per Investigator 
Discretion 
+ 3 D 
30 to 35 D After 
EOT 
Overnight fast before visit 
7.8 
 
X 
X 
 
X 
 
 
 
 
Serum chemistry 
7.5.5.1 
X 
X
c 
X 
X 
X 
X 
 
X 
X 
Hematology with differential 
7.5.5.1 
X 
Xc 
X 
X 
X 
X 
 
X 
X 
Coagulation panel
d 
7.5.5.1 
X 
Xc 
X 
X 
X 
X 
 
X 
X 
Factor VII protein/antigen assayd 
7.5.5.1 
X 
Xc 
X 
X 
X 
X 
 
X 
X 
Urinalysis
e 
7.5.5.1 
X 
 
 
 
Xe 
 
 
X 
X 
Lipid panel (requires overnight fast for 
Part 3 only)e 
7.5.5.3 
 
X 
 
 
Xe 
 
 
X 
 
Hepatitis testing 
7.5.5.2 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
7.5.5.2 
X 
X
f 
 
 
 
 
 
X 
X 
Cardiac troponin (either T or I) 
  7.5.5.4  
 
X 
 
 
X 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1. 
b After a subject has been on study for 6 months, Day 11 visits at subsequent cycles will be optional at the discretion of the investigator. 
c If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
d All subjects will have coagulation panel including Factor VII protein concentration by the Factor VII antigen assay conducted at screening, C1D1, C1D8, C1D15, C2D1, C2D11, and C3D1.  
Coagulation panel is conducted on Day 1 of each subsequent cycle beginning with Cycle 4, more frequent if clinically indicated.  Factor VII protein/antigen assay will also be collected upon a Grade 2 
increased INR, or if clinically indicated.  If the last Factor VII result before the EOT visit is within normal range, Factor VII does not need to be tested at EOT.  If the Factor VII result at the EOT visit 
is within normal range, Factor VII does not need to be tested at the safety follow-up visit.  If a subject is on a coumarin-based anticoagulant, such as warfarin, in addition to required testing per 
Protocol, coagulation panel may be tested as per standard of care or at the investigator's discretion.  Study visits do not need to be delayed waiting on the Factor VII results as long as INR/PT results 
are eligible according to enrollment eligibility. 
e Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles there after (eg, Cycle 10, Cycle 13, etc).  For Part 3, subjects will have fasting lipid panels at C1D1; for Part 4, 
subjects will have lipid panels performed at the screening visit, and fasting is not required. 
f If screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
 
 
 
 
 
 
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Table 25: 
Schedule of Timed Pharmacokinetic Assessments – Combination INCB057643 and Ruxolitinib (Part 3 
C-ES-TGE and Part 4 C-EX-TGC) 
Visit 
Fasting 
Requirement 
HOLD 
AM Dose 
Predose
a 
Drug Administration 
Time Postdosea 
Drug Administration 
0.5 h ± 
15 min 
1 h ± 
15 min 
Snack or 
Meal 
2 h ± 
15 min 
4 h ± 
15 min 
C1D1 
At least 8 h 
before the 
study drugs 
N/A 
X 
Ruxolitinib 
X 
X 
X 
X 
X 
INCB057643 
C1D8 
At least 8 h 
before the 
study drugs 
X 
X 
INCB057643 
X 
X 
X 
X 
X 
Ruxolitinib 
C2D1 
At least 8 h 
before the 
study drugs 
X 
X 
INCB057643 + Ruxolitinib 
X 
X 
X 
X 
X 
N/A 
a Collect timed PK samples predose (any time within 30 min of drug administration) and at 0.5 (± 5 min), 1 (± 15 min), 2 (± 15 min), and 4 (± 15 min) hours after drug administration on C1D1, C1D8 
(+ 2 D), and C2D1 (± 2 D). 
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Table 26: 
Schedule of Assessments – Combination INCB057643 and Azacitidine (Part 3 C-ES-TGF and Part 4 
C-EX-TGD) 
Visit Day 
Section 
Screening 
Treatment 
EOT 
Safety Follow-Up 
28-Day Cycles (Anchored to Azacitidine Schedule)
a 
D-28 to D-1 
D1 
D8 
D15 
D22
b 
D29 to D42
c 
Evaluation Window 
 
± 2 D 
(C2D1+) 
± 2 D 
± 2 D 
± 2 D 
± 2 D 
+ 3 D 
30 to 35 D After 
EOT 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3 
X 
X
d 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
 
 
X 
 
Medical and cancer history 
7.3 
X 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X
e 
X 
X 
X 
X 
X 
X 
X 
Administer azacitidine in clinic
f 
5.2.2.6 
 
X 
X 
 
 
 
 
 
Administer INCB057643 in clinic 
5.2.1.1 
 
X 
X 
X 
 
 
 
 
Drug dispense/compliance check
g 
5.2.1.4, 5.3 
 
X 
 
X
h 
 
X
i 
Xh 
 
Complete physical examination 
7.5.2.1 
X
j 
 
 
 
 
 
X 
X 
Targeted physical examination 
7.5.2.2 
 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
7.6.1 
X 
X 
 
 
 
 
X 
X 
Vital signs/height/weight
k 
7.5.3 
Xk 
Xk 
X 
X 
X 
X 
Xk 
Xk 
12-lead ECG 
7.5.4.1 
X 
X 
 
 
 
 
X 
X 
AE assessment 
7.5 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
0 
X 
X 
X 
X 
X 
X 
X 
X 
Buccal swab 
7.9.10 
X 
 
 
 
 
 
 
 
AML disease assessment
l 
Appendix D 
X 
X 
 
 
 
 
X 
 
Bone marrow examination
m 
7.7.4 
X 
Xl 
 
 
 
 
 
 
Immunophenotyping
n 
7.7.5 
X 
When confirming response 
 
Provide reminder card 
7.10.1 
X 
X 
X 
X 
X 
X 
X 
 
Safety follow-up 
6.4.1 
 
 
 
 
 
 
 
X 
Echocardiogram or MUGA 
7.5.4.4  
 
X 
 
 
 
 
X 
X 
a From Cycle 4 onward, subjects are only required to receive azacitidine at the clinic on Day 1 of each cycle.  All other azacitidine doses and study assessments may be performed at a local clinic.  
Day 8 assessments are not required beginning with Cycle 4.  Data from local clinic assessments do not need to be entered into the eCRF. 
b Day 22 assessments are performed in Cycle 1 only.  
c If subjects have not sufficiently recovered from chemotherapy-related toxicities after 28 days, they will be seen weekly until such time that a subsequent cycle can be started.  These visits will be 
entered as unscheduled visits in the eCRF.  If subjects cannot start a subsequent cycles within 42 days, the site will contact the medical monitor.  
d On C1D1 only, review inclusion/exclusion criteria before dose administration. 
e Prior medications documented only at screening. 
f Azacitidine will be administered as 75 mg/m2 IV or SC for 7 days during a 9-day or less period (ie, a 2-day break allowed on weekend, if needed) of a 28-day cycle. 
g All study drug for Cycle 1 will be dispensed at C1D1; subjects will bring unused study drug to the clinic for compliance check on C1D15.  Study drug will be dispensed at Day 1 of all subsequent 
cycles, and compliance will be checked at the start of the next subsequent cycle.  
h Compliance check only.  
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i If needed. 
j Height measured at screening only. 
k Weight required at screening, Day 1 of each cycle, EOT, and the safety follow-up visit. 
l Investigators will perform disease and efficacy assessments per their own discretion.  AML disease assessments will be performed on Day 1 of each cycle.  Bone marrow biopsy and/or aspirates for 
response is to be performed at C4D1 or earlier, as clinically indicated, followed by every other month as clinically indicated, or upon circulating blood cell recovery, to assess anti-leukemic activity 
(cytogenetic testing is not required if CR is not present).  Note:  For subjects who have a significant blast count reduction (as determined by the investigator) but have not completely cleared 
circulating blasts, the C4D1 bone marrow is still strongly encouraged to be performed to assess the impact of treatment on the bone marrow blast content.  See Section 7.7.4 for additional details.  
m 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 will 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.   
n Immunophenotyping appropriate to AML will be conducted by flow cytometry at screening and when confirming CR.  
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Table 27: 
Schedule of Laboratory Assessments – Combination INCB057643 and Azacitidine (Part 3 C-ES-TGF and Part 4 
C-EX-TGD) 
Visit Day 
Section 
Screening
a 
Treatment 
EOT 
Safety 
Follow-Up 
28-Day Cycles (Anchored to Azacitidine Schedule) 
D-28 to D-1 
D1 
D8
b 
D15 
D22 
D29 to D42
c 
Evaluation Window 
 
± 2 D (C2D1+) 
± 2 D 
± 2 D 
± 2 D 
± 2 D 
+ 3 D 
30 to 35 D 
After EOT 
Overnight fast before visit
d 
7.8 
 
 
X 
X 
 
 
 
 
Serum chemistry 
7.5.5.1 
X 
X
e 
X 
X 
X 
X 
X 
X 
Hematology with differential 
7.5.5.1 
X 
Xe 
X 
X 
X 
X 
X 
X 
LFT panel 
7.5.5.1 
X 
Xe 
X 
X 
X 
X 
X 
X 
Coagulation panel
f 
7.5.5.1 
X 
Xe 
X 
X 
X 
X 
X 
X 
Factor VII protein/antigen assayf 
7.5.5.1 
X 
Xe 
X 
X 
X 
X 
X 
X 
Urinalysis
g 
7.5.5.1 
X 
Xg 
 
 
 
 
X 
Xg 
Lipid panelg 
7.5.5.1 
X 
Xg 
 
 
 
 
X 
X 
Hepatitis testing 
7.5.5.3 
X 
 
 
 
 
 
 
 
Serum pregnancy test 
7.5.5.2 
X
h 
Xh 
 
 
 
 
X 
X 
Cardiac troponin (either T or I) 
7.5.5.4  
 
X 
 
 
 
 
X 
X 
a Screening laboratory tests must be performed within 14 days before C1D1. 
b Day 8 assessments are not required beginning with Cycle 4.  Day 22 assessments are performed in Cycle 1 only. 
c If subjects have not sufficiently recovered from chemotherapy related toxicities after 28 days, they will be seen weekly until such time that a subsequent cycle can be started.  These visits will be 
entered as unscheduled visits in the eCRF.  If subjects cannot start a subsequent cycle within 42 days, the site will contact the medical monitor. 
d Cycle 1 only. 
e If completed within 3 days before C1D1, this laboratory assessment may be omitted. 
f All subjects will have coagulation panel including Factor VII protein concentration by the Factor VII antigen assay conducted at screening, C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, and C3D1.  
Coagulation panel is conducted on Day 1 of each subsequent cycle beginning with Cycle 4, more frequent if clinically indicated.  Factor VII protein/antigen assay will also be collected upon a Grade 2 
increased INR, or if clinically indicated.  If the last Factor VII result before the EOT visit is within normal range, Factor VII does not need to be tested at EOT.  If the Factor VII result at the EOT visit 
is within normal range, Factor VII does not need to be tested at the safety follow-up visit.  If a subject is on a coumarin-based anticoagulant, such as warfarin, in addition to required testing per 
Protocol, coagulation panel may be tested as per standard of care or at the investigator's discretion.  Study visits do not need to be delayed waiting on the Factor VII results as long as INR/PT results 
are eligible according to enrollment eligibility. 
g Urinalysis and lipid panel only performed at Cycles 2, 4, and 7 and every 3 cycles there after (eg, Cycle 10, Cycle 13, etc) during the treatment period.  If there are no clinically significant findings at 
EOT, urinalysis does not need to be performed at the safety follow-up visit. 
h If screening serum pregnancy test was completed within 3 days before C1D1, a urine pregnancy test may be performed. 
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Table 28: 
Schedule of Timed Pharmacokinetic Assessments – Combination INCB057643 and Azacitidine (Part 3 
C-ES-TGF and Part 4 C-EX-TGD) 
Visit 
Fasting 
Requirement 
HOLD 
AM Dose 
Predose
a 
INCB057643 
Dose
b 
Azacitidine 
Dose 
Time Postdosea 
1 h ± 15 min 
Snack or 
Meal 
2 h ± 15 min 4 h ± 15 min 6 h ± 15 min 
8 h ± 30 min 
C1D8
c 
At least 8 h before 
the study drugs 
N/A 
X 
♦ 
♦ 
X 
X 
X 
X 
X 
X 
C1D15 
At least 8 h before 
the study drugs 
X 
X 
♦ 
 
X 
X 
X 
X 
X 
X 
a Collect timed PK samples predose (any time within 30 minutes of INCB057643 administration) and at 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 8 (± 30 min) hours after 
INCB057643 administration on C1D8 and C1D15. 
b INCB057643 dose will be administered just before the daily dose of azacitidine. 
c Use the ± 2-day window to ensure that the samples are collected on a day when both INCB057643 and azacitidine are administered. 
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Table 29: 
Schedule of Timed Translational/Pharmacodynamic Assessments – Combination INCB057643 and Azacitidine 
(Part 3 C-ES-TGF and Part 4 C-EX-TGD) 
Sampling 
Section 
Treatment 
EOT 
C1D1
a 
C2D1 
C3D1 
Bone Marrow Assessment
b 
Please refer to the Laboratory Manual for further instructions for collection.  
a May be drawn after the subject signs the ICF, is approved for enrollment, and within 7 days before dose administration on C1D1. 
b Investigators will perform efficacy assessments per their own discretion.  Blood samplings will be conducted at each time when a bone marrow assessment is conducted for response. 
 
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Table 30: 
Local Laboratory Tests:  Required Analytes 
Blood Chemistries 
Hematology 
Serology
a 
Albumin  
ALP 
ALT 
AST 
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
HbA1c
b 
LDH 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
> ULN)
c 
Total protein 
Uric acid 
CBC, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including
d : 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
• Blasts
e 
HBV surface antibody 
HBV surface antigen 
HBV core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
Pregnancy 
Female subjects of childbearing potential require a 
serum pregnancy test at screening.  
 
Pregnancy tests (serum or urine) will be repeated 
during the study as required by local regulations.   
Coagulation 
PT 
aPTT 
INR 
Factor VII
f 
Lipids 
Urinalysis With Microscopic Examination 
Total cholesterol 
Triglycerides 
LDL 
HDL  
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Urobilinogen 
mCRPC Only 
PSA 
Cardiac Monitoring 
Cardiac troponin (either T or I) 
a 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 surface antibody is the only positive result. 
b HbA1c needs to be performed for every subject during screening for eligibility and when clinically indicated during the study. 
c Direct bilirubin will only be performed when total bilirubin is > ULN and the subject does not have Gilbert's syndrome. 
d Absolute values must be provided for lymphocytes and neutrophils.   
e Required at intervals specified where peripheral blast count is part of disease assessments such as AML or HR-MDS, 
MDS/MPN and MF. 
f All subjects will have coagulation panel and factor VII conducted as indicted in the laboratory schedule of assessments.   
6.1. 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(Cycle 1 Day 1).  Screening may not exceed 28 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined criteria and has been 
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performed in the timeframe of the study (ie, within 28 days of Cycle 1 Day 1).  All information 
associated with eligibility requirements must be entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
initiation of study treatment 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).   
6.2. 
Treatment 
6.2.1. 
Day 1 
The treatment period begins on the day the subject receives the first dose of study drug; in 
Parts 1 and 2 this is defined as Cycle 1 Day 1 and continues until a decision is made to 
permanently discontinue the study drug.  In Parts 3 and 4, Cycle 1 Day 1 is defined as the first 
day of SOC agent administration.  At Cycle 1 Day 1, results from screening assessments will be 
reviewed to determine if the subject continues to meet the eligibility requirements as specified in 
the Protocol. 
6.2.2. 
Visit Scheduling 
Dates for subsequent study visits will be determined based on Cycle 1 Day 1, and should occur 
within the allowable visit window of the scheduled date unless delayed for safety reasons.  For 
combination therapy groups, Day 1 of each study cycle will correspond with the first day of SOC 
agent administration in that cycle; thus study cycles may become out of sync with the originally 
planned disease assessment schedule.  In this event, disease assessments will remain on the 
original schedule for that treatment group and will be measured from the baseline 
(screening) disease assessment.  All other assessments will shift to coincide with the revised 
treatment (cycle) schedule.  For example, if one of the SOC agents has a delay in beginning 
therapy on Cycle 2 Day 1, the next scheduled visit when SOC agent is administered will be 
Cycle 2 Day 1 and all other assessments will coincide with that Cycle 2 Day 1 visit schedule.  
All planned assessments are shown in Section 6.  Other clinical assessments, or PK/PD 
assessments, may be added if medically indicated or indicated by emerging data, to maintain 
safety.  
6.3. 
End of Treatment 
If a decision is made that the subject will permanently discontinue study drug, the EOT visit will 
be conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations will be 
conducted in addition to those required for the regularly scheduled visit, and the data will be 
entered in the EOT visit in the eCRF.  The subject should be encouraged to return for the safety 
follow-up visit. 
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6.4. 
Follow-Up 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and 30 days after the last dose 
of study drug or the scheduled follow-up visit, whichever is later.  Reasonable efforts should be 
made to have the subject return for the safety follow-up visit, to be scheduled 30 to 35 days after 
the EOT visit (or after the last dose of study drug if the EOT visit was not performed) and to 
report any AEs that occur during this time.  Adverse events and SAEs must be reported up until 
at least 30 days after the last dose of study drug, the date of the follow-up visit, or until toxicities 
resolve, return to baseline, or are deemed irreversible, whichever is longer.  
6.4.2. 
Unscheduled Visits 
Clinic visits or diagnostic laboratory visits not prescribed in the Protocol may be performed at 
any time clinically indicated.  Results of assessments performed at these visits will be entered as 
"unscheduled" visits in the eCRF.  The sponsor may also request additional visits to be 
performed, if needed, based on emerging safety data. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
All study assessments and procedures detailed in this section are to be performed as indicated in 
the appropriate schedule of assessments (see Section 6). 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6, and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology Procedure 
The investigator or designee will assign a subject ID number when a subject enters the screening 
phase.  The IRT will be contacted at each visit at which study drug is dispensed to update the 
study drug supply.  Refer to the IRT manual for detailed instructions.  Additional details 
regarding the IRT may be referenced in Section 5.1.1. 
7.3. 
Demography and 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. 
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7.3.1. 
Transfusion History Status (Myelofibrosis 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 in the eCRF. 
7.3.2. 
Screening Symptom Form (Myelofibrosis Combination Cohorts Only) 
In order to satisfy inclusion criteria for Part 3 C-ES-TGE and Part 4 C-EX-TGC, active 
symptoms of MF at screening, as demonstrated by presence of 1 symptom score ≥ 5 or 
2 symptom scores ≥ 3 using the Screening Symptom Form, will be recorded in the eCRF 
(see Appendix P). 
7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  Prior medications will be documented at screening only.  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 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. 
7.5.2. 
Physical Examinations 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
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7.5.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include height (at screening only), body weight, 
and assessment of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; lymph nodes; and a 
brief neurological examination.  Disease-specific features (eg, plasmacytomas in MM subjects) 
that can be appreciated on physical examination will be noted as well. 
7.5.2.2. 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation.  The targeted physical 
assessment will evaluate the body systems or organs, as indicated by subject symptoms, AEs, or 
other findings. 
7.5.3. 
Vital Signs and Weight 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the subject in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Clinically notable abnormalities that are considered 
clinically significant in the judgment of the investigator are to be reported as AEs.  On Day 1 of 
each cycle, weight will be assessed for all subjects.   
7.5.4. 
Cardiac Monitoring 
7.5.4.1. 
Twelve-Lead Electrocardiograms 
The sites will use their own local ECG machine to obtain ECGs per the schedule of assessment 
tables.  The 12-lead ECGs will be interpreted by the investigator at the site for immediate subject 
management.    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 will 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 will not be performed within 15 minutes after a blood collection.  A single 12-lead ECG 
will be performed at each timepoint indicated in the appropriate schedule of assessments; when 
timed ECGs are required, the additional procedures are outlined in Section 7.5.4.3. 
7.5.4.3. 
Additional Instructions for Timed Electrocardiograms (Part 1 and Part 2 Only) 
Timed triplicates ECGs will be conducted before the clinic administration of study drug 
(predose) and using the timed schedule shown in Table 9.  
All timed ECGs conducted will be performed in triplicate.  The ECGs will 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. 
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7.5.4.4. 
Echocardiogram or MUGA 
Echocardiogram or MUGA, as per investigator discretion, will be performed according to 
institution guideline on Day 1 of each cycle, EOT, and 30-day safety follow-up.  The same 
methodology should be used for each subject.  Ejection fraction will be calculated from each 
echocardiogram or MUGA assessment according to established guideline. 
7.5.5. 
Laboratory Assessments 
7.5.5.1. 
Chemistry, Hematology, Urinalysis, Coagulation Panel, Factor VII, Serology, 
and Endocrine Function Testing 
Chemistry, hematology, coagulation panel, Factor VII, serology, and endocrine function will all 
be analyzed by the local site laboratory.  The investigative site will not enter the local laboratory 
results and laboratory normal ranges into the eCRF unless the abnormal laboratory values are 
considered reportable as clinically significant AEs, in which case they should be entered into the 
eCRF as an AE.  All local laboratory assessments will be performed using standard procedures 
on the days indicated in the appropriate schedule of assessments.  Table 30 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. 
On Day 1, laboratory data must be reviewed to confirm eligibility to start treatment (both 
monotherapy and combination therapy).  Laboratory samples collected for the Day 1 evaluation 
must be performed before dose administration on Day 1.  After Cycle 1, predose laboratory 
procedures can be conducted within the allowed visit window, and results will 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 applicable).  Subsequently, pregnancy tests (either serum or urine, unless 
otherwise indicated) may be conducted as medically indicated or as required per local guidelines.  
If the screening serum pregnancy test is completed within 3 days before Cycle 1 Day 1, a urine 
pregnancy test may be performed on Cycle 1 Day 1. 
7.5.5.3. 
Hepatitis Screening Tests 
Testing for hepatitis (detailed in Table 30) is required at screening, and results will be reviewed 
before Day 1 to confirm eligibility.  Generally hepatitis serology tests should be submitted early 
in the screening process because of the length of time frequently needed to obtain the results.  If 
hepatitis B and/or C serology results are positive, subjects will be required to undergo additional 
testing for HBV-DNA and HCV-RNA by polymerase chain reaction (PCR) assay to assess 
active infection.  Subjects with chronic (carrier state) or cleared hepatitis B or C will be allowed 
to enroll.  For hepatitis B, chronic disease (carrier state) is defined as subjects with positive HBV 
surface antigen and positive HBV total core antibody but with negative HBV core antibody 
immunoglobulin M (IgM) and positive HBV antibody; these subjects would have low risk of 
liver damage. 
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7.5.5.4. 
Cardiac Troponin (Either T or I) Testing 
Cardiac troponin (T and/or I) test will be performed according to institutional guideline on Day 1 
of each cycle, EOT, and 30-day safety follow-up. 
7.6. 
Performance and Health-Related Quality of Life Assessments 
7.6.1. 
ECOG Performance Status 
An ECOG performance score will be required at screening to evaluate eligibility and will be 
assessed at other study visits noted in the appropriate schedule of assessments.  Performance 
status must be assessed by a medically qualified individual and recorded in the eCRF. 
7.7. 
Efficacy Assessments 
The following disease response criteria will be used for each of the malignancies included in this 
study: 
• 
AML:  International Working Group Response Criteria for Acute Myeloid Leukemia 
(Cheson et al 2003; Appendix D) 
− Additionally, peripheral blood blast response will be used, which is defined as 
clearance of AML blasts in the peripheral blood lasting more than 4 weeks.  
• 
Glioblastoma Multiforme:  Updated Response Assessment Criteria for High-Grade 
Gliomas:  Response Assessment in Neuro-Oncology (RANO) Working Group 
(Wen et al 2010; Appendix E) 
• 
MDS:  International Working Group Response Criteria For Myelodysplastic Syndrome 
(Cheson et al 2006; Appendix F) 
• 
MDS/MPNs: International Consortium Proposal of Uniform Response Criteria for 
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN) In Adults 
(Savona et al 2015; Appendix G) 
• 
MF:  International Working Group-Myeloproliferative Neoplasms Research and 
Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report 
(Tefferi et al 2013; Appendix H):   
− Spleen response will be used as the preliminary efficacy endpoint for MF 
subjects. 
• 
MM:  International Uniform Response Criteria for Multiple Myeloma (Durie et al 2006; 
Appendix I) 
• 
MM (minimal response only):  Criteria for Evaluating Disease Response and Progression 
in Patients With Multiple Myeloma Treated by High-Dose Therapy And Haemopoietic 
Stem Cell Transplantation:  Myeloma Subcommittee of the European Society for Blood 
and Marrow Transplantation (EBMT; Blade et al 1998; Appendix J) 
• 
Lymphoma:  Response Criteria For Lymphoma – The Lugano Classification 
(Cheson et al 2014; Appendix K) 
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• 
Solid tumors:  RECIST v1.1 (Eisenhauer et al 2009):  
− Objective response rate will be used as the preliminary efficacy endpoint for any 
measurable disease according to RECIST v1.1. 
• 
Waldenström macroglobulinemia:  VIth International Workshop on Waldenström 
macroglobulinemia response assessment for subjects with Waldenström 
macroglobulinemia (Owen et al 2013; Appendix L) 
• 
Chronic lymphocytic leukemia (CLL):  International Workshop on Chronic Lymphocytic 
Leukemia criteria for CLL (Hallek et al 2008, Cheson et al 2012; Appendix M) 
• 
Prostate Cancer Clinical Trial Working Group 3 (Sher et al 2016; Appendix N):   
− Prostate-specific antigen response and ORR will be used as the preliminary 
efficacy endpoints for mCRPC subjects. 
Efficacy assessments will be performed at screening (this will be considered the baseline disease 
assessments) and at the intervals according to local standards or at the investigator's discretion. 
7.7.1. 
Lymphoma, Chronic Lymphocytic Leukemia, and Myelofibrosis:  CT Scan or 
MRI 
If CT or MRI is used as a functional imaging tool for staging or response assessment of 
lymphoma as a part of the standard of care (based on the specific histotype of that subject) or 
MF, the results obtained during any study phase will be captured in the eCRF.  If CT or MRI 
assessment was performed, under standard of care, before the signing of the ICF but within 
30 days of Cycle 1 Day 1, the result of that assessment may be recorded in the eCRF in lieu of a 
study-specific assessment.  The same imaging modality will be used throughout the study in 
evaluating response. 
7.7.1.1. 
MRI or CT Scan in Myelofibrosis Combination Cohort Subjects 
For MF combination cohort subjects only, the primary measure of spleen size will be by MRI (or 
CT scan in applicable subjects).  An MRI of the upper and lower abdomen and pelvis will be 
performed at baseline and every 12 weeks thereafter through Week 108.  An MRI will be 
performed with a body coil, because the objective is to measure organ volume, not to find very 
small lesions.  The MRIs will be read by local radiologists, and all images for a subject (baseline 
and on-treatment scans) must be read by the same reader.  Spleen and liver volume will be 
obtained by outlining the circumference of the organ and determining the volume using the 
validated technique of least squares.  The MRI will not determine spleen length below the costal 
margin, as there are no validated approaches for determining this measurement. 
An MRI is the preferred method for obtaining spleen volume data.  However, CT scans may be 
performed at the visits where MRI is designated if the subject is not a candidate for MRI 
(eg, because of the presence of metal clips in the body, because of claustrophobia) or if MRI is 
not readily available.  Note:  the same method (MRI vs CT) must be used for all visits for a given 
subject unless a new contraindication to the use of MRI occurs (eg, pacemaker insertion). 
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7.7.2. 
Lymphoma:  FDG-PET or Combined PET-CT 
If [18F] fluorodeoxyglucose (FDG)-PET or combined PET-CT is used as a functional imaging 
tool for staging or response assessment of lymphoma as a part of the standard of care (based on 
the specific histotype of that subject), the results obtained during any study phase will be 
captured in the eCRF.  If PET or PET/CT assessment was performed, under standard of care, 
before signing of the ICF but within 30 days of Cycle 1 Day 1, the result of that assessment may 
be recorded in the eCRF in lieu of a study-specific assessment.  The same imaging modality will 
be used throughout the study in evaluating response. 
7.7.3. 
Solid Tumors and Lymphoma:  Tumor Biopsy 
Baseline tumor biopsy samples are required for subject participation in all parts of the study, 
except for subjects with glioblastoma.  Fresh biopsies are preferred, however a biopsy of 
research quality obtained for other purposes may be used if the subject has not had any 
intervening systemic therapy from the time of the biopsy to the start of treatment (Cycle 1 Day 1) 
and if 25 slides or tissue block may be submitted.  See Section 7.9.9 for additional details.  In 
addition to baseline tumor biopsy samples, biopsy during treatment and/or at disease progression 
is strongly recommended but not mandatory.  Subjects who obtain a biopsy while on treatment, 
or at disease progression will need to sign an additional ICF for "optional tumor biopsy while on 
treatment."  The consent for on-treatment biopsy can be withdrawn by the subject at any time 
during the study.  If the subject signs the ICF for on-treatment biopsy, the feasibility of the 
on-treatment biopsy will be evaluated by the investigator and/or radiologist at the time of the 
biopsy. 
7.7.4. 
Leukemia, High-Risk Myelodysplastic Syndrome, Myelodysplastic 
Syndrome/Myeloproliferative Neoplasm, Myelofibrosis, and Multiple 
Myeloma:  Bone Marrow Biopsy 
Bone marrow examination (aspirate and biopsy) is required at screening for subjects with 
diseases that are typically monitored though bone marrow examination, including leukemia, 
HR-MDS, MM, MDS/MPN, and MF.  If disease status requires assessment with bone marrow 
aspirate or biopsy, subjects with leukemia, HR-MDS, MDS/MPN, or MF will have a bone 
marrow aspirate and/or biopsy performed approximately 3, 6, and 12 months after Day 1 and 
then every 12 months on the nearest Cycle Day 1 (± 7 days) after the first dose of treatment and 
as clinically indicated.  If possible, bone marrow examinations should be scheduled to coincide 
with other disease assessments, including peripheral blood or, for MF, imaging studies.  
For AML subjects, bone marrow disease assessment during Cycle 2 is strongly recommended 
unless contraindicated. 
Subjects with MM only require a postbaseline bone marrow examination to confirm CR, after 
2 consecutive laboratory disease assessments (Durie et al 2006) demonstrating negative serum 
and/or urine immunofixation, and as clinically indicated. 
Data from the pathology report result from the bone marrow examination will be captured in the 
eCRF.  All bone marrow examinations will include a unilateral aspiration and biopsy with 
fluorescence in situ hybridization (FISH) and cytogenetic testing, when feasible.  Subjects may 
be enrolled based on a biopsy only when a "packed marrow" precludes aspiration at the 
discretion of the medical monitor.  Results of assessments performed under standard of care 
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before the signing of ICF may be used as the baseline disease assessment in lieu of a study-
specific procedure if performed within 60 days of the first dose of study drug (Cycle 1 Day 1). 
7.7.5. 
Leukemia and Lymphoma:  Immunophenotyping 
For subjects with leukemia, lymphoma, MDS/MPN, and MF, immunophenotyping appropriate to 
the underlying pathology will be conducted by flow cytometry at the local laboratory at 
screening and at subsequent times only as part of confirmation of response.  If appropriate to the 
histologic subtype, immunophenotyping will be performed at screening and may be conducted 
on study in subjects with lymphoma as part of routine standard of care and/or at response 
assessment.  Results will be captured in the eCRF. 
7.7.6. 
Leukemia, HR-MDS, and MDS/MPN:  Peripheral Blood Blast Counts 
For disease assessment timepoints in leukemia, HR-MDS, and MDS/MPN, peripheral blood 
blast counts (appropriate to underlying pathology) will be evaluated by microscopic evaluation 
or other appropriate methodology and will be used as appropriate in conjunction with other 
parameters (eg, complete blood counts [CBCs]) in determining disease status. 
7.7.7. 
Multiple Myeloma:  Disease Assessment 
Multiple myeloma laboratory assessments will be performed as per the schedule in Table 9 (as 
applicable).  Required analytes for MM disease assessments are detailed in Table 31.  In 
addition, a bone marrow examination (aspirate and biopsy) will be required to confirm CR. 
Table 31: 
Required Analytes for Multiple Myeloma Subjects 
Routine Disease Assessment 
• Serum protein electrophoresis with quantitative M-protein 
• Urine protein electrophoresis with quantitative M-protein 
• Quantitative immunoglobulins 
• Serum FLCs 
• Beta-2 microglobulin 
Baseline, Confirming CR and as Clinically Indicated 
• Bone marrow aspirate and biopsy 
• FISH/cytogenetics 
Note:  For subjects who do not show evidence of urine paraprotein at screening, only spot urine with urine protein electrophoresis 
required; if the subject subsequently shows evidence of urine paraprotein, a 24-hour collection will be required along with the 
urine protein electrophoresis. 
7.7.8. 
Multiple Myeloma:  Skeletal Survey 
A series of x-rays will be conducted of the skull, long bones, spine, pelvis, and ribs.  Skeletal 
surveys will be conducted at screening and then subsequently at the investigator's discretion. 
7.7.9. 
Myelofibrosis:  Spleen Palpitation (Myelofibrosis Combination Cohorts Only) 
Spleen length will be assessed by manual palpation at every study visit (laboratory-only visits 
not included) and will be used for routine subject management.  Investigators will be provided 
with a soft centimeter ruler so that palpable spleen length is measured in centimeters instead of in 
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finger breadths.  The edge of the spleen shall be determined by palpation and measured in 
centimeters, using a soft ruler, from the costal margin to the point of greatest splenic protrusion.  
Spleen length must be recorded in the eCRF. 
7.7.10. 
Castrate Resistant Prostate Cancer:  Prostate Cancer Clinical Trials Work 
Group 3 
The disease assessments of mCRPC subjects will be conducted as defined by the PCWG3 
guidelines (see Appendix N) as indicated in Table 20 and Table 21, including ECOG every 
cycle, laboratory parameters (ie, PSA, ALP, lactate dehydrogenase [LDH], serum chemistry, and 
CBC) every cycle, and imaging (bone scans and CT/MRI) every 8 to 9 weeks for the first 
24 weeks and then every 12 weeks thereafter.  Patient outcomes/analgesic consumption tools will 
not be used in this study. 
7.8. 
Pharmacokinetic Assessments 
7.8.1. 
Blood Sample Collection 
Pharmacokinetic samples will be obtained to evaluate plasma PK parameters as described in 
Appendix B.  The study drug will be administered in clinic with approximately 240 mL of water.  
Subjects will remain fasting from food for 8 hours predose and 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 time and contents of the most recent meal. 
Subjects will receive reminder cards in advance of the study visit providing instructions to 
prepare for the visit (see Section 7.10.1).  Instructions for plasma preparation and sample 
shipping will be provided in the Laboratory Manual.  The specified postdose timepoints may be 
adjusted based on emerging PK data. 
7.8.2. 
Urine Sample Collection 
A predose void must be collected and the time recorded.  Urine will be collected from all 
subjects at Cycle 1 Day 8 after administration of INCB057643 and a predose void.  Total urine 
will be collected over an 8-hour interval following study drug administration.  Urine containers 
will be kept at reduced temperature (refrigerated or ice bath) during collection.  After the 
interval, the total urine volume and the pH will be measured and recorded in the individual 
eCRF.  Urine will be mixed thoroughly, and two 10 mL aliquots 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 the sponsor's designee for parameters described in Appendix B. 
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7.8.3. 
Bioanalytical Methodology and Analysis 
Plasma samples will be analyzed by the sponsor or the sponsor's designee using a validated 
assay. 
 
 Pharmacokinetic parameters that will be analyzed are shown in Appendix B, and 
the analysis methodology is described in Section 9.4.3. 
7.8.4. 
Food-Effect Pharmacokinetic Testing 
Pharmacokinetic testing for food effect on drug exposure will be performed in the first 
12 subjects enrolled into Part 2/TGA only.  Additional subjects may be enrolled if there are data 
quality issues among the initial 12 subjects.  There will be no food-effect PK testing conducted 
in Part 3 or Part 4.  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 
30 minutes before administration of study drug.  Subjects must consume the entire breakfast 
within 25 minutes, and study drug administration will begin 5 minutes after completing 
breakfast. 
The high-fat, high-calorie breakfast (50% kcal from fat) will consist of: 
• 2 eggs fried in butter 
• 2 strips of bacon 
• 1 English muffin with butter 
• 4 oz hash brown potatoes 
• 8 oz whole milk 
Alternative menus with the same caloric and fat content may be substituted with the prior 
approval of the study sponsor. 
Pharmacokinetic samples for food-effect are collected only on the first 12 subjects in 
Part 2/TGA, only in Cycle 2, as follows:  at predose (after the meal and before study drug 
administration) and at 0.5 (± 5 min), 1 (± 15 min), 2 (± 15 min), 4 (± 15 min), 6 (± 30 min), and 
8 (± 30 min) hours after administration on Cycle 2 Day 1 and predose Cycle 2 Day 2. 
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7.10. 
Other Study Procedures 
7.10.1. 
Distribution of Subject Reminder Cards 
Subjects will be provided with subject reminder cards at each visit.  The subject reminder cards 
will indicate the date and time of the next visit.  The reminder cards will have a field for the 
subject to enter the date and time of the last dose taken before the visit and to record the time of 
the last meal before visits on which PK draws will be performed.  Reminder cards will also 
include instructions specific for study visits at which the study drug will be administered in 
clinic.  All necessary instructions, such as those for study drug administration, concomitant 
medications, and laboratory tests will be provided to the subject in writing on this reminder card 
or on accompanying written materials. 
8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an AE is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related, that occurs 
after a subject provides informed consent.  Abnormal laboratory values or test results occurring 
after informed consent constitute AEs only if they induce clinical signs or symptoms, are 
considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 30 days after the last dose of study drug.  Adverse 
events (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE (eg, 
resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
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reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 4.  The CTCAE 
v4.03 severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly 
using Grades 1 through 4 and have the outcome noted as fatal.  If an event is not classified by 
CTCAE, the severity of the AE will be graded according to the scale below to estimate the grade 
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. 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no).  
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per SAE definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
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When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE does not automatically indicate an SAE unless it meets the definition 
of serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may 
be required (see Section 5.4) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.   
− An elective surgery 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 and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
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• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 30 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug. 
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment. 
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
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relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.4.2 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 IB.  Additional safety information collected 
between IB updates will be communicated in the form of 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 
Not applicable. 
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. 
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All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9. 
STATISTICS 
9.1. 
Study Populations 
The populations to be analyzed include the following: 
• The safety evaluable population includes all subjects who are enrolled and received at 
least 1 dose of study drug.  This population will be used in the analyses of safety, 
study drug administration, and compliance data. 
• The efficacy evaluable population includes all subjects who are enrolled and received 
at least 1 dose of study drug.  This population will be used in the analyses of 
demographic, baseline, and efficacy data. 
• The PK evaluable population includes all subjects who received at least 1 dose of 
study drug and had at least 1 PK sample collected and analyzed. 
• The PD evaluable population includes all subjects who received at least 1 dose of 
study drug and had at least 1 PD sample collected and analyzed. 
9.2. 
Selection of Sample Size 
Part 1 is a standard dose-escalation design, and the sample size depends on the occurrence of 
safety finding such as DLTs.  Approximately 3 to 6 subjects will be enrolled in each dose level.  
Using this design, the probability of dose escalation for various DLT rates is given in Table 32. 
Table 32: 
Probability of Dose Escalation by DLT Rate 
True DLT Rate 
Probability of Dose Escalation 
10% 
90.6% 
20% 
70.9% 
30% 
49.4% 
40% 
30.9% 
50% 
17.2% 
60% 
8.2% 
Part 2/TGA will enroll up to approximately 165 subjects with specified solid tumors or 
lymphoma.  Approximately 5 to 15 subjects will be enrolled in the pancreatic adenocarcinoma, 
breast cancer, glioblastoma multiforme, Ewing's sarcoma, and NHL groups.  The high-grade 
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serous ovarian cancer and mCRPC groups will include approximately 20 subjects each.  The 
tumor group of any solid tumor or lymphoma (except the specified) with any pathway alteration 
relevant to BET protein signaling, such as MYC pathway activation, will enroll up to 20 subjects 
as well. 
Part 2/TGB will enroll up to 45 subjects with AML, HR-MDS, MDS/MPN, or MF; and 
Part 2/TGC will enroll up to 15 subjects with MM.  This will provide > 80% chance of detecting 
at least 1 responder if the underlying response rate is 30%. 
Part 3 will use a 3 + 3 design to evaluate different doses of INCB057643 in combination with 
gemcitabine, paclitaxel, rucaparib, abiraterone, ruxolitinib, or azacitidine in 6 treatment groups.  
Dose escalation for 6 treatment groups will proceed independently.  Approximately 3 to 
6 subjects will be enrolled in each dose level for each treatment group.  The total number of 
subjects will depend on the frequency of DLTs and the number of dose levels tested before the 
MTD and RP2D are reached.  Using this design, the probability of dose escalation for various 
DLT rates is given in Table 32. 
In Part 4, approximately 71 subjects will be enrolled across 4 possible expansion treatment 
groups to further evaluate the safety, tolerability, efficacy, PK, and PD of the RP2Ds selected 
from Part 3.  Cohorts for ovarian and mCRPC will enroll up to 20 subjects each.  The MF cohort 
will enroll approximately 16 subjects, and the AML/HR-MDS cohort will enroll 15 subjects.  
This will provide > 80% chance of detecting at least 1 responder if the underlying response rate 
is 30%. 
9.3. 
Level of Significance 
No formal statistical tests will be performed.  All CIs will be reported with 95% confidence 
level. 
9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
There is no primary efficacy analyses due to the nature of the study. 
9.4.1.2. 
Secondary Efficacy Analyses 
• Objective response rate is defined as the proportion of subjects who have an objective 
response using the applicable disease assessment criteria.  Objective response rate 
will be estimated with 95% CI, which will be calculated based on the exact method 
for binomial distributions. 
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9.4.2. 
Safety Analyses 
9.4.2.1. 
Adverse Events 
A treatment-emergent AE is any AE either reported for the first time or worsening of a 
pre-existing event after first dose of study drug.  Analysis of AEs will be limited to treatment-
emergent AEs, but data listings will include all AEs regardless of their timing relative to study 
drug administration.  Adverse events will be tabulated by the MedDRA preferred term and 
system organ class.  Severity of AEs will be based on the NCI CTCAE v4.03 using Grades 1 
through 4. 
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. 
9.4.2.2. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value using CTCAE grade. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 33), 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 33: 
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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9.4.2.4. 
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 34).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
Table 34: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
QTcF = Fridericia correction. 
9.4.3. 
Pharmacokinetic Analysis 
The PK parameters of Cmax, Tmax, Cmin (INCB057643), AUC0-t, AUC0-τ (INCB057643) and Cl/F 
(INCB057643) will be calculated from the blood plasma concentrations of INCB057643 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 > 15 minutes for samples collected up to 
4 hours after administration and > 30 minutes for samples collected more than 4 hours after 
administration; in these cases, actual time will be used for PK analysis.  The PK parameters of 
INCB057643 will be summarized by descriptive statistics by part, treatment, and dose group.  
For the food-effect portion of the study, the log-transformed PK parameters will be compared 
between the fed and fasted treatments using an analysis of variance for a 1-way crossover design.  
The geometric mean relative bioavailability and 90% CIs will be calculated for comparing Cmax 
and AUC between the fed (test) and fasted (reference) treatments.  Additional details of analyses 
will be described in the Statistical 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). 
9.4.4. 
Pharmacodynamic Analysis 
Tumor biopsy samples will be used by the sponsor or its designee to investigate molecular 
signatures associated with response or resistance to treatment with the study drug.  DNA and/or 
RNA may be extracted from these samples to perform somatic mutation analysis and genetic 
expression analysis, including that of known oncogenes.  Chromosomal alterations may be 
examined. 
 
 
 
Somatic mutations in tumor samples may be confirmed by assessing the specific sequence 
change in a normal sample obtained by buccal swab or peripheral blood from the whole blood 
PD sample. 
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Plasma analytes may include cytokines and other markers of inflammation and immune status, 
tumor markers, and markers of metabolism and nutritional status.  
 
 
Correlative PD analysis will utilize markers available in whole blood to identify associations 
with response or safety and may include examining plasma or serum for circulating free DNA or 
RNA or examining specific cell populations using standard methods.  Such analyses may be 
conducted by the sponsor or designee. 
Data will be analyzed and presented using summary statistics. 
9.5. 
Analyses for the Data Monitoring Committee 
Not applicable. 
9.6. 
Interim Analysis 
No interim analysis is planned. 
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 
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study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− 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. 
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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. 
• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
study drug.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
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is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 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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11. 
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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 INCB057643 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 
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 selfcare but unable to carry out any work activities.  Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours  
4 
Completely disabled.  Cannot carry on any selfcare.  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 E. RESPONSE CRITERIA FOR GLIOBLASTOMA 
RANO Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Response 
Criteria 
Complete response 
Requires all of the following:  complete disappearance of all enhancing measurable and 
nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable or improved 
nonenhancing (T2/FLAIR) lesions; subjects must be off corticosteroids (or on physiologic 
replacement doses only); and stable or improved clinically.  Note:  Subjects with 
nonmeasurable disease only cannot have a complete response; the best response possible 
is stable disease. 
Partial response 
Requires all of the following:  ≥ 50% decrease compared with baseline in the sum of 
products of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or 
improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared with baseline scan; the corticosteroid dose at the time of the scan evaluation 
should be no greater than the dose at time of baseline scan; and stable or improved 
clinically.  Note:  Subjects with nonmeasurable disease only cannot have a partial 
response; the best response possible is stable disease. 
Stable disease 
Requires all of the following: does not qualify for complete response, partial response, or 
progression; stable nonenhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan.  In the event that the corticosteroid dose was 
increased for new symptoms and signs without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered to 
show stable disease will be the scan obtained when the corticosteroid dose was equivalent 
to the baseline dose. 
Progression 
Defined by any of the following:  ≥ 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions compared with the smallest tumor measurement obtained 
either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids
a; significant increase in T2/FLAIR nonenhancing lesions on stable or 
increasing doses of corticosteroids compared with baseline scan or best response after 
initiation of therapya not cause by comorbid events (eg, radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any 
new lesion; clear clinical deterioration not attributable to other causes apart from the 
tumor (eg, seizures, medication adverse effects, complications of therapy, cerebrovascular 
events, infection, and so on) or changes in corticosteroid dose; failure to return for 
evaluation as a result of death or deteriorating condition; or clear progression of 
nonmeasurable disease. 
FLAIR = fluid-attenuated inversion recovery. 
Note:  Radiologic interpretation guidelines, definitions and tumor measurement instructions will be provided 
separately. All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline. 
a Stable doses of corticosteroids include subjects not on corticosteroids. 
Source:  Wen et al 2010. 
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Summary of the RANO Response Criteria 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium 
disease 
None 
≥ 50% decrease 
< 50% decrease but , 
25% increase 
≥ 25% increase
a 
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increasea 
New lesion 
None 
None 
None 
Presenta 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA
b 
Clinical status 
Stable or increase 
Stable or increase 
Stable or increase 
Decreasea 
Requirement for 
response 
All 
All 
All 
Anya 
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; FLAIR = fluid-
attenuated inversion recovery; NA = not applicable. 
a Progression occurs when this criterion is present. 
b Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration. 
For purposes of this study, the minimum time from baseline for determination of SD will be 
6 weeks. 
Best overall response (BOR) should be determined based on response designations recorded per 
RANO defined criteria.  The subject's BOR assignment will depend on the findings of both 
target and non-target disease, and will also take into consideration the appearance of new lesions.  
The assessments that will contribute to the evaluation of BOR include the response assessment 
recorded between the date of randomization and the first to occur of the following: 
1. The date of objectively documented progression per RANO criteria 
OR 
2. The date of subsequent therapy 
OR 
3. The date of pathology results from diagnostic surgical resection 
Among the available response assessment, the criteria listed in the table below will be used to 
determine BOR. 
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Assessment of Best Overall Response 
Best Overall Response 
Criteria 
Complete Response (CR) 
CR observed in consecutive assessments ≥ 4 weeks apart per RANO 
Partial Response (PR) 
PR observed in consecutive assessments ≥ 4 weeks apart per RANO 
Stable Disease (SD)
a 
SD observed and dose not quality for CR or PR  
Or 
Suspected PD followed with histologic results not confirming PD, and no CR, PR, 
or SD observed 
Not Evaluable (NE) 
Insufficient data to determine disease progression or response 
Progressive Disease (PD) 
No CR, PR, or SD before PD 
a  To qualify for SD there must be a minimum on-treatment period of 6 weeks. 
In order to distinguish potential treatment-associated pseudoprogression from progressive 
disease and minimize premature discontinuation of study medication, subjects who initially meet 
radiologic criteria for disease progression but are believed to derive clinical benefit and are 
tolerating study medication should continue receiving study medication until confirmation of 
progression with a follow up MRI.  Such subjects may be allowed to continue on study therapy 
for up to 12 additional weeks as long as they are no developing significant new or worsened 
neurologic deficits related to underlying tumor. 
If the follow-up imaging after 12 weeks from initial tumor progression confirms further 
progression, the date of progression will be the date at which progression was first determined.  
For purposes of this study, the minimum duration between baseline (start of treatment) and first 
on-study scan in order to determine BOR of SD is 6 weeks.  If the minimum time is not met 
when SD is otherwise the best timepoint response, the subject's best response will depend on the 
subsequent assessments.  For example, a subject who has SD at a timepoint < 6 weeks and PD at 
a second assessment will have a best response of PD. 
Subjects with a complete or partial response must have that response sustained for 4 weeks. 
Subjects who do not qualify for complete response, partial response, or confirmed progression 
will be considered as stable disease for the protocol BOR analysis. 
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APPENDIX F. INTERNATIONAL WORKING GROUP RESPONSE 
CRITERIA FOR MYELODYSPLASTIC SYNDROME 
Category 
Response Criteria (Responses Must Be at Least 4 Weeks in Duration) 
Complete remission (CR) 
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell lines 
Persistent dysplasia will be noted 
Peripheral blood: 
Hemoglobin (Hgb) ≥ 11 g/dL, Platelets ≥ 100 × 109/L, Neutrophils ≥ 1.0 × 109/L 
Blasts 0% 
Partial remission (PR) 
All CR criteria if abnormal before treatment, except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CR 
Bone marrow:  ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment 
Peripheral blood:  if HI responses, they will be noted in addition to marrow CR 
Stable disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 weeks 
Treatment failure 
Death during treatment 
Disease progression characterized by worsening of cytopenias, increase in % of 
bone marrow blasts, or progression to a more advanced MDS FAB subtype than 
pretreatment 
Disease progression (PD) 
For patients with: 
- Less than 5% blasts:  ≥ 50% increase in blasts to > 5% blasts 
- 5%-10% blasts:  ≥ 50% increase in blasts to > 10% blasts 
- 10%-20% blasts:  ≥ 50% increase in blasts to > 20% blasts 
- 20%-30% blasts:  ≥ 50% increase in blasts to > 30% blasts 
Any of the following: 
- At least 50% decrement from maximum remission/response levels in 
granulocytes or platelets 
- Reduction in Hgb concentration by ≥ 2 g/dL  
- Transfusion dependence 
Disease transformation 
Transformation to AML (30% or more blasts) 
Relapse after CR or PR 
At least one of the following: 
- Return to pretreatment bone marrow blast % 
- Decrement of ≥ 50% from maximum remission/response levels in granulocytes 
or platelets 
- Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
CYTOGENETIC RESPONSE 
Complete 
Disappearance of the chromosomal abnormality without appearance of new ones 
Partial 
At least 50% reduction of the chromosomal abnormality 
HEMATOLOGICAL IMPROVEMENT (HI) 
Erythroid response (HI-E) 
(Pretreatment < 11 g/dL) 
Hgb increase by ≥ 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at least 
4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in 
the previous 8 weeks.  Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL 
pretreatment will count in the RBC transfusion evaluation 
Platelet response (HI-P) 
(Pretreatment < 100 × 109/L) 
Absolute increase of ≥ 30 × 109/L for patients starting with > 20 × 109/L 
Increase from < 20 × 109/L to > 20 × 109/L and by at least 100% 
Neutrophil response (HI-N) 
(Pretreatment < 1.0 × 109/L) 
At least 100% increase and an absolute increase of > 0.5 × 109/L 
Source:  Cheson et al 2006. 
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APPENDIX G. INTERNATIONAL CONSORTIUM PROPOSAL OF 
UNIFORM RESPONSE CRITERIA FOR 
MYELODYSPLASTIC/MYELOPROLIFERATIVE 
NEOPLASMS IN ADULTS 
Response 
Subcategory 
Response Criteria 
Complete 
Remission (CR) 
• Presence of all of the following improvements: 
• Bone marrow:  ≤ 5% myeloblasts (including monocytic blast equivalent in case of chronic 
myelomonocytic leukemia) with normal maturation of all cell lines and return to normal 
cellularity* 
• Osteomyelofibrosis absent or equal to "mild reticulin fibrosis" (≤ Grade 1 fibrosis)† 
• Peripheral blood‡ 
- 
WBC ≤ 10 × 109 cells/L 
- 
Hgb ≥ 11 g/dL 
- 
Platelets ≥ 100 × 109/L; ≤ 450 × 109/L 
- 
Neutrophils ≥ 1.0 × 109/L 
- 
Blasts 0% 
- 
Neutrophil precursors reduced to ≤ 2% 
- 
Monocytes ≤ 1 × 109/L 
• Extramedullary disease:  Complete resolution of extramedullary disease present before 
therapy (eg, cutaneous disease, disease-related serous effusions), including palpable 
hepatosplenomegaly 
Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasia* 
Complete 
Cytogenetic 
Remission  
Resolution of previously present chromosomal abnormality (known to be associated with 
myelodysplastic, syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic 
karyotyping with minimal of 20 metaphases or FISH § 
Partial Remission 
(PR) 
Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and 
blast equivalents) reduced by 50%, but remaining  > 5% of cellularity except in cases of 
MDS/MPN with ≤ 5% bone marrow blasts at baseline. 
Marrow Response 
• Optimal marrow response:  Presence of all marrow criteria necessary for CR without 
normalization of peripheral blood indices as presented above. 
• Partial marrow response:  Bone marrow blasts (and blast equivalents) reduced by 50%, but 
remaining > 5% of cellularity, or reduction in grading of reticulin fibrosis from baseline 
on at least 2 bone marrow evaluations spaced at least 2 months apart. 
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Response 
Subcategory 
Response Criteria 
Clinical Benefit 
Requires 1 of the following in the absence of progression or CR/partial response and 
independent of marrow response (cord blood response must be verified at ≥ 8 week) to be 
considered a clinical benefit: 
 
Erythroid response: 
• Hgb increase by ≥ 2.0 g/dL 
• Transfusion independence (TI) for > 8 week for patients requiring at least 4 packed red 
blood cell transfusions in the previous 8 weeks. 
• Only red blood cell transfusions given based on physician's judgment for a pretreatment 
Hgb of ≤ 8.5 g/dL will count in the red blood cell TI response evaluation|| 
 
Platelet response: 
• Transfusion independence when previously requiring platelet transfusions of at least a rate 
of 4 platelet transfusions in the previous 8 weeks. 
• Pretreatment ≤ 20 × 109/L:  increase from < 20 × 109/L to >20 × 109/L and by ≤ 100% 
• Pretreatment > 20 × 109/L but ≤ 100 × 109/L:  absolute increase of ≥ 30 × 109/L|| 
 
Neutrophil response: 
• Pretreatment ≤ 0.5 × 109/L:  at least 100% increase and an absolute increase ≥ 0.5 × 109/L 
• Pretreatment > 0.5 × 109/L and ≤ 1.0 × 109/L:  at least 50% increase and an absolute 
increase ≥ 0.5 × 109/L|| 
 
Spleen response: 
• Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 
10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not 
palpable becomes not palpable. 
* Presence of dysplastic changes, which may be interpreted within the scope of normal range of dysplastic changes, may 
still exist in the presence of CR as allowed in MDS IWG.  Marrow should exhibit age-adjusted normocellularity in CR. 
† If there is no significant fibrosis present on the initial bone marrow biopsy, a second biopsy is not required to prove 
resolution of fibrosis.  Grading of fibrosis in measurement of treatment response should be according to the European 
Consensus System. 
‡ Given the current lack of a validated tool to assess complete resolution of symptoms in MDS/MPN, "CR with resolution 
of symptoms" (a complete resolution of disease-related symptoms as noted by the MPN-SAF TSS in presence of CR) 
will be a provisional category of disease response. 
§ Loss of cytogenetic burden of disease by (via FISH or classic karyotyping) known to adversely affect prognosis is 
required to reach complete cytogenetic remission.  Decrease in the cytogenetic burden of disease must be by ≥ 50% (via 
FISH or classic karyotyping) to be indicative of a partial cytogenetic response.  Given variability of fluorescent probes 
used in FISH, cytogenetic normalization via FISH will depend on the performance characteristics of the specific probes 
used. 
|| Resolution of abnormal peripheral blood counts must persist for at least 2 separate analyses over at least 8 weeks.  In the 
case of proliferative MDS/MPN, CR will include resolution of thrombocytosis to a normal platelet count (150-450 × 
109/L) and resolution of leukocytosis to WBC ≤ 10 × 109 cells/L but ≥ 1.5 × 109/L. Hemoglobin should be maintained > 
11 g/dL and platelets ≥100 × 109/L without the support of transfusions.  Clinical benefit may occur when these changes 
occur in absence of other changes required for CR or marrow response.  Platelet and packed red blood cell TI would be 
considered for clinical benefit, and duration of TI should be monitored.  Reduction in myeloid precursors 
(promyelocytes, myelocytes, metamyelocytes, nucleated red blood cells) to less than appreciable levels (≤ 2%-3%) 
and/or 1 × 109/L monocytosis in the absence of infection, cytokine treatment, or other reactive causes. 
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Response 
Subcategory 
Response Criteria 
Progressive 
Disease 
Combination of 2 major criteria, 1 major and 2 minor criteria, or 3 minor criteria from list: 
 
Major criteria: 
Increase in blast count* 
• < 5% blasts:  ≥ 50% increase and to > 5% blasts 
• 5%-10% blasts:  ≥ 50% increase and to > 10% blasts 
• 10%-20% blasts:  ≥ 50% increase and to > 20% blasts 
• 20%-30% blasts:  ≥50% increase and to > 30% blasts† 
 
Evidence of cytogenetic evolution‡ 
• Appearance of a previously present or new cytogenetic abnormality in complete 
cytogenetic remission via FISH or classic karyotyping 
• Increase in cytogenetic burden of disease by ≥ 50% in partial cytogenetic remission via 
FISH or classic karyotyping 
 
New extramedullary disease 
• Worsening splenomegaly 
- 
Progressive splenomegaly that is defined by IWG-MRT:  the appearance of a 
previously absent splenomegaly that is palpable at > 5 cm below the left costal 
margin or a minimum 100% increase in palpable distance for baseline splenomegaly 
of 5-10 cm or a minimum 50% increase in palpable distance for baseline 
splenomegaly of > 10 cm. 
• Extramedullary disease outside of the spleen 
Minor criteria: 
• Transfusion dependence§ 
• Significant loss of maximal response on cytopenias ≥ 50% decrement from maximum 
remission/response in granulocytes or platelets. 
• Reduction in Hgb by ≥1.5g/dL from best response or from baseline as noted on CBC. 
• Evidence of clonal evolution (molecular)¶ 
* Blasts as measured from the bone marrow. 
† Patients with development of acute myeloid leukemia from MDS/MPN; 20%-30% blasts may be allowed on some 
clinical trials for patients with MDS/MPN. 
‡ Increase in cytogenetic burden of disease by ≥ 50% (via FISH or classic karyotyping).  Given variability of 
fluorescent probes used in FISH, cytogenetic normalization via FISH will depend on specific probes used. 
§ Transfusion dependency is defined by a history of at least 2 U of red blood cell transfusions in the past month for a 
hemoglobin level < 8.5 g/dL that was not associated with clinically overt bleeding.  Cytopenias resulting from 
therapy should not be considered in assessment of progression. 
¶ The identification of new abnormalities using single nucleotide polymorphism arrays or sequencing or a clearly 
significant increase in mutational burden of a previously detected abnormality.  Precise criteria for defining new 
abnormalities and what exactly constitutes a significant increase in mutational burden are open to interpretation; 
this criterion should be used conservatively based on current evidence. 
Source: Savona et al 2015. 
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APPENDIX H. REVISED RESPONSE CRITERIA FOR 
MYELOFIBROSIS:  INTERNATIONAL WORKING 
GROUP-MYELOPROLIFERATIVE NEOPLASMS 
RESEARCH AND EUROPEAN LEUKEMIANET 
CONSENSUS REPORT 
Response 
Category 
Required Criteria 
(for all categories, benefit must last for ≥ 12 weeks to qualify as a response) 
Complete 
response 
• Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤ Grade 1 MF† 
• Hemoglobin ≥ 100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and < UNL; 
• Platelet count ≥ 100 × 109/L and < UNL; < 2% immature myeloid cells‡ 
• Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH 
Partial response 
• Hemoglobin ≥100 g/L and < UNL; neutrophil count ≥ 1 × 109/L and < UNL; platelet count 
≥ 100 × 109/L and < UNL; < 2% immature myeloid cells‡ 
• Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH 
• Bone marrow:* Age-adjusted normocellularity; < 5% blasts; ≤ Grade 1 MF†, and 
peripheral blood:  Hemoglobin ≥ 85 but < 100 g/L and < UNL; neutrophil count 
≥ 1 × 109/L and < UNL; platelet count ≥ 50, but < 100 × 109/L and < UNL; < 2% immature 
myeloid cells‡ 
• Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH 
Clinical 
improvement 
• The achievement of anemia, spleen or symptoms response without progressive disease or 
increase in severity of anemia, thrombocytopenia, or neutropenia§ 
Anemia response  
• Transfusion-independent patients:  a ≥ 20 g/L increase in hemoglobin level|| 
• Transfusion-dependent patients:  becoming transfusion-independent¶ 
Spleen response 
• Baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not 
palpable** or 
• Baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by ≥ 50%** 
- 
Baseline splenomegaly that is palpable at < 5 cm, below the LCM, is not eligible for 
spleen response 
- 
Spleen response requires confirmation by MRI or computed tomography showing 
≥ 35% spleen volume reduction. 
Progressive 
disease‡‡ 
• Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
• ≥ 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm 
or 
• 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm or 
• Leukemic transformation confirmed by a bone marrow blast count of ≥ 20% or 
• Peripheral blood blast content of ≥ 20% associated with an absolute blast count of 
≥ 1 × 109/L that lasts for at least 2 weeks 
Stable disease 
• Belonging to none of the above listed response categories. 
Relapse 
• No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
• Loss of anemia response persisting for at least 1 month, or 
• Loss of spleen response persisting for at least 1 month. 
* Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process.  
Cytogenetic and molecular responses are not required for CR assignment. 
† Grading of MF is according to the European classification. 
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‡ Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + nucleated red blood 
cells.  In splenectomized patients, < 5% immature myeloid cells is allowed. 
§ See above for definitions of anemia response, spleen response, and progressive disease.  Increase in severity of 
anemia constitutes the occurrence of new transfusion dependency or a ≥ 20 g/L decrease in hemoglobin level from 
pretreatment baseline that lasts for at least 12 weeks.  Increase in severity of thrombocytopenia or neutropenia is 
defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according 
to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  In addition, assignment to CI 
requires a minimum platelet count of ≥ 25,000 × 109/L and absolute neutrophil count of ≥ 0.5 × 109/L. 
|| Applicable only to patients with baseline hemoglobin of < 100 g/L.  In patients not meeting the strict criteria for 
transfusion dependency at the time of study enrollment (see as follows), but who have received transfusions within 
the previous month, the pretransfusion hemoglobin level should be used as the baseline. 
¶ Transfusion dependency before study enrollment is defined as transfusions of at least 6 units of packed red blood 
cells (PRBCs), in the 12 weeks before study enrollment, for a hemoglobin level of < 85 g/L, in the absence of 
bleeding or treatment-induced anemia.  In addition, the most recent transfusion episode must have occurred in the 
28 days before study enrollment.  Response in transfusion-dependent patients requires absence of any PRBC 
transfusions during any consecutive "rolling" 12-week interval during the treatment period, capped by a 
hemoglobin level of ≥ 85 g/L. 
# In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy. 
** Spleen or liver responses must be confirmed by imaging studies where a ≥ 35% reduction in spleen volume, as 
assessed by MRI or CT, is required.  Furthermore, a ≥ 35% volume reduction in the spleen or liver, by MRI or CT, 
constitutes a response regardless of what is reported with physical examination. 
‡‡ Progressive disease assignment for splenomegaly requires confirmation by MRI or computed tomography 
showing a ≥ 25% increase in spleen volume from baseline.  Baseline values for both physical examination and 
imaging studies refer to pretreatment baseline and not to posttreatment measurements. 
Source:  Tefferi et al 2013. 
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APPENDIX I. INTERNATIONAL UNIFORM RESPONSE CRITERIA 
FOR MULTIPLE MYELOMA 
Response 
Subcategory 
Response Criteria 
sCR 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by 
immunohistochemistry or immunofluorescence.1 
CR 
Negative immunofixation on the serum and urine, disappearance of any soft tissue 
plasmacytomas, and < 5% plasma cells in bone marrow. 
VGPR 
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or 
greater reduction in serum M-protein with urine M-protein level < 100 mg per 24 hours. 
PR 
• ≥ 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥ 90% 
or to < 200 mg per 24 hours. 
• If the serum and urine M-protein are unmeasurable, a ≥ 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria. 
• If serum and urine M-protein and serum FLC are unmeasurable2, then ≥ 50% reduction in 
plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell 
percentage was ≥ 30%. 
• In addition to the above-listed criteria, if present at baseline, a ≥ 50% reduction in the size 
of soft tissue plasmacytomas is also required. 
SD 
Not meeting criteria for CR, VGPR, PR, MR, or PD. 
PD 
Any one or more of the following: 
• Increase of ≥ 25% from lowest response level in: 
- 
serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL) 
- 
urine M-component and/or (the absolute increase must be ≥ 200 mg/24 h) 
• Only in subjects without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels.  The absolute increase must be > 10 mg/dL. 
• Bone marrow plasma cell percentage:  the absolute % must be ≥ 10% 
• Definite development of new bone lesions or soft tissue plasmacytomas or definite increase 
in the size of existing bone lesions or soft tissue plasmacytomas. 
• Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) 
that can be attributed solely to the plasma cell proliferative disorder. 
1 Presence/absence of clonal cells is based upon the κ/λ ratio.  An abnormal κ/λ ratio by immunohistochemistry 
and/or immunofluorescence requires a minimum of 100 plasma cells for analysis.  An abnormal ratio reflecting 
presence of an abnormal clone is κ/λ of > 4:1 or < 1:2. 
2 Measurable disease:  serum M-protein ≥ 1 g/dL, urine M-protein > 200 mg/24 hr, or serum involved FLC levels 
> 10 mg/dL with a normal κ/λ ratio. 
All response categories require 2 consecutive assessments made at any time before the institution of any new 
therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies 
were performed.  Radiographic studies are not required to satisfy these response requirements. 
Source:  Durie et al 2006. 
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APPENDIX J. CRITERIA FOR EVALUATING DISEASE RESPONSE 
AND PROGRESSION IN SUBJECTS WITH MULTIPLE 
MYELOMA TREATED BY HIGH-DOSE THERAPY AND 
HAEMOPOIETIC STEM CELL TRANSPLANTATION:  
MYELOMA SUBCOMMITTEE OF THE EUROPEAN 
SOCIETY FOR BLOOD AND MARROW 
TRANSPLANTATION 
Minimal 
Response 
• 
≥ 25% but ≤ 49% reduction of serum M-protein and reduction in 24-hour urine 
M-protein by 50% to 89%.  
• 
In addition to the above criteria, if present at baseline, 25% to 49% reduction 
in the size of soft tissue plasmacytomas is also required. 
• 
No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response). 
Source:  Blade et al 1998. 
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APPENDIX K. RESPONSE CRITERIA FOR LYMPHOMA – THE 
LUGANO CLASSIFICATION 
Site 
PET–Based Response 
CT/MRI-Based Response 
 
Complete metabolic response 
Complete radiologic response 
(all of the following) 
Lymph nodes 
and 
extralymphatic 
sites 
Score 1, 2, or 3 with or without a residual mass 
on 5PS.
a 
Target nodes/nodal masses must regress to 
≤ 1.5 cm in LDi. 
Nonmeasured 
lesion 
Not applicable. 
Absent. 
Organ 
enlargement 
Not applicable. 
Regress to normal. 
New lesions 
None. 
None. 
Bone marrow 
No evidence of FDG-avid disease in marrow. 
Normal by morphology; if indeterminate, IHC 
negative. 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes 
and 
extralymphatic 
sites 
• Score 4 or 5a with reduced uptake compared 
with baseline and residual mass(es) of any 
size. 
 
• ≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites. 
• When a lesion is too small to measure on CT, 
assign 5 mm × 5 mm as the default value. 
• When no longer visible, 0 × 0 mm. 
For a node > 5 mm × 5 mm but smaller than 
normal, use actual measurement for calculation. 
Nonmeasured 
lesions 
Not applicable. 
Absent/regressed, but no increase. 
Organ 
enlargement 
Not applicable. 
Spleen must have regressed by > 50% in length 
beyond normal. 
New lesions 
None. 
None. 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes from chemotherapy allowed).  If there 
are persistent focal changes in the marrow in 
the context of a nodal response, consideration 
should be given for further evaluation with 
MRI or biopsy at interval scan. 
Not applicable. 
 
No metabolic response 
Stable disease 
Target nodes/ 
nodal masses, 
extranodal 
lesions 
Score of 4 or 5a with no significant change in 
FDG uptake from baseline at interim or EOT. 
< 50% decrease from baseline in SPD of up to 
6 dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are 
met. 
Nonmeasured 
lesions 
Not applicable. 
No increase consistent with progression. 
Organ 
enlargement 
Not applicable. 
No increase consistent with progression. 
New lesions 
None. 
None. 
Bone marrow 
No change from baseline. 
Not applicable. 
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Site 
PET-CT–Based Response 
CT-Based Response 
 
Progressive metabolic disease: 
Progressive disease (requires at least 1 of the 
following): 
Individual 
target 
nodes/nodal 
lesions 
Individual target nodes/nodal lesions: 
• Score 4 or 5a with an increase in intensity of 
uptake from baseline and/or 
• New FDG-avid foci consistent with 
lymphoma at interim or EOT assessment. 
 
Extranodal lesions: 
• New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment. 
 
New lesions: 
• New FDG-avid foci consistent with 
lymphoma rather than another etiology (eg, 
infection, inflammation).  If uncertain 
regarding etiology of new lesions, biopsy or 
interval scan may be considered. 
 
Bone marrow: 
• New or recurrent FDG-avid foci. 
PPD progression: 
• An individual node/lesion must be abnormal 
with all of the following:   
o LDi > 1.5 cm  
o Increase by ≥ 50% from PPD nadir 
o An increase in LDi or SDi from nadir 
 0.5 cm for lesions ≤ 2 cm 
 1.0 cm for lesions > 2 cm 
• In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent 
of its prior increase beyond baseline (eg, a 
15-cm spleen must increase to > 16 cm).  If 
no prior splenomegaly, must increase by at 
least 2 cm from baseline. 
• New or recurrent splenomegaly. 
• New or clear progression of preexisting 
nonmeasured lesions. 
• Regrowth of any previously resolved lesions. 
• A new node > 1.5 cm in any axis. 
• A new extranodal site > 1.0 cm in any axis; if 
< 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma. 
• Assessable disease of any size unequivocally 
attributable to lymphoma. 
• New or recurrent involvement of the bone 
marrow. 
5PS = 5-point scale; LDi = longest transverse diameter of lesion; MRI = magnetic resonance imaging; PPD = cross 
product of the LDi and perpendicular diameter; SDi = shortest axis perpendicular to the LDi; SPD = sum of the 
product of the perpendicular diameters for multiple lesions. 
a PET 5-point scale: 1, no uptake above background; 2, update ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 
4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. 
Source:  Cheson et al 2014. 
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APPENDIX L. RESPONSE ASSESSMENT IN WALDENSTRÖM 
MACROGLOBULINEMIA 
Categorical Response Definitions in Waldenström Macroglobulinemia 
Response Category 
Response Definition 
Complete response 
• 
Absence of serum monoclonal IgM protein by immunofixation. 
• 
Normal serum IgM level. 
• 
Complete resolution of extramedullary disease, ie, 
lymphadenopathy and splenomegaly if present at baseline. 
• 
Morphologically normal bone marrow aspirate and trephine 
biopsy. 
Very good partial response 
• 
Monoclonal IgM protein is detectable ≥ 90% reduction in serum 
IgM level from baseline.a 
• 
Complete resolution of extramedullary disease, ie, 
lymphadenopathy/splenomegaly if present at baseline. 
• 
No new signs or symptoms of active disease. 
Partial response 
• 
Monoclonal IgM protein is detectable ≥ 50% but < 90% 
reduction in serum IgM level from baseline.
a 
• 
Reduction in extramedullary disease, ie, 
lymphadenopathy/splenomegaly if present at baseline. 
• 
No new signs or symptoms of active disease. 
Minor response 
• 
Monoclonal IgM protein is detectable ≥ 25% but < 50% 
reduction in serum IgM level from baseline.a 
• 
No new signs or symptoms of active disease. 
Stable disease 
• 
Monoclonal IgM protein is detectable < 25% reduction and 
< 25% increase in serum IgM level from baseline.a 
• 
No progression in extramedullary disease, ie, 
lymphadenopathy/splenomegaly. 
• 
No new signs or symptoms of active disease. 
Progressive disease 
• 
≥ 25% increase in serum IgM levela from lowest nadir (requires 
confirmation) and/or 
• 
Progression in clinical features attributable the disease. 
.a Sequential changes in IgM levels may be determined either by M-protein quantification by densitometry or total 
serum IgM quantitation by nephelometry. 
Source:  Owen et al 2013. 
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APPENDIX M. RESPONSE ASSESSMENT IN CHRONIC 
LYMPHOCYTIC LEUKEMIA 
Complete Response (CR) 
CR requires all of the following criteria as assessed:  
1. Absence of clonal lymphocytes in the peripheral blood. 
2. Absence of significant lymphadenopathy (eg, lymph nodes > 1.5 cm in diameter) by 
physical examination and in CT scan of the chest abdomen and pelvis. 
3. No hepatomegaly or splenomegaly by physical examination and confirmed by CT scan. 
4. Absence of constitutional symptoms. 
5. Blood counts above the following values: 
a. Neutrophils > 1.5 × 109/L without the need exogenous growth factors. 
b. Platelets > 100 × 109/L without the need for exogenous growth factors. 
c. Hemoglobin > 110 g/L without the red blood cell transfusion or need for exogenous 
erythropoietin. 
6. A marrow aspirate and biopsy should be performed if clinical and laboratory results listed 
in criteria 1 through 5 demonstrate that a CR has been achieved.  The marrow should be 
assessed by flow cytometry and immunohistochemistry to demonstrate that the marrow is 
free of clonal B lymphocytes.  If marrow is hypocellular a repeat marrow should be 
conducted in about 4 to 6 weeks provided criteria 1 through 5 are still satisfied. 
Partial Response (PR) 
To define a PR, the following parameters need to be documented for a minimum of 2 months' 
duration.  Constitutional symptoms persisting for more than 1 month should be recorded. 
1. A decrease in the number of blood lymphocytes by 50% or more from the values before 
therapy.  Note:  Persistent lymphocytosis should not interfere with the time of designation 
of a PR, which should be based more on the other measurable aspects of the disease than 
on lymphocytosis. 
2. Reduction in lymphadenopathy by CT scan as defined by the following: 
a. A decrease in lymph node size by 50% or more in the sum products of up to 6 lymph 
nodes or in 1 lymph node diameter if only a single lymph node was present before 
therapy. 
b. No increase in any lymph node and no new enlarged lymph node.  In small lymph 
nodes (< 2 cm) an increase of < 25% is not considered to be significant. 
3. A reduction in the noted pretreatment enlargement of the spleen or liver by 50% or more, 
as detected by CT scan (clinical studies) or palpation (general practice). 
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4. The blood count should show one of the following: 
a. Neutrophils > 1.5 × 109/L without the need for exogenous growth factors. 
b. Platelets > 100 × 109/L without the need for exogenous growth factors 
c. Hemoglobin > 11.0 g/dL without the red blood cell transfusion or need for exogenous 
erythropoietin. 
Progressive Disease* 
Progressive disease during or after therapy is characterized by at least one of the following that is 
confirmed with repeated observations and incorporates indicators of progressive disease that are 
not typically associated with tumor flare OR rely on indicators of progressive disease that do not 
resolve after use of measures to mitigate the signs or symptoms of tumor flare: 
1. Lymphadenopathy:  
a. Appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), 
splenomegaly, hepatomegaly, or other organ infiltrates. 
b. An increase by 50% or more in greatest determined diameter of any previous site.  A 
lymph node of 1 to 1.5 cm must increase by 50% or more to a size greater than 
1.5 cm in the longest axis.  A lymph node of more than 1.5 cm must increase to more 
than 2.0 cm in the longest axis. 
c. An increase of 50% or more in the sum of the product of diameters of multiple nodes. 
d. Appearance of new lesions such as new lymphadenopathy (> 1.5 cm), splenomegaly, 
hepatomegaly, or other organ infiltrates.  
2. An increase in the liver or spleen size by 50% or more or the de novo appearance of 
hepatomegaly or splenomegaly. 
3. An increase in the number of blood lymphocytes by 50% or more with at least 
5,000 B lymphocytes/μL AND at least 1 sign or symptom of disease progression.  
Lymphocytosis alone should not be considered progressive disease. 
4. Transformation to a more aggressive histology (eg, Richter syndrome).  This diagnosis 
should be established by lymph node biopsy. 
5. Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL. 
* Including modified criteria as referenced in Cheson et al 2012. 
Stable Disease 
Subjects who have not achieved a CR or a PR and who have not exhibited PD will be considered 
to have stable disease (which is equivalent to a nonresponse). 
Source:  Hallek et al 2008, Cheson et al 2012. 
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APPENDIX N. PROSTATE CANCER WORKING GROUP 3 
GUIDELINES 
Prostate Cancer Working Group 3 (PCWG3) guidelines (Sher et al 2016) will be used in this 
study for the following: 
• Baseline disease assessments by the investigators, based on Table 2 (Table N1) in the 
PCWG3 guideline.  Data will be collected through castration-resistant protein cancer 
(CRPC)-specific electronic case report form (eCRF) modules. 
• Disease progression assessments by the investigators, based on blood-based PSA and 
imaging (nodes, viscera, and bone), as defined in Table 3 (Table N2) in the PCWG3 
guideline.  Data will be collected through CRPC-specific eCRF modules. 
• Disease response assessments by the investigators, based on blood-based 
prostate-specific antigen testing and imaging (nodes, viscera, and bone) as defined in 
Table 5 (Table N3) in the PCWG3 guideline.  Data will be collected through 
CRPC-specific eCRF modules. 
 
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Table N1: 
Standard Baseline Disease Assessments Recommended by PCWG3 in Comparison With PCGW2 
Recommendations 
 
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Table N2: 
Criteria for Progression at Trial Entry by Disease Manifestation 
 
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Table N3: 
Suggested Outcome Measures for Clinical Trials in Metastatic Prostate Cancer 
 
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APPENDIX O. CYP3A4 INHIBITORS AND INDUCERS 
University of Washington School of Pharmaceutics: Drug Interaction Database Program. 2002. 
http://www.druginteractioninfo.org.  Accessed October 2017. 
Yellow highlighted rows indicate changes from the last database update in July 2017.
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In Vivo CYP3A Inhibitors 
 
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In Vivo CYP3A Inducers 
 
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APPENDIX P. SCREENING SYMPTOM FORM 
Instructions to Subjects:  Please answer all questions to the best of your ability, based on your 
memory over the past 7 days (1 week).  There is no right or wrong answer. 
1. During the past 7 days, how severe 
were your worst night sweats (or 
feeling hot or flushed) due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
2. During the past 7 days, how severe 
was your worst itchiness due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
3. During the past 7 days, how severe 
was your worst abdominal discomfort 
(feel uncomfortable, pressure or 
bloating) due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
4. During the past 7 days, how severe 
was your worst pain under the ribs on 
the left side due to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
5. During the past 7 days, what was the 
worst feeling of fullness (early satiety) 
you had after beginning to eat, due to 
MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
6. During the past 7 days, how severe 
was your worst bone or muscle pain 
due to MF (diffuse, not joint or 
arthritis pain)? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
7. During the past 7 days, what was the 
worst degree of inactivity (including 
work and social activities) you had due 
to MF? 
 
0 (Absent)  1    2    3    4    5    6    7    8    9    10 (Worst Imaginable) 
 
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Investigators/Site Staff: 
 
Please complete the table below to confirm the criterion used to confirm the subject's eligibility 
in the trial based on an assessment of his/her active symptoms of myelofibrosis. 
ELIGIBILITY CRITERION 
CONFIRMATION 
A symptom score of at least 5 on at least 1 of the symptoms 
□ Yes □ No 
A symptom score of 3 or greater on at least 2 of the symptoms 
□ Yes □ No 
 
 
 
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APPENDIX Q. MANAGEMENT OF 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 adverse event (AE)/serious adverse event (SAE) reporting according to the outcome of 
the review and assessment in line with standard safety reporting processes. 
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. 
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. 
DEFINITIONS 
For the purpose of this process definitions are as follows 
Potential Hy's Law 
An increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × upper 
limit of normal (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 timeframe. 
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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, for example, elevated serum alkaline 
phosphatase (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, then proceed as follows: 
− Determine without delay whether the subject meets PHL criteria by reviewing 
laboratory reports from all previous visits. 
− Enter the laboratory data into the laboratory case report form (CRF) as soon as 
possible. 
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 timeframe), 
irrespective of ALP, please follow the instruction below: 
• Perform follow-up on subsequent laboratory results according to the guidance 
provided in Section 5.4.2 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 timeframe), 
irrespective of ALP, please follow the instructions 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. 
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• 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 were 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, the following: 
• 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 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, 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, then proceed as follows: 
• Have the subject permanently discontinue study drug and perform end-of-treatment 
procedures. 
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• 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. 
Source:  FDA 2009. 
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APPENDIX R. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
18 JAN 2016 
Amendment (Version) 2: 
08 JUL 2016 
Amendment (Version) 3: 
14 MAR 2017 
Amendment (Version) 4: 
07 JUN 2017 
Amendment (Version) 5: 
11 OCT 2017 
Amendment (Version) 6: 
06 MAY 2018 
Amendment (Version) 7:  
22 OCT 2018 
Amendment 7 (22 OCT 2018) 
Overall Rationale for the Amendment: 
The primary purpose of Protocol Amendment 7 is to remove the disease status follow-up and 
survival follow-up for subjects who end study treatment.  Disease assessments will also be 
conducted per investigator discretion. 
This amendment includes the changes to Protocol INCB 57643-101 Amendment 6 (06 MAY 
2018) summarized below.  A redline version of the amendment depicting the updated and 
previous text is also provided. 
1. 
 
 
 Section 4.1, Overall Study Design; Section 7.6.2, Myeloproliferative 
Neoplasms Symptom Assessment Form Total Symptom Score; Section 7.6.3, Patient 
Global Impression of Change; Section 9.4.1.2, Secondary Efficacy Analyses; 
; Appendix Q, Patient Global 
Impression of Change; Appendix R, Myeloproliferative Neoplasms Symptom 
Assessment Form Total Symptom Score. 
Description of change:  Part 4 will not open in Amendment 7. 
Rationale for change:  This study was placed on screening and enrollment hold in 
MAR 2018, and no further subjects will be entered onto the study; therefore, Part 4 will 
not open (see Section 1.6.2). 
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2. Synopsis; Section 5.5.2, Withdrawal Procedures; Section 6, Study Assessments; 
Section 6.4.2, Disease Status Follow-Up; Section 6.4.3, Survival Follow-Up (Part 2 
and Part 4 Only); Section 7.7, Efficacy Assessments; Section 7.10.2, Data Collection 
for Survival Follow-Up 
Description of change:  Disease status follow-up and survival follow-up will not be 
required after end of study treatment in Amendment 7.  Efficacy and disease assessments 
will be conducted at the discretion of the investigator. 
Rationale for change:  No further development of INCB057643 will be conducted after 
these subjects end study treatment; therefore, follow-up will not be collected.  
Investigators may keep the subject on study treatment if they believe that the subject is 
receiving clinical benefit and the subject agrees by re-consenting; therefore, the 
investigator may follow efficacy and disease assessments at their own discretion.  
3. Section 7.5.4.1 Twelve-Lead Electrocardiograms 
Description of change:  With Amendment 7, local ECGs will not be collected by a 
central vendor. 
Rationale for change:  All subjects currently on study treatment have passed the serial 
ECG part of the study; therefore, ECGs that have clinically significant findings per the 
investigator may be collected as adverse events. 
4. Section 7.5.5.1, Chemistry, Hematology, Urinalysis, Coagulation Panel, Factor VII, 
Serology, and Endocrine Function Testing 
Description of change:  The investigative site will not enter local laboratory results into 
the eCRF with Amendment 7.  Abnormal laboratory values that are considered clinically 
significant adverse events should be entered into the eCRF as an adverse event.  
Rationale:  In order to reduce site burden, only abnormal laboratory values that are 
considered clinically significant will be entered into the eCRF as adverse events. 
5. Section 1.5.1, Preclinical Safety and Risks; Section 1.6, Clinical Experience With 
INCB057643 in Study INCB 57643-101 
Description of change:  Preclinical safety and risks as well as clinical experience during 
the INCB 57643-101 study were updated. 
Rationale:  These sections were updated with emerging data.  
6. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
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Amendment 6 (06 MAY 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is add new preclinical safety data and cardiac 
monitoring assessments. 
1. Section 1.5.1, Preclinical Safety and Potential Risks 
Description of change:  Updated to include safety data from a 3-month monkey study. 
Rationale for change:  To provide updated data. 
2. Section 5.4.2, INCB057643 Dose Interruptions and Reductions (Table 8) 
Description of change:  Guidelines for study drug interruption/discontinuation for 
cardiac toxicities were added to Table 8. 
Rationale for change:  Guidance on cardiac toxicity needed based on updated preclinical 
safety data. 
3. Section 6, Study Assessments (Schedule of Assessment Tables 10, 12, 15, 18, 21, 24, 
and 27); Section 7.5.4.4, Echocardiogram or MUGA 
Description of change:  Echocardiogram or MUGA assessment was added. 
Rationale for change:  Cardiac monitoring added based on updated preclinical safety 
data.  
4. Section 6, Study Assessments (Laboratory Assessment Tables 11, 13, 16, 19, 22, 25, 
28, and 31); Section 7.5.5.4, Cardiac Troponin (Either T or I) Testing 
Description of change:  Cardiac troponin (either T or I) testing was added. 
Rationale for change:  Cardiac monitoring added based on updated preclinical safety 
data. 
5. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
The following revisions from Administrative Change 3 (dated 23 MAR 2018) were also 
incorporated: 
6. Section 5.3, Treatment Compliance 
Description of change:  The following statement was added:  "Drug accountability will 
not be captured in InForm for standard of care agents used in this study."  
Rationale for change:  To correct an inadvertent omission. 
7. Section 6, Study Assessments (Tables 11, 12, 14, 15, 26, and 27) 
Description of changes:   
• For Tables 11, 12, 14, and 15, where Cycle 1 and Cycle 2 are combined under 
1 column, a ± 3-day evaluation window was added for Cycle 2 Day 1 only. 
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• For Table 26 and Table 27, where all cycles are combined under 1 column, a ± 2-day 
evaluation window was added for Cycle 2 Day 1 and subsequent cycles. 
Rationale for changes:  To clarify and to update for consistency. 
8. Section 6, Study Assessments (Tables 9, 10, 17, 18, 20, 21, 23, and 24) 
Description of change:  A footnote was added to the Day 11 cell to indicate that after a 
subject has been on study for 6 months, Day 11 visits at subsequent cycles will be 
optional at the discretion of the investigator. 
Rationale for change:  To decrease the number of visits for subjects who are clinically 
stable without clinically significant AEs. 
9. Section 6, Study Assessments (Tables 10, 12, 15, 18, 21, 24, and 27) 
Description of changes: 
• Table 10, footnote e was updated to indicate that sampling does not need to be 
repeated on Day 11 of Cycle 3 or any subsequent cycles; however, it should be 
performed any time there is a Grade 2 increased INR. 
• Tables 10 (footnote e), 12 (footnote d), 15 (footnote d), 18 (footnote e), 
21 (footnote d), 24 (footnote d), and 27 (footnote f) were updated to indicate that 
study visits do not need to be delayed waiting on the Factor VII protein/antigen assay 
results as long as INR/PT results are within normal limits. 
• Tables 18, 21, and 24 weree updated to remove the following statement from footnote 
d, which does not apply:  "Coagulation panel is also sampled on C1D2." 
Rationale for changes:  To clarify and/or to correct an error. 
10. Section 6, Study Assessments (Table 12) 
Description of change:  Timed PK plasma assessment was removed. 
Rationale for change:  To correct an error, as Table 12 currently indicates that timed PK 
assessments need to be obtained in Cycle 2.  This is not correct and contradicts Table 13, 
which details timed PK assessments separately. 
11. Section 6, Study Assessments (Tables 12, 24, and 27) 
Description for change:  A serum pregnancy test at safety follow-up was added. 
Rationale for change:  To correct an error. 
12. Section 6, Study Assessments (Tables 13, 16, 19, 22, and 28) 
Description of changes:  The collection of serial PK sampling should be conducted after 
INCB057643 administration.  In Tables 13, 16, 19, 22, and 28, footnote a was revised to 
specify "INCB057643 administration" instead of "drug administration." 
Rationale for changes:  To clarify timing of PK sampling, as the purpose of the serial 
PK sampling in combination therapy cohorts is to assess whether the standard of care 
agent will affect INCB057643 PK. 
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13. Section 6, Study Assessments (Table 17 and Table 23) 
Description of change:  Disease assessments was added at end of treatment. 
Rationale for change:  To correct an error. 
14. Section 7.8.1, Blood Sample Collection 
Description of change:  Fasting restrictions were updated to reflect that subjects do not 
need to refrain from water for 8 hours before or 1 hour after any PK sampling.  
Rationale for change:  It is not necessary to refrain from water before or after PK 
sampling. 
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Amendment 5 (11 OCT 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to add dose-finding and dose-expansion cohorts to 
evaluate INCB057643 in combination with select standard of care (SOC) agents in advanced 
malignancies and to update aspects of the monotherapy design based on emerging data from the 
current study.  
This amendment includes the changes to Protocol INCB 57643-101 Amendment 4 (Version 4 
dated 07 JUN 2017) 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; Section 11, References; Appendix N, Prostate 
Cancer Working Group 3 Guidelines; Appendix P, Screening Symptom Form; 
Appendix Q, Patient Global Impression of Change; Appendix R, Myeloproliferative 
Neoplasms Symptom Assessment Form Total Symptom Score; Appendix S, 
Management of Potential Hy's Law Cases 
Description of change:  The study design was revised to include 6 combination 
INCB057643 and SOC dose-finding cohorts (ie, INCB057643 in combination with 
gemcitabine, paclitaxel, rucaparib, abiraterone plus prednisone, ruxolitinib, and 
azacitidine) and 4 combination INCB057643 and SOC dose-expansion cohorts 
(ie, INCB057643 in combination with rucaparib, abiraterone plus prednisone, ruxolitinib, 
and azacitidine).  All relevant Protocol sections, including tables, figures, and appendices, 
were either added or revised accordingly.  Study objectives and endpoints were revised in 
consideration of combination therapy. 
Rationale:  To provide the background, rationale, study design, study 
objectives/endpoints, inclusion/exclusion criteria, treatment details, study assessments, 
and statistical considerations necessary in order to research INCB057643 in combination 
with SOC regimens in advanced malignancies. 
2. Synopsis; Section 3.1, Subject Inclusion Criteria; Section 4.1.2, Part 2 – 
Monotherapy Dose Expansion (Figure 1); Section 9.2, Selection of Sample Size 
Description of change:  Ewing's sarcoma tumor type was added to Part 2 Monotherapy 
Dose Expansion.  
Rationale for change:  In a model of Ewing sarcoma, expressions of fusion transcription 
factors caused by the translocation of EWS and ETS genes results in global epigenetic 
reprogramming.  These changes are associated with the expression of an oncogenic 
program that characterizes Ewing sarcoma.  Treatment of Ewing cell lines with BET 
inhibitors was shown to block EWS-ETS dependent transcription and to reduce the 
growth of these cells and tumors in vitro and in vivo.  These data suggest a therapeutic 
role for BET inhibitors across a wide range of cancers and demonstrate that neoplasms 
derived from aberrant activity of lineage-determining transcription factors may be 
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particularly responsive.  Therefore, Ewing sarcoma was added to Part 2 Treatment 
Group A for further exploration in the clinical setting.  
3. Synopsis; Section 3.2, Exclusion Criteria; Section 5.7.1, Restricted Medications 
Description of change:  Coagulation criteria were added to increase surveillance of 
coagulation factors, particularly for subjects who are taking coumarin-based 
anticoagulants, such as warfarin.  Investigators will be asked to consider switching 
subjects from warfarin to an alternate anticoagulation therapy that does not directly target 
Factor VII.  Bleeding considerations were added to the exclusion criteria for subjects 
experiencing clinically significant bleeding within 14 days of Cycle 1 Day 1. 
Rationale for change:  A subject experienced a Grade 4 event of increased international 
normalized ratio while taking INCB057643 and warfarin; therefore, stricter monitoring 
on coagulation laboratory values was added.  Thrombocytopenia was found to be a dose 
limiting toxicity; and, therefore, subjects who are at a high risk for bleeding will be 
excluded from this study.  
4. Section 1.6, Clinical Experience With INCB057643 in Study INCB 57643-101 
Description of change:  The clinical pharmacokinetics and clinical study experience 
were revised to include emerging data from ongoing analyses. 
Rationale for change:  To provide an update on the emerging data in INCB057643 
monotherapy. 
5. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment, including the addition of the summary of changes for all amendments to 
Appendix T. 
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Amendment 4 (07 JUN 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise the exclusion criterion for inadequate organ 
function based on FDA comments. 
This amendment includes the changes to Protocol INCB 57643-101 Amendment 3 
(14 MAR 2017) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Synopsis; Section 1.4, INCB057643 Preclinical Safety and Potential Risks; 
Section 3.2, Subject Exclusion Criteria 
Description of change:  Exclusion criteria 2d was revised to indicate that subjects in 
both Part 1 and Part 2 will be excluded if creatinine clearance is < 50 mL/min based on 
Cockroft-Gault formula or 24-hour urinalysis (< 30 mL/min for multiple myeloma).  
Pharmacokinetic data were added to Section 1.4. 
Rationale for change:  The pharmacokinetics of INCB057643 was characterized in rats, 
dogs, and monkeys.  The urinary excretion of INCB057643 was determined to be 12.5% 
of dose in monkeys, 17.6% in rats, and 26.1% in dogs.  Further, in vitro and in vivo 
metabolism studies in animals indicate generation of major and minor metabolites.  These 
data indicate that renal clearance is not the major route of clearance for INCB057643 and 
that metabolism is likely the predominant clearance pathway.  The clearance mechanism 
of the active metabolite, INCB057228, is less clear; however, exposure of this metabolite 
in patients is only about 10% to 15% of parent. 
Enrollment of patients with mild to moderate organ impairment (≤ G2 creatinine 
clearance) in the carefully monitored Phase 1 setting would allow us to better understand 
the impact of such organ dysfunction on the disposition of INCB057643 and in turn 
would inform the inclusion/exclusion criteria for Phase 2 studies. 
Upon further consideration, the threshold for creatinine clearance for both Parts 1 and 2 
will be the same (ie, exclusion of subjects with creatinine clearance < 50 mL/min based 
on Cockroft-Gault formula or 24-hour urinalysis and < 30 mL/min for subjects with 
multiple myeloma). 
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Amendment 3 (14 MAR 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to amend the definition of pharmacologically active 
dose (PAD), treatment group population, number of subjects, maximum tolerated dose (MTD), 
dose-limiting toxicity (DLT), study assessments, including coagulation laboratory monitoring, 
and inclusion/exclusion criteria. 
This amendment includes the changes to Protocol INCB 57643-101 Amendment 2 
(08 JUL 2016) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Synopsis; Section 3, Subject Eligibility; Section 4, Investigational Plan; 
Section 5.4.1, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose (Table 3: Definition of Dose-Limiting Toxicity) 
Description of changes:  
• The PAD definition of plasma concentration exceeding ex vivo or projected c-Myc 
IC50 for approximately 12 hours has been modified to "for approximately 6-12 hours 
or achieves clinical response." 
• The following language was added:  The sponsor along with the investigator may 
now elect to investigate 1 or more dose levels less than the nontolerated dose (NTD) 
or expand a dose cohort(s) deemed tolerable up to 12 subjects in order to obtain 
additional pharmacokinetic (PK), pharmacodynamic (PD), and safety data before 
determining the MTD. 
• Singular or nonfasting elevations in blood glucose ≥ Grade 3 will not be considered 
DLTs; blood glucose excursions will be considered DLTs if fasting blood glucose is 
≥ Grade 3 on 2 separate occasions and 3 days apart. 
• For Part 1 Dose Escalation and Part 2 Dose Expansion, Treatment Group B (TGB) 
was revised to add 'acute' to leukemia as well as myelodysplastic 
syndrome/myeloproliferative neoplasms (MDS/MPN), or myelofibrosis (MF); 
MDS/MPN and MF were removed from Treatment Group C (TGC). 
• In Part 2 Dose Expansion, the following tumor types were removed from Treatment 
Group A (TGA):  colorectal cancer, non−small cell lung cancer, and NUT midline 
carcinoma. 
• The number of subjects has been increased to 255.  Part 1 will include up to 
approximately 60 subjects.  In Part 2 TGA, the number of subjects has increased from 
60 to 120.  The pancreatic adenocarcinoma, breast cancer, glioblastoma multiforme, 
and non-Hodgkin's lymphoma groups will enroll 5 to 15 subjects; the additional 
group (any solid tumor or lymphoma with aberrations in Myc or other genes in which 
BET proteins are relevant) will enroll up to 20 subjects.  The high-grade serous 
ovarian cancer group will include approximately 20 subjects.  At least 5 of these will 
have BRD4 amplification, and another 5 will have MYC 
amplification/overexpress/translocation.  The BRD4 and MYC molecular signature 
will be identified either by known status before subject screening or retrospectively 
after subject enrollment.  The castration-resistant prostate cancer group will include 
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approximately 20 subjects.  At least 5 of these will have androgen receptor splice 
variant 7 (AR-V7), and another 5 will have neuroendocrine phenotype.  The AR 
molecular signature will be identified either by known status before subject screening 
or retrospectively after subject enrollment.  Part 2/TGB will enroll approximately 5 to 
15 subjects for each of the 4 tumor types (up to 60 subjects), and Part 2/TGC will 
enroll initially 5 to 15 subjects with MM.  
Rationale for changes:  Based on preclinical, PK, and emerging safety data, the PAD, 
tumor target types, number of subjects, and DLT criteria were refined. 
2. Synopsis; Section 3, Subject Eligibility 
Description of changes: 
• In inclusion criterion 3a (prior therapy for Parts 1 and 2/TGA and TGB), the 
following statements were added:  Subjects with AML are eligible if they have 
relapsed and/or refractory disease; if they are ≥ 65 years of age and are not candidates 
for or have refused standard chemotherapy, or if they have no established standard of 
care that is known to provide clinical benefit in the judgement of the investigator.  
Subjects with MF must be resistant, refractory, or intolerant to ruxolitinib therapy.  
Epithelial ovarian cancer was changed to high-grade serous ovarian cancer.  
• In inclusion criterion 4, the timeframe of pretreatment tumor biopsy was clarified to 
be preferably ≤ 1 year old. 
• In exclusion criterion 2, the following clarifications were added for inadequate organ 
function status: 
− Total bilirubin > 1.5 × ULN is acceptable if direct bilirubin ≤ 1.2 × ULN or with a 
diagnosis of Gilbert's syndrome.  
− Creatinine clearance was differentiated for Part 1 and Part 2.  The original 
language is assigned to Part 1 and reads as follows:  Creatinine clearance 
< 50 mL/min based on Cockroft-Gault formula or 24-hour urinalysis 
(< 30 mL/min for MM).  Part 2 states creatinine clearance < 40 mL/min based on 
Cockroft-Gault formula or 24-hour urinalysis (< 30 mL/min for MM). 
• Exclusion criterion 3d (receipt of anticancer medication) was revised to < 4 weeks for 
immunotherapy or antibody therapy.  The following statements were also added: 
− Low-dose corticosteroids (prednisone or the equivalent ≤ 10 mg per day) may be 
administered.   
− Hydroxyurea should not be used within at least 48 hours before and on the day of 
the 
 sample collection 
. 
− For Parts 1 and 2/TGC:  Receipt of less than 160 mg dexamethasone within 
14 days before receiving the first dose of study drug is allowed. 
− Denosumab and zoledronic acid are permitted to treat cancer-related bone 
diseases. 
• Exclusion criterion 11 was changed to Type 1 diabetes or uncontrolled Type 2 
diabetes, and a required exclusion criterion 11b has been added to include that HbA1c 
of ≥ 8% at screening will exclude a subject. 
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• Exclusion criterion 15 relating to brain or central nervous system metastases has been 
revised to state that subjects with glioblastoma are not subjected to this criterion with 
medical monitor approval. 
• Exclusion criterion 17 was revised to indicate a history of cardiac condition of 
≤ 1 year.  A statement was also add that subjects with a pacemaker and well-
controlled rhythm for at least 1 month before first dose of study drug will be allowed. 
• Exclusion criterion 27 was added to exclude subjects with any sign of clinically 
significant bleeding. 
Rationale for changes:  The inclusion and exclusion criteria was modified either due to 
emerging safety data or to provide clarity. 
3. Section 1.5, Clinical Experience With INCB057643 in Study INCB 57643-101 
Description of change:  Preliminary PK and safety data from the current study were 
added. 
Rationale for change:  To provide investigators with current clinical data. 
4. Section 5.6, Concomitant Medications 
Description of change:  The following statements were added to restricted medications: 
• Subjects with glioblastoma may be treated with corticosteroids (prednisone or 
equivalent) > 10 mg/day with approval from the medical monitor. 
• Additional timed PK testing following the schedule for Cycle 1 Day 15 may be 
required if subjects initiate or require a dose adjustment of inhibitors or inducers of 
CYP3A4 during the study. 
• Use of anticoagulants that will increase the INR, such as coumarin-based 
anticoagulants (eg, warfarin), is discouraged, but not prohibited.  Coagulation panel 
should be monitored more closely while a subject is on any anticoagulant.   
• Hydroxyurea for controlling proliferative disease is permitted with medical monitor 
approval, but should not be used within 48 hours before and on the day of PD sample 
collection. 
The following statements were added to prohibited medications: 
• Denosumab and zoledronic acid are permitted to treat cancer-related bone diseases. 
• Use of potent inducers and inhibitors of CYP3A4 (see Appendix N) with the 
exception of certain topical medications such as ketoconazole, based on its low 
overall bioavailability. 
Rationale for changes:  Revised due to emerging safety data and to provide clarity. 
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5. Section 6, Study Assessments (Tables 5-7);  Section 6.4.3, Survival Follow-Up; 
Section 7.5.5.2, Pregnancy Testing; Section 7.5.5.3, Hepatitis Screening Tests; 
Section 7.8.2, Urine Sample Collection 
Description of changes:   
• In Table 5, triplicate ECGs revised to include 0.5-, 6-, and 8-hour timepoints to match 
serial PK sampling.  A statement was added to obtain the triplicate ECGs with a 1- to 
3-minute break between evaluations.  
• In Table 5 footnote h, a statement was added to obtain bone marrow disease 
assessments during Cycle 2 unless contraindicated. 
• In Table 6, weekly (Cycle 1 Day 1, Day 2, Day 8, and Day 15) coagulation panel was 
added during Cycle 1.  For subjects who experience a treatment-emergent increased 
INR/PT, a Factor VII concentration is requested along with the coagulation panel for 
Cycle 1 Day 1, Cycle 1 Day 15, and as needed.  
• The following statements were added to Table 6:   Screening laboratory tests must be 
performed within 14 days before Cycle 1 Day 1.  Serum chemistry and hematology 
may be omitted on Cycle 1 Day 1 if completed within 3 days before Cycle 1 Day 1.  
If the screening serum pregnancy test was completed within 3 days before Cycle 1 
Day 1, a urine pregnancy test may be performed on Cycle 1 Day 1. 
• Table 6 and Section 7.8.2 revised to indicate that when a PK urine sample is 
collected, a predose void should be collected and recorded. 
• Table 7 revised to include HbA1c at screening. 
• Table 7 and Section 7.5.5.3 revised to indicate that 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 surface antibody is the 
only positive result. 
• In Section 6.4.3, a time frame of up to 2 years was added for survival follow-up. 
Rationale for change:  Based on emerging safety data, HbA1c at screening and more 
frequent monitoring of the coagulation panel were added.  The other statements are 
clarifications or corrections. 
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7. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
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Amendment 2 (08 JUL 2016) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to amend the dose-limiting toxicity criteria. 
This summary of changes includes the changes to Protocol INCB 57643-101 Amendment 1 
(15 MAY 2016) summarized below.  A redline version of the amendment depicting the updated 
and previous text is also provided. 
1. Section 5.4.2, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose (Table 1) 
Description of change:  Nonhematologic toxicity was defined as any ≥ Grade 3 
nonhematologic toxicity except nausea, vomiting, and diarrhea adequately controlled 
with medical therapy within 48 hours.  This has now been amended to define 
nonhematologic toxicity as any ≥ Grade 3 toxicity except nausea, vomiting, and diarrhea 
adequately controlled with medical therapy within 48 hours; any nonhematologic toxicity 
clearly and incontrovertibly related to the underlying disease or its progression; alopecia; 
and Grade 3 fatigue, asthenia, fever, anorexia, or constipation. 
Rationale for change:  This is a first-in-human Phase 1 protocol to test an agent in 
subjects with advanced malignancies.  The patient population often have very advanced 
disease and have had multiple of lines of treatment and, as a result, often have multiple 
persistent physical symptoms such as fatigue and pain.  Those symptoms are often 
Grade 1 or Grade 2 at enrollment, and the severity/grades often fluctuate, especially at the 
time of disease progression.  Declaring a toxicity as a DLT when it's clearly associated 
with the underlying disease or disease progression will seriously hinder the ability to test 
an anticancer agent in the clinic to meet an unmet medical need. 
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Amendment 1 (18 JAN 2016) 
Overall Rationale for the Amendment: 
The primary objectives of this amendment are to remove Part 3 of the study, to add stopping 
rules for unacceptable toxicity observed during the dose-expansion portion, and to update the 
dose-limiting toxicity (DLT) and dose interruption/reduction criteria. 
This amendment includes changes to Protocol INCB 57643-101 (17 DEC 2015) 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 8, Safety Monitoring and Reporting; Section 9, Statistics; 
Section 11, References 
Description of change:  Part 3 of the study was removed.  
Rationale:  Change requested by FDA. 
2. Synopsis; Section 3.2, Subject Exclusion Criteria 
Description of change:  Revised Exclusion Criterion #2a to include total bilirubin levels 
only. 
Rationale:  Change requested by FDA. 
3. Synopsis; Section 4.1.2, Part 2 - Dose Expansion 
Description of change:  Stopping criteria were added to the dose-expansion portion 
(Part 2) of the study.  
Rationale:  Change requested by FDA. 
4. Section 5.4.2, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose 
Description of change:  The DLT definition was updated to remove references to 
investigator attribution. 
Rationale:  Change requested by FDA. 
5. Section 5.4.2, Dose-Limiting Toxicity and Determination of Maximum Tolerated 
Dose; Table 1 
Description of change:  The DLT definition for thrombocytopenia was updated to 
include ≥ Grade 3 events associated with bleeding or any requirement for platelet 
transfusion in all treatment groups.  
Rationale:  Change requested by FDA. 
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6. Section 5.4.6, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drug; Table 2 
Description of change:  Guidelines for toxicity management were updated to remove 
any consideration of investigator attribution.  
Rationale:  Change requested by FDA. 
7. Section 5.4.6, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drug; Table 2 
Description of change:  Guidelines for toxicity management were updated to 
recommend interruption of study drug for Grade 3 events and recovery to ≤ Grade 1 prior 
to resumption of dosing at the next lower dose level; guidelines for Grade 4 events were 
updated to require discontinuation from the study.  An exception for hematologic 
toxicities without clinical consequence (eg, no fever, infection, bleeding) was added. 
Rationale:  Change requested by FDA. 
8. Section 6, Study Assessments; Table 3, Schedule of Assessments – Part 1 and Part 2 
Description of change: Timepoints for drug dispensing and compliance check were 
updated.  
Rationale:  To clarify appropriate timepoints for dispensing of drug and monitoring of 
study drug compliance.  
9. Section 6, Study Assessments; Table 3, Schedule of Assessments – Part 1 and Part 2 
Description of change:  Footnote "d" was updated as follows:  "Triplicate ECGs will be 
performed predose and 1, 2, and 4 hours postdose on both Cycle 1 Day 1 and Cycle 1 
Day 15."  The X indicating ECG assessment on Cycle 1 Day 8 was deleted. 
Rationale:  To provide consistency with the Protocol-required timepoints for triplicate 
ECGs.  
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Signature Manifest
Document Number: IC-DEV-PROT-AMEND-0403
Revision: 0
Title: INCB 57643-101 Protocol Amendment 7
All dates and times are in Eastern Standard Time.
57643-101 Protocol Am 7
Approval and Release
Name/Signature
Title
Date
Meaning/Reason
22 Oct 2018, 03:35:28 PM
Approved
 
22 Oct 2018, 04:04:32 PM
Approved
23 Oct 2018, 11:36:54 AM
Approved
23 Oct 2018, 04:32:15 PM
Approved