A Phase 1/2, Open-Label, Dose Escalation, Safety and Tolerability Study of INCB050465 and Iitacitinib in Subjects With Previously Treated B-Cell Malignancies (CITADEL-101)
Phase: PHASE1
Conditions: B-Cell Malignancies
Sponsor: Incyte Corporation

Official Title: 
NCT Number: 
NCT02018861
Document Date: 
Clinical Study Protocol Version 10: 07 August 2019 
A Phase 1/2, Open-Label, Dose Escalation, Safety and Tolerability Study of 
INCB050465 and Iitacitinib in Subjects With Previously Treated B-Cell Malignancies 
(CITADEL-101)

Incyte Corporation 
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Protocol INCB 50465-101 Am 10 
Version 10 
07 AUG 2019 
Clinical Study Protocol 
INCB 50465-101 
A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability 
Study of INCB050465 and INCB039110 in Subjects With Previously 
Treated B-Cell Malignancies (CITADEL-101) 
Product: 
INCB050465 and INCB039110 
IND Number: 
121,474 
124,540 (INCB050465 in combination with INCB039110) 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
13 DEC 2013 
Amendment (Version) 1: 
03 FEB 2014 
Amendment (Version) 2: 
13 NOV 2014 
Amendment (Version) 3: 
06 MAR 2015 
Amendment (Version) 4: 
12 NOV 2015 
Amendment (Version) 5: 
30 NOV 2015 
Amendment (Version) 6: 
19 MAY 2016 
Amendment (Version) 7: 
28 JUN 2016 
Amendment (Version) 8: 
29 NOV 2016 
Amendment (Version) 9: 
02 AUG 2017 
Amendment (Version) 10: 
07 AUG 2019 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the US 
Code of Federal Regulations Parts 50, 54 56, 312, and Part 11 as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 
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Protocol INCB 50465-101 Am 10 
Version 10 
07 AUG 2019 
INVESTIGATOR'S AGREEMENT 
I have received and read the Investigator's Brochures for INCB050465 and INCB039110.  I have 
read the INCB 50465-101 Protocol Amendment 10 (dated 07 AUG 2019) and agree to conduct 
the study as outlined.  I agree to maintain the confidentiality of all information received or 
developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
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Protocol INCB 50465-101 Am 10 
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07 AUG 2019 
SYNOPSIS 
Name of Investigational Product:  INCB050465 and INCB039110 
Title of Study:  A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of 
INCB050465 and INCB039110 in Subjects With Previously Treated B-Cell Malignancies 
Protocol Number:  INCB 50465-101 
Study Phase:  1/2 
Primary Objective: 
• To assess the safety and tolerability of the planned study treatments and select doses for further 
evaluation. 
Secondary Objectives: 
• To assess preliminary efficacy by assessing the overall response rate (ORR) of the planned study 
treatments 
• To assess the pharmacokinetics (PK) of planned study treatments and assess the effect of food on the 
PK of INCB050465 monotherapy 
Overall Study Design: 
The study consists of 4 parts.  Monotherapy dose escalation (Part 1) will determine the maximum 
tolerated dose (MTD) and the recommended dose(s) of INCB050465 to be evaluated further.  The 
recommended dose(s) will be defined as dose(s) at least equivalent to the pharmacologically active 
dose (PAD; a dose that produces substantial pharmacologic target inhibition) and no higher than the 
MTD.   
Combination regimen dose escalation (Part 2) will evaluate the combination of INCB050465 and 
INCB039110 to determine the recommended dose(s) of the combination.   
Expansion (Part 3), which consists of 5 cohorts, will evaluate the recommended dose(s) of 
INCB050465 as monotherapy and in combination with INCB039110.  The monotherapy 
dose-expansion cohorts will evaluate INCB050465 in subjects with B-cell malignancies, indolent  
lymphoma (eg, follicular and marginal zone lymphoma), diffuse large B-cell lymphoma (DLBCL), and 
Hodgkin's lymphoma (HL).  The combination expansion cohorts will evaluate the chosen combination 
dose of INCB050465 and INCB039110 in subjects with B-cell malignancies.  Note that expansion 
cohorts for INCB050465 monotherapy may explore more than 1 recommended dose and schedule to 
obtain long-term safety data on multiple dose levels and schedules.    
Part 6 will include a safety assessment of INCB050465 in combination with the chemotherapy regimen 
R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) in subjects with B-cell malignancies, 
followed by an expansion cohort in DLBCL.   
Timing for the initiation of Part 6 will be determined by the sponsor based on emerging data from 
Parts 1 and 3 of the study. Note, for purposes of consistency and database completion, this will remain 
Part 6. 
Note:  With Amendment 10, Protocol-required procedures have been reduced for ongoing subjects.  
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Protocol INCB 50465-101 Am 10 
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Part 1 – Monotherapy Dose Escalation of INCB050465 
Dose escalation will be conducted with a 3 + 3 design, with the exception that the first cohort (dose 
level of 5 mg QD) will be a single subject cohort.  There will be an observation period of 21 days 
before enrollment of the next cohort and administration of the next dose level.  For each subsequent 
dose level, dose escalation will be conducted with a 3 + 3 dose titration design.  
• The initial cohort will consist of a single subject (the cohort may include an additional subject to 
ensure completion of 1 evaluable subject through Day 21); the initial dose will be 5 mg QD. 
− If a Grade 2 or greater adverse event (AE) is observed, the cohort will be expanded to 3 subjects.  
If the initial cohort is expanded to 3 subjects, the safety assessment will follow the 3 + 3 design.  
Subsequent cohorts will have increases in the dose of INCB050465 limited to no more than 50%. 
− If a Grade 2 or greater AE is not observed, the dose of INCB050465 will be increased to 10 mg QD 
(or 5 mg twice daily [BID] depending on PK data) in the subsequent cohort, and dose escalation 
will be conducted using a 3 + 3 dose titration design.  After the 10 mg QD (or 5 mg BID) dose 
level cohort, subsequent increases in the dose of INCB050465 will be limited to no more than 50%. 
− If the MTD has been exceeded or the PAD has been achieved in the initial cohort, this cohort may 
be expanded to at least 3 subjects and a lower dose of INCB050465 (eg, 2.5 mg QD) may be 
explored. 
• With the 3 + 3 design, each cohort will enroll a minimum of 3 subjects.  If no dose-limiting toxicities 
(DLTs) are observed in the initial 3 subjects, the next cohort will begin enrollment.  If 1 DLT is 
observed in the first 3 subjects, 3 additional subjects will be enrolled in the cohort.  If DLTs occur in 
> 1 of the first 3 subjects or the total cohort of 6 subjects, then the MTD will be deemed to have been 
exceeded and the next lower tolerable dose level will be deemed to be the MTD. 
• If the dose increment has been 100% and deemed exceeding the MTD, an intermediate dose level 
may be explored (eg, from 10 mg QD to 7.5 mg QD). 
If a dose level is reached that provides a suitable profile of pharmacologic target inhibition before 
reaching the MTD (PAD), then this dose may be deemed a recommended dose(s) and used to move to 
Part 3 monotherapy dose-expansion, as well as taken to Part 2 for testing in the combination.  Dose 
escalation of the monotherapy may continue at doses above the PAD until the MTD is reached or dose 
escalation is stopped. 
Part 2 – Dose Escalation With the Combination of INCB050465 and INCB039110 
Dose escalation will proceed using a 3 + 3 design with a starting dose of INCB050465 approximately 
25% (rounded down to the nearest tablet size combination) below the recommended dose determined 
in Part 1 followed by escalation of INCB050465 in combination with INCB039110 at 300 mg QD.  
Escalation of the dose of INCB050465 will continue in combination with INCB039110 300 mg QD 
until the recommended dose is determined.  If the starting dose of INCB050465 cannot be combined 
safely with INCB039110 300 mg QD, INCB039110 at 200 mg QD will be tested.  If that combination 
is tolerated, escalation of INCB050465 will proceed with INCB039110 200 mg QD.  Additional dose 
de-escalation may occur with INCB050465 if DLTs occur with a causality that can be reasonably 
assigned to INCB050465.  Additional dose escalation or de-escalation of INCB039110 may be 
considered if supported by emerging safety, PK, 
 data in this combination. 
Part 3 – Expansion 
Expanded cohorts for both monotherapy and combination therapy will be treated with the selected 
doses of INCB050465 as a single agent, INCB039110 as a single agent, and both agents in 
combination, to further determine safety, tolerability, efficacy, PK, 
 in this population.  The 
subjects with B-cell malignancies in the INCB050465 monotherapy expansion cohort (Part 3 
Cohort A) will also be used for an optional evaluation of food effect.  Expansion Cohorts A through D 
may proceed with recommended dose(s) identified in Part 1.  Note that expansion cohorts for 
INCB050465 monotherapy may explore more than 1 recommended dose and schedule to obtain 
long-term safety data on multiple dose levels and schedules. 
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When the recommended dose for combination therapy has been determined from Part 2, enrollment 
will proceed simultaneously for Expansion Cohort E.  Details regarding the dose expansion cohorts are 
described in the table below. 
If ≥ 5 subjects in the first 15 subjects of any cohort, cumulatively, (or more than 33% of subjects in 
cohorts larger than 15 subjects) experience DLTs during Cycle 1, further enrollment to the cohort will 
be stopped, and a lower dose level may be explored.  Based on emerging data, the sponsor may decide 
on the number of subjects with a specific subtype of an indication to be enrolled into each expansion 
cohort (eg, non–germinal center B-cell like [non-GCB] or GCB in DLBCL). 
Part 
Cohort 
Population 
# of Subjects 
Treatment 
3 
 
A 
B-cell malignancies 
15-30 
INCB050465 monotherapy 
B 
HL 
≤ 15 
C 
DLBCLa 
≤ 15 
D 
Indolent lymphoma 
≤ 30 
E 
B-cell malignancies 
≤ 15 
INCB050465 + INCB039110 
a  Based on emerging data, the sponsor may decide on the number of subjects with a specific subtype of an indication to be 
enrolled (eg, non-GCB or GCB). 
Part 6 – Dose Evaluation and Expansion With the Combination of INCB050465 and R-ICE 
Initiation of Part 6 dose evaluation will be dependent on preliminary data from Parts 1 and 3 of the 
study.  Dose evaluation would proceed in subjects with DLBCL using a 3 + 3 design with a starting 
dose of INCB050465 approximately 25% (rounded down to the nearest tablet size combination) below 
the recommended dose determined in Part 1 in combination with the chemotherapy components at the 
following doses in a 21-day cycle for a total of 3 cycles: 
• Rituximab 375 mg/m2 given on Day 1 and Day 2 of Cycle 1, and on Day 1 of Cycles 2 and 3. 
• Ifosfamide 5000 mg/m2 continuous IV infusion over 24 hours on Day 3  
- Mesna should be added to ifosfamide infusion. 
• Carboplatin area under the curve (AUC) = 5 mg/mL (maximum dose 800 mg) IV infusion on Day 3 
• Etoposide 100 mg/m2 IV on Days 3 to 5. 
If tolerated, the dose of INCB050465 will be escalated to the recommended dose in combination with 
R-ICE.  INCB050465 will be given daily and may be continued until a criterion is met for treatment 
discontinuation.  If the starting dose of INCB050465 cannot be combined safely with R-ICE at the 
schedule described above, the dose of INCB050465 will be reduced to 25% below the dose first 
administered in combination with R-ICE.  Additional dose de-escalation may occur with INCB050465 
if DLTs occur with a causality that can be reasonably assigned to INCB050465.  Additional dose 
de-escalation of INCB050465 may be considered if supported by emerging safety, PK, 
 data in 
this combination.  Following the identification of a tolerable dose of the combination of INCB050465 
and R-ICE (a dose less than or equal to the MTD), expanded Cohort L will be opened to further 
evaluate the safety, efficacy, PK, 
: 
Part 
Cohort 
Population 
# of Subjects 
Treatment 
6 
L 
DLBCLa 
~15 
INCB050465 + R-ICE 
a Based on emerging data, the sponsor may decide on the number of subjects with a specific subtype of an indication to be 
enrolled (eg, non-GCB or GCB). 
If ≥ 5 subjects in Cohort L experience DLTs during Cycle 1, further enrollment to the cohort will be 
stopped, and a lower dose level may be explored. 
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Protocol INCB 50465-101 Am 10 
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Study Drug, Dosage, and Mode of Administration for INCB050465:   
INCB050465 tablets (2.5 mg and 5 mg strengths) will be administered without regard to food (except 
on Cycle 2 Day 1 in the optional monotherapy expansion cohort [Expansion Cohort A] for food effect) 
orally QD or BID as determined by emerging PK
 data.  Tablet strength of 20 mg may also be 
used depending on the dose escalation of INCB050465.  For QD administration, if a dose is missed by 
more than 12 hours, the subject should skip the dose and take the next scheduled dose at the usual time.  
For BID administration, if the morning or evening dose is missed by more than 4 hours, the subject 
should skip that dose and take next scheduled dose at the usual time.  For once-weekly dosing, if the 
dose is missed by more than 2 days, the subject should skip the dose and take the next scheduled dose.  
One cycle will be defined as 21 days of treatment (eg, 21 continuous days of QD treatment, 21 days of 
once-weekly treatment). 
The initial dose in Part 1 will be 5 mg QD with dose escalation to 10 mg QD (or 5 mg BID depending 
on emerging PK
data) if a Grade 2 or greater AE is not reported.  Subsequent cohort expansion will 
proceed with dose escalation limited to approximately 50% increments in the total daily dose.  If a 
Grade 2 or greater AE is reported in the initial cohort, it will be expanded to 3 subjects, and subsequent 
cohort expansion will proceed with dose escalation limited to approximately 50% increments in the 
total daily dose. 
INCB050465 should be administered in the clinic on days when PK 
 sampling is 
scheduled. 
The sponsor may implement alternative dose regimens such as intermediate doses, BID doses, or 
alternative formulations, depending on PK, 
 and safety results. 
Study Drug, Dosage, and Mode of Administration for INCB039110: 
INCB039110 tablets (100 mg strength) should be taken on an empty stomach if possible (refrain from 
food consumption during the period 2 hours before and 1 hour after INCB039110 administration) and 
can be administered at the same time as INCB050465 where applicable.   
In Part 2, INCB050465 will be given in combination with INCB039110.  The starting dose of 
INCB039110 will be 300 mg orally given QD (tablet strength 100 mg) and will de-escalate to 200 mg 
QD if 300 mg QD cannot be tolerated in combination with INCB050465.  Subjects may have dose 
reductions of INCB039110 during the course of treatment, based upon safety and laboratory 
assessments; guidelines for dose adjustments and restart are provided in the body of the Protocol. 
INCB039110 should be administered in the clinic on Days 1, 8, and 15 of Cycle 1.  INCB039110 will 
be given after all INCB050465 PK sampling is complete on Day 1. 
The dose of INCB039110 in combination with INCB050465 selected after Part 2 will be administered 
in Part 3 Cohort E. 
All subjects receiving INBC050465, either as monotherapy or in combination therapy, must receive 
prophylaxis against Pneumocystis jirovecii pneumonia from the start of study treatment to at least 2 to 
6 months after the last dose of study drug. 
Dosage and Mode of Administration for Components of R-ICE Regimen: 
Rituximab, ifosfamide, carboplatin, and etoposide will be administered as open-label commercial 
product to subjects in Part 6 for 3 cycles. 
Rituximab 375 mg/m2 will be given on Day 1 and Day 2 of Cycle 1 and Day 1 of Cycles 2 and 3.  
Ifosfamide will be administered via continuous infusion over 24 hours at a dose of 5000 mg/m2 on 
Day 3 of each cycle.  Carboplatin will be administered on Day 3 as a dose of AUC = 5 mg/mL.  
Etoposide 100 mg/m2 will be given IV on Days 3 to 5. 
As an alternate to the Protocol-specified dose and dose schedule, R-ICE may be administered 
according to institutional practice with medical monitor approval. 
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Duration of Participation: 
Subjects will be treated until withdrawn from the study.  This may occur due to toxicity, disease 
progression, refusal to continue, the subject becomes eligible for a stem cell transplant or investigator, 
sponsor, or regulatory authority decision to terminate the study or institute a clinical hold.  Subjects 
who have evidence of objective clinical benefit, regardless of dose level, may continue to be treated at 
that dose level.  
Subjects enrolled onto INCB050465 monotherapy have the option of crossing over to combination 
therapy upon progressive disease at the discretion of the investigator if a combination cohort is 
currently enrolling. 
The average duration of participation is expected to be approximately 6 months. 
Study Population:   
Individuals diagnosed with B-cell malignancies (except Burkitt's lymphoma and precursor 
B-lymphoblastic leukemia/lymphoma) or HL who have failed or are refractory to available treatments. 
Key Inclusion Criteria: 
• Aged 18 years or older with lymphoid malignancies of B-cell origin including the following: 
− Indolent / aggressive B-cell non-Hodgkin's lymphoma (NHL) 
o EXCLUDING:  Burkitt's lymphoma and precursor B-lymphoblastic leukemia/lymphoma 
o INCLUDING:  any non-Hodgkin's B-cell malignancy such as chronic lymphocytic leukemia 
(CLL) and rare non-Hodgkin's B-cell subtypes such as hairy cell leukemia, Waldenström 
macroglobulinemia (WM), mantle cell lymphoma, and transformed NHL histologies 
− Hodgkin's lymphoma 
• For Part 3 Expansion, Cohort B, subjects must have relapsed/refractory HL. 
• For Part 3 Expansion, Cohort C, and Part 6, Cohort L, subjects must have relapsed/refractory 
DLBCL.  Note:  DLBCL subtype (eg, GCB) should be known at study entry. 
• For Part 3 Expansion, Cohort D, subjects must have relapsed/refractory indolent lymphoma.  Indolent  
lymphoma is defined as histologically confirmed follicular lymphoma Grade 1, 2, or 3a, or 
histologically confirmed marginal zone lymphoma. 
• Life expectancy of 12 weeks or longer. 
• Subject must have received ≥ 1 prior treatment regimen(s). 
• The subject must not be a candidate for potentially curative therapy, including hematopoietic 
stem-cell transplantation, except where one of the standard therapy regimen combinations (such as 
R-ICE) may be used prior to transplantation per standard medical practice. 
• For Part 6, subjects must be CD20-positive (assessed at the site) and must be currently eligible to 
receive rituximab. 
Key Exclusion Criteria: 
• Received an investigational study drug within 28 days or 5 half-lives (whichever is longer) before 
receiving the first dose of study drug or with medical monitor approval. 
• Received any approved anticancer medications within 21 days or 5 half-lives (whichever is longer) 
before receiving the first dose of study drug(s) (42 days for nitrosoureas) EXCEPT steroids at 
≤ 10 mg prednisone daily (or equivalent), or with medical monitor approval.  
• Any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable chronic 
toxicities (≤ Grade 2) not expected to resolve, such as stable Grade 2 peripheral neurotoxicity. 
• History of brain metastasis or spinal cord compression (unless treated, asymptomatic, and stable on 
most recent imaging and enrolling in expansion cohort), or lymphoma involving the central nervous 
system (permitted in Expansion Cohorts A and E). 
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• ECOG performance status of ≥ 3 (≥ 2 during dose escalation). 
• Received allogeneic hematopoietic stem-cell transplant within the last 6 months, has active 
graft-versus-host disease following allogeneic transplant, or is currently receiving 
immunosuppressive therapy following allogeneic transplant. 
• Received autologous hematopoietic stem-cell transplant within the last 3 months. 
• Any of the following laboratory results at screening unless directly resulting from the bone marrow 
infiltration of the underlying malignancy.  Screening values must be independent of blood product or 
hematopoietic growth factor support.  All of the following laboratory tests should be performed 
within 14 days of treatment initiation. 
Laboratory Parameter 
For Monotherapy 
Cohorts (No Bone 
Marrow Involvement) 
For Combination Therapy 
Cohorts (No Bone Marrow 
Involvement) 
Bone Marrow Infiltration of 
Underlying Malignancy  
(for Any Cohort) 
Hemoglobin 
≤ 8.0 g/dL 
≤ 9.0 g/dL 
≤ 8.0 g/dL 
Platelet count 
≤ 50 × 109/L 
≤ 100 × 109/L 
≤ 50 × 109/L 
Absolute neutrophil count 
≤ 1.0 × 109/L 
≤ 1.5 × 109/L 
≤ 1.0 × 109/L 
• Any of the following laboratory results at screening irrespective of causality: 
− Total bilirubin ≥ 1.2 × upper limit of normal (ULN) (if total bilirubin is ≥ 1.2 × ULN then the direct 
bilirubin must be < 1.2 × ULN). 
− Alkaline phosphatase ≥ 2.5 × ULN (or ≥ 5 × ULN if bone metastases are present and hepatic 
parenchymal metastases are absent). 
− Aspartate aminotransferase or alanine aminotransferase ≥ 2.0 × ULN. 
− Creatinine clearance ≤ 50 mL/min measured or calculated by Cockroft-Gault equation or estimated 
glomerular filtration rate ≤ 50 mL/min/1.73 m2 using the modification of diet in renal disease 
formula. 
• Known human immunodeficiency virus infection, or hepatitis B virus (HBV) or hepatitis C virus 
(HCV) viremia or at risk for HBV or HCV reactivation.  HBV DNA and testing for HCV RNA must 
be undetectable.  At risk for HBV reactivation is defined as hepatitis B surface antigen positive or 
anti–hepatitis B core antigen antibody positive.  At risk for HCV reactivation is defined as HCV 
antibody positive. 
• Prior treatment with a PI3Kδ inhibitor or pan-PI3K inhibitors (excluded in Part 1 and Part 3 
Expansion Cohorts A, B, C, and D only, or with medical monitor approval). 
• Radiation treatment within the previous 4 weeks.  Palliative radiation treatment to nonindex or bone 
lesions may be considered with medical monitor approval. 
• Prior treatment with a JAK inhibitor (excluded in Part 2 and Part 3 Cohorts E only). 
• For Part 2 and Part 3 (Cohort E) subjects only:  Any ≤ Grade 2 immune-related AEs from prior 
immunotherapy must have complete resolution and must have resolved at least 2 weeks before 
Cycle 1 Day 1.  Subjects with a history of a Grade 3 or 4 immune-related AE or any grade ocular 
immune-related AE from prior immunotherapy are excluded. 
Study Schedule/Procedures: 
Subjects will have scheduled study visits as follows: 
• Screening 
• Cycle 1:  Day 1, Day 8 (applicable only to certain parts of the study), Day 15 
• Subsequent Cycles:  Day 1 
• End of treatment 
• Follow-up 
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Protocol INCB 50465-101 Am 10 
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Local laboratory tests:   
Study visits will include sample collection for hematology, chemistry, coagulation, and urinalysis 
testing to be conducted at a local laboratory.  Additionally, the screening visit will include hepatitis 
screening and fertility/pregnancy testing conducted at a local laboratory.   
Central laboratory tests: 
 PK samples will be collected at designated visits and shipped to the sponsor or 
designee for analysis. 
Clinical assessments: 
Electrocardiograms (ECGs), physical examinations, ECOG performance status, tumor assessments, and 
other assessments will be performed by the investigative site.   
An objective assessment of disease status will be performed at screening, appropriate to the malignancy 
type.  For example: 
• Computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography 
(PET)/CT (as applicable by subtype) for subjects with HL or NHL. 
• Bone marrow biopsy and immunophenotyping. 
Subsequently, disease measurable by CT, MRI, or PET/CT will be assessed every 9 weeks or at a 
frequency consistent with the standard of care for the subject's disease.  For disease status assessed in 
bone marrow, on-treatment biopsies will occur only if needed to confirm complete response (CR).  
Immunophenotyping will be performed after 1 cycle and if confirming CR for subjects with CLL. 
Note:  With Amendment 10, Protocol-required procedures have been reduced for ongoing subjects. 
Primary Endpoint: 
• Safety and tolerability of the planned study treatments as assessed by summary of AEs, clinical 
laboratory assessments, physical examination results, and 12-lead ECGs.  
Secondary Endpoints: 
• Efficacy as measured by ORR, defined as the sum of subjects achieving a minor response (only 
among subjects with WM), partial response, very good partial response (only among subjects with 
WM), and a CR to the planned study treatments based on: 
− International Workshop on Chronic Lymphocytic Leukemia criteria for chronic lymphocytic 
leukemia. 
− VIth International Workshop on Waldenström Macroglobulinemia response assessment for 
subjects with WM. 
− Revised response criteria for lymphoma for HL and NHL. 
• Cmax, Tmax, Cmin,  AUC0-t, and AUC0-τ at Cycle 1 Day 15 of INCB039110 in combination with 
INCB050465. 
• Cmax, Tmax, Cmin, AUC0-t, and AUC0-τ of INCB050465 as monotherapy and in combination with 
INCB039110. 
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Planned Number of Subjects:  Up to approximately 150 subjects 
Planned Number of Study Sites:  Approximately 15 sites 
Principal Coordinating Investigator:  
, MD, 
 
. 
Estimated Study Duration:  36 months 
Statistical Methods: 
  The clinical safety 
data (vital signs, ECGs, routine laboratory tests, physical examinations, and AEs) will be summarized 
descriptively. 
The ORR will be estimated with 95% exact confidence interval (CI). 
 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................19 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Background .................................................................................................................22 
1.1.1. 
PI3Kδ in Oncology .....................................................................................................22 
1.1.2. 
JAK1 Inhibition in Oncology and Lymphoma ...........................................................23 
1.1.3. 
Targeting JAK1 in DLBCL and Rationale for Combining PI3Kδ and JAK 
Inhibition .....................................................................................................................24 
1.1.4. 
Rationale for Combining INCB050465 With the Chemotherapy Regimen R-
ICE in DLBCL ............................................................................................................25 
1.2. 
Overview of INCB050465 ..........................................................................................26 
1.2.1. 
Pharmacology of INCB050465 ..................................................................................26 
 
27 
 
28 
1.2.3. 
Potential Risks of INCB050465 .................................................................................28 
1.2.3.1. 
Potential Risks of INCB050465 Based on Preclinical Safety ....................................28 
1.2.3.2. 
Potential Risks of PI3Kδ Inhibition Based on Other Agents in Class ........................29 
1.2.4. 
Clinical Summary of INCB050465 ............................................................................30 
1.3. 
Overview of INCB039110 ..........................................................................................31 
1.3.1. 
Pharmacology Summary .............................................................................................31 
1.3.2. 
Drug Disposition Summary ........................................................................................31 
 
32 
1.3.4. 
Clinical Summary of INCB039110 ............................................................................32 
1.3.5. 
Potential Risks of INCB039110 .................................................................................32 
1.4. 
Overview of the Combination of INCB050465 and INCB039110 ............................33 
1.4.1. 
Nonclinical Pharmacokinetics and Drug Metabolism of the Combination ................33 
1.4.2. 
Clinical Summary of Combination Treatment with INCB050465 and 
INCB039110 ...............................................................................................................33 
1.4.3. 
Clinical Summary of Combination Treatment With PI3Kδ Inhibition 
(INCB040093) and JAK Inhibition (INCB039110) ...................................................33 
1.4.4. 
Potential Risks of Combination Therapy of INCB050465 and INCB039110 ...........34 
1.5. 
Overview of Standard Therapies ................................................................................34 
1.5.1. 
Rituximab ...................................................................................................................34 
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1.5.1.1. 
Pharmacology Summary .............................................................................................34 
1.5.1.2. 
Potential Risks ............................................................................................................34 
1.5.2. 
R-ICE ..........................................................................................................................35 
1.5.2.1. 
Ifosfamide ...................................................................................................................35 
1.5.2.2. 
Carboplatin .................................................................................................................35 
1.5.2.3. 
Etoposide ....................................................................................................................36 
1.6. 
Study Rationale ...........................................................................................................36 
1.7. 
Justification of Route, Dose Regimen, and Treatment Period ....................................37 
1.7.1. 
INCB050465 ...............................................................................................................37 
1.7.2. 
INCB039110 ...............................................................................................................39 
1.7.3. 
R-ICE in Combination With INCB050465 ................................................................39 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................40 
2.1. 
Primary Objective .......................................................................................................40 
2.2. 
Secondary Objectives .................................................................................................40 
 
40 
3. 
SUBJECT ELIGIBILITY ...........................................................................................41 
3.1. 
Study Population .........................................................................................................41 
3.2. 
Subject Inclusion Criteria ...........................................................................................41 
3.3. 
Subject Exclusion Criteria ..........................................................................................42 
4. 
INVESTIGATIONAL PLAN .....................................................................................44 
4.1. 
Study Drugs ................................................................................................................44 
4.2. 
Overall Study Design ..................................................................................................44 
4.2.1. 
Part 1 – Monotherapy Dose Escalation of INCB050465 ............................................45 
4.2.2. 
Part 2 – Dose Escalation With the Combination of INCB0504065 and 
INCB039110 ...............................................................................................................46 
4.2.3. 
Part 3 – Expansion ......................................................................................................46 
4.2.4. 
Part 6 – Dose Evaluation and Expansion With the Combination of 
INCB050465 and R-ICE .............................................................................................47 
4.2.5. 
Crossover to Combination Therapy After Monotherapy Treatment ..........................48 
4.3. 
Study Endpoints ..........................................................................................................48 
4.3.1. 
Primary Endpoint ........................................................................................................48 
4.3.2. 
Secondary Endpoints ..................................................................................................48 
 
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4.4. 
Measures Taken to Avoid Bias ...................................................................................49 
4.5. 
Number of Subjects ....................................................................................................49 
4.6. 
Study Termination ......................................................................................................49 
5. 
TREATMENT OF SUBJECTS ..................................................................................50 
5.1. 
Treatment Groups and Administration of Study Drug ...............................................50 
5.1.1. 
INCB050465 Monotherapy ........................................................................................50 
5.1.2. 
INCB050465 and INCB039110 Combination Therapy .............................................50 
5.1.3. 
INCB050465 and R-ICE Combination Therapy ........................................................50 
5.2. 
Treatment Compliance ................................................................................................51 
5.3. 
Randomization and Blinding ......................................................................................51 
5.4. 
Duration of Treatment and Subject Participation .......................................................51 
5.5. 
Rationale for Dose Modification ................................................................................51 
5.5.1. 
Dose-Limiting Toxicity ..............................................................................................51 
5.5.2. 
Follow-Up of Dose-Limiting Toxicities .....................................................................53 
5.5.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................53 
5.6. 
Dose Adjustment of Study Drug.................................................................................53 
5.6.1. 
Planned Dose Adjustments .........................................................................................53 
5.6.2. 
Criteria and Procedures for Dose Interruptions and Dose Reductions of 
INCB050465 and INCB039110 .................................................................................53 
5.6.2.1. 
Supportive Care Guidelines for Diarrhea/Colitis .......................................................56 
5.6.2.2. 
Dose Interruptions for Standard Therapies .................................................................56 
5.6.3. 
Criteria for Permanent Discontinuation of Study Drug ..............................................57 
5.7. 
Withdrawal of Subjects From the Study .....................................................................57 
5.7.1. 
Withdrawal Criteria ....................................................................................................57 
5.7.2. 
Withdrawal Procedures ...............................................................................................58 
5.8. 
Concomitant Medications and Measures ....................................................................58 
5.8.1. 
Supportive Care Measures ..........................................................................................58 
5.8.2. 
Pneumocystis jirovecii Pneumonia Prophylaxis .........................................................59 
5.9. 
Restricted Medications and Measures ........................................................................59 
5.10. 
Prohibited Medications and Measures ........................................................................59 
6. 
STUDY ASSESSMENTS ..........................................................................................60 
6.1. 
Screening Phase ..........................................................................................................73 
6.2. 
Treatment Phase ..........................................................................................................73 
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6.3. 
End of Treatment ........................................................................................................73 
6.4. 
Follow-Up Phase ........................................................................................................73 
6.5. 
Unscheduled Visits .....................................................................................................74 
6.6. 
Early Termination .......................................................................................................74 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................74 
7.1. 
Administration of Informed Consent Form ................................................................74 
7.2. 
Interactive Response Technology Procedure ..............................................................74 
7.3. 
Demography, Medical History, Medication Usage ....................................................74 
7.3.1. 
Demographics and Medical History ...........................................................................74 
7.3.2. 
Prior/Concomitant Medications ..................................................................................75 
7.4. 
Safety Assessments .....................................................................................................75 
7.4.1. 
Adverse Events ...........................................................................................................75 
7.4.2. 
Comprehensive Physical Examination .......................................................................75 
7.4.3. 
Targeted Physical Examination ..................................................................................75 
7.4.4. 
Vital Signs ..................................................................................................................76 
7.4.5. 
Electrocardiograms .....................................................................................................76 
7.4.5.1. 
Timed Electrocardiograms ..........................................................................................76 
7.4.6. 
Laboratory Assessments .............................................................................................76 
7.4.6.1. 
Chemistry ....................................................................................................................76 
7.4.6.2. 
Hematology .................................................................................................................76 
7.4.6.3. 
Urinalysis ....................................................................................................................76 
7.4.6.4. 
Coagulation Panel .......................................................................................................77 
7.4.6.5. 
Fertility Testing ..........................................................................................................77 
7.4.6.6. 
Pregnancy Testing ......................................................................................................77 
7.4.6.7. 
Hepatitis Screening .....................................................................................................77 
7.5. 
Efficacy Assessments .................................................................................................77 
7.5.1. 
CT Scan or MRI ..........................................................................................................77 
7.5.2. 
FDG-PET or Combined PET-CT ...............................................................................78 
7.5.3. 
Bone Marrow Examination .........................................................................................78 
7.5.4. 
Immunophenotyping ...................................................................................................78 
7.5.5. 
Immunoglobulin M Monitoring ..................................................................................78 
7.6. 
Performance Status .....................................................................................................78 
7.7. 
Pharmacokinetic Assessments ....................................................................................79 
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7.7.1. 
Blood Sample Collection ............................................................................................79 
7.7.2. 
Urine Sample Collection .............................................................................................80 
7.7.3. 
Bioanalytical Methodology and Analysis ...................................................................81 
7.7.4. 
Pharmacokinetic Analysis ..........................................................................................81 
 
81 
 
81 
 
81 
 
81 
 
82 
 
82 
 
82 
 
82 
7.10. 
Other Study Procedures ..............................................................................................83 
7.10.1. 
Drug Administration ...................................................................................................83 
7.10.1.1. 
Administration of INCB050465 .................................................................................83 
7.10.1.2. 
Dispensing of INCB050465 .......................................................................................83 
7.10.1.3. 
Assessment of Compliance With INCB050465 .........................................................83 
7.10.1.4. 
Administration of INCB039110 .................................................................................83 
7.10.1.5. 
Dispensation of INCB039110 .....................................................................................84 
7.10.1.6. 
Assessment of Compliance With INCB039110 .........................................................84 
7.10.1.7. 
Sourcing and Administration of Standard of Care Agents .........................................84 
7.10.1.8. 
Assessment of Compliance With Standard of Care Agents .......................................84 
7.10.1.9. 
Administration of Supportive Care .............................................................................84 
7.10.2. 
Distribution of Subject Reminder Cards/Subject Diaries ...........................................84 
8. 
SAFETY MONITORING AND REPORTING .........................................................85 
8.1. 
Adverse Events ...........................................................................................................85 
8.1.1. 
Definitions and Reporting ...........................................................................................85 
8.2. 
Laboratory Test Abnormalities ...................................................................................86 
8.2.1. 
Definitions and Reporting ...........................................................................................86 
8.3. 
Serious Adverse Events ..............................................................................................87 
8.3.1. 
Definitions ..................................................................................................................87 
8.3.2. 
Reporting ....................................................................................................................87 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................88 
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8.5. 
Pregnancy ...................................................................................................................88 
8.6. 
Warnings and Precautions ..........................................................................................89 
8.7. 
Data Monitoring Committee .......................................................................................89 
8.8. 
Adverse Events of Special Interest .............................................................................90 
8.9. 
Product Complaints ....................................................................................................90 
9. 
STATISTICS ..............................................................................................................90 
9.1. 
Study Populations .......................................................................................................90 
9.2. 
Selection of Sample Size ............................................................................................90 
9.3. 
Level of Significance ..................................................................................................91 
9.4. 
Statistical Analyses .....................................................................................................91 
9.4.1. 
General Methodology .................................................................................................91 
9.4.2. 
Efficacy Analyses .......................................................................................................91 
9.4.3. 
Safety Analyses ..........................................................................................................92 
9.4.3.1. 
Adverse Events ...........................................................................................................93 
9.4.3.2. 
Clinical Laboratory Tests ...........................................................................................94 
9.4.3.3. 
Vital Signs ..................................................................................................................94 
9.4.3.4. 
Electrocardiograms .....................................................................................................95 
9.4.4. 
Other Analyses ............................................................................................................95 
9.5. 
Data Monitoring Committee .......................................................................................96 
9.6. 
Interim Analysis ..........................................................................................................96 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................96 
10.1. 
Investigational Product Description – INCB050465 ..................................................96 
10.1.1. 
Packaging, Labeling, and Preparation of Study Drug ................................................96 
10.1.2. 
Formulation and Chemical Properties of INCB050465 .............................................96 
10.1.3. 
Storage and Stability of INCB050465 ........................................................................96 
10.2. 
Investigational Product Description – INCB039110 (Comedication for Part 2 
and Expansion Cohort E) ............................................................................................96 
10.2.1. 
Packaging, Labeling, and Preparation of INCB039110 .............................................96 
10.2.2. 
Formulation and Chemical Properties of INCB039110 .............................................96 
10.2.3. 
Storage and Stability of INCB039110 ........................................................................96 
10.3. 
Accountability, Handling, and Disposal of Study Drug .............................................97 
11. 
STUDY ADMINISTRATION ...................................................................................97 
11.1. 
Data Management .......................................................................................................97 
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11.1.1. 
Data Collection ...........................................................................................................97 
11.1.2. 
Data Management .......................................................................................................97 
11.2. 
Study Monitoring ........................................................................................................98 
11.3. 
Protocol Adherence ....................................................................................................98 
11.4. 
Financial Disclosure ...................................................................................................99 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................99 
12.1. 
Sponsor Audits............................................................................................................99 
12.2. 
Inspection by Regulatory Authorities .........................................................................99 
13. 
ETHICS ....................................................................................................................100 
13.1. 
Ethical Conduct of the Study ....................................................................................100 
13.2. 
Written Informed Consent ........................................................................................100 
13.3. 
Ethics Review ...........................................................................................................100 
13.4. 
Data Privacy ..............................................................................................................101 
14. 
DATA HANDLING AND RECORDKEEPING .....................................................101 
14.1. 
Inspection of Records ...............................................................................................101 
14.2. 
Retention of Records ................................................................................................102 
14.3. 
Confidentiality ..........................................................................................................102 
15. 
PUBLICATION POLICY ........................................................................................102 
16. 
REFERENCES .........................................................................................................103 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................106 
APPENDIX B. PHARMACOKINETIC ANALYTICAL PARAMETERS ............................107 
APPENDIX C. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................108 
APPENDIX D. RESPONSE CRITERIA FOR LYMPHOMA .................................................109 
APPENDIX E. RESPONSE CRITERIA FOR CLL .................................................................111 
APPENDIX F. RESPONSE ASSESSMENT IN WALDENSTRÖM 
MACROGLOBULINEMIA .....................................................................................113 
APPENDIX G. PROHIBITED AND RESTRICTED MEDICATIONS ..................................114 
 
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LIST OF TABLES 
Table 1: 
Part 3 Expansion Cohorts ...........................................................................................47 
Table 2: 
Part 6 Expansion Cohort .............................................................................................48 
Table 3: 
Definition of Dose-Limiting Toxicity ........................................................................52 
Table 4: 
Guidelines for Interruption and Restart of Study Drug ..............................................54 
Table 5: 
Schedule of Assessments for Parts 1, 2, and 3 ...........................................................61 
Table 6: 
Schedule of Laboratory Assessments for Parts 1, 2, and 3 .........................................63 
Table 7: 
Schedule of Assessments for Part 6 ............................................................................66 
Table 8: 
Laboratory Assessments for Part 6 .............................................................................68 
Table 9: 
Schedule of Assessments for Ongoing Subjects in All Cohorts Upon 
Implementation of Protocol Amendment 10 ..............................................................71 
Table 10: Schedule of Laboratory Assessments for Ongoing Subjects in All Cohorts 
Upon Implementation of Protocol Amendment 10 ....................................................71 
Table 11: Local Laboratory Tests:  Required Analytes (Not Applicable After 
Implementation of Protocol Amendment 10) .............................................................72 
Table 12: Pharmacokinetic Blood Sampling Schedule ...............................................................79 
Table 13: Probability of Dose Escalation for Specific Dose-Limiting Toxicity Rates 
During 3 + 3 Dose Escalation .....................................................................................91 
Table 14: Criteria for Clinically Notable Vital Sign Abnormalities ...........................................94 
Table 15: Criteria for Clinically Notable ECG Abnormalities ...................................................95 
 
LIST OF FIGURES 
Figure 1: 
Synergistic Anti-Proliferative Activity of PI3Kδ and JAK Inhibition .......................25 
Figure 2: 
Study Design ...............................................................................................................45 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Term 
Explanation 
ABC 
activated B cell 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
anti-HBc 
antibody against hepatitis B core antigen 
anti-HBsAg  
antibody against hepatitis B surface antigen 
AST 
aspartate aminotransferase 
BCR 
B-cell receptor 
BID 
twice daily 
BTK 
Bruton's tyrosine kinase 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
CMV 
cytomegalovirus 
CR 
complete response 
CRF 
case report form  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
 
 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FSH 
follicle-stimulating hormone 
GCB 
germinal center B-cell like 
GCP 
Good Clinical Practice 
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Term 
Explanation 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HL 
Hodgkin's lymphoma 
IB 
Investigator's Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IL 
interleukin 
IN 
Investigator notification 
IRB 
institutional review board 
ITT 
intent to treat 
IV 
intravenous 
IWCLL 
International Workshop on Chronic Lymphocytic Leukemia 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
minor response 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NHL 
non-Hodgkin's lymphoma 
NOAEL 
no-observed-adverse-effect level 
ORR 
overall response rate 
PD 
pharmacodynamics 
PAD 
pharmacologically active dose 
PET 
positron emission tomography 
 
 
P-gp 
P-glycoprotein 
PI3K 
phosphatidylinositol 3-kinase 
PIP3 
phosphatidylinositol-3,4,5-trisphosphate 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
pharmacokinetics 
PP 
per Protocol 
PR 
partial response 
QD 
once daily 
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Term 
Explanation 
R-ICE 
rituximab, ifosfamide, carboplatin, and etoposide 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SCM 
stromal conditioned media 
SD 
stable disease 
SPD 
sum of product of diameters 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TYK2 
tyrosine kinase 2 
ULN 
upper limit of normal  
VGPR 
very good partial response 
WM 
Waldenström macroglobulinemia 
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1. 
INTRODUCTION 
1.1. 
Background 
Phosphatidylinositol 3-kinases (PI 3-kinases or PI3Ks) belong to a family of lipid signaling 
kinases that phosphorylate phosphoinositides at the D3 position of the inositol ring 
(Cantley 2002).  PI3Ks are divided into 3 classes (Class I, II, and III) according to their structure, 
regulation, and substrate specificity.  Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, and 
PI3Kδ, are dual-specificity lipid and protein kinases that catalyze the phosphorylation of 
phosphatidylinositol-4,5-bisphosphate, giving rise to phosphatidylinositol-3,4,5-trisphosphate 
(PIP3).  PIP3 functions as a second messenger that controls a number of cellular processes, 
including growth, survival, adhesion, and migration.  The recognition that aberrant signal 
transduction occurs in malignant B-lymphocytes via the PI3K pathways resulting in disease 
progression has led to a focus on agents that modulate these signaling pathways. 
INCB039110 is an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases with 
selectivity for JAK1.  Janus kinases play an important role in signal transduction following 
cytokine and growth factor binding to their receptors.  Aberrant production of cytokines and 
growth factors has been associated with neoplasms, therefore inhibition of this pathway may be 
beneficial in the treatment of these conditions. 
Incyte is proposing to study INCB050465, an inhibitor of PI3Kδ, as monotherapy and in 
combination with INCB039110 for the treatment of relapsed/refractory diffuse large B-cell 
lymphoma (DLBCL), Hodgkin's lymphoma (HL), and other lymphoid malignancies, including 
indolent lymphoma.  In addition, INCB050465 will be studied in combination with agents 
considered as part of the standard of care in this population, including bendamustine, rituximab, 
and the chemotherapy regimen R-ICE (rituximab, ifosfamide, carboplatin, and etoposide). 
1.1.1. 
PI3Kδ in Oncology 
The B-cell receptor (BCR) is present on both normal and most malignant B cells.  Engagement 
of the BCR provides important survival signals, and interruption of the B-cell survival signal can 
lead to B-cell death (Kraus et al 2004).  Elegant studies performed with siRNA to inhibit BCR 
expression have shown that constitutive signaling by BCR is critical for the survival and 
proliferation of human B-cell lymphomas (Gururajan et al 2006).  The primary role of BCR 
signaling in these cells seems to be activation of spleen tyrosine kinase (Benschop and Chambier 
1999), which in turn leads to several downstream events that promote cell survival, including 
activation of Bruton's tyrosine kinase (BTK), PI3K, and protein kinase B (Akt).  Aberrant 
activation of PI3Kδ specifically has been associated with increased malignant B-cell 
proliferation and survival.  Although no mutations have been identified in PI3Kδ, it has been 
shown to be oncogenic in cell culture (Kang et al 2005).  Consistent overexpression of PI3Kδ has 
also been observed in acute myeloblastic leukemia, and inhibitors of PI3Kδ can prevent the 
growth of leukemic cells in vitro.  Phosphatidylinositol 3-kinase δ was also shown to be 
expressed in Hodgkin's and Reed-Sternberg cells.  Inhibition of PI3Kδ with idelalisib blocked 
phosphorylation of Akt and induced apoptosis in the HL cell line (Meadows et al 2012).  The 
role of the PI3K pathway in BCR signaling is beginning to be clarified for non-Hodgkin's 
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lymphoma (NHL) subtypes.  It has been shown that the activated B-cell (ABC) subtype of 
DLBCL through chronic active BCR signaling engages PI3K, augmenting anti-apoptotic nuclear 
factor-κB (NF-κB) signaling and survival signals and that inhibition of the PI3K/Akt pathway 
synergizes with NF-κB inhibition in killing ABC DLBCL cell lines in vitro (Monti et al 2005).  
BCR signaling has also been shown to activate the PI3K/Akt pathway in Burkitt's lymphoma and 
in other types of NHL. 
Several PI3Kδ selective inhibitors, including idelalisib, INCB040093, and duvelisib (formerly 
IPI-145), have been advanced into the clinic for the treatment of hematological malignancies.  
The orally available PI3Kδ selective inhibitor, idelalisib, was shown to specifically inhibit the 
growth of cell lines representative of B-cell malignancies and multiple myeloma in preclinical 
models (Kahl et al 2014).  Based on this and other clinical studies, idelalisib was approved by the 
FDA as monotherapy for patients with relapsed follicular lymphoma and small lymphocytic 
lymphoma and as combination therapy with rituximab for patients with chronic lymphocytic 
lymphoma.  In addition, the approval of ibrutinib, the BTK inhibitor for the treatment of subjects 
with relapsed or refractory mantle cell lymphoma (MCL), demonstrated a 66% overall response 
rate (ORR), with 17% of subjects achieving a complete response (CR).  The median response 
duration was 17.5 months.  Responses to ibrutinib increase with longer time on study treatment 
(Wang et al 2012).  Ibrutinib and idelalisib have demonstrated a high ORR and durable 
remissions in most subjects with chronic lymphocytic leukemia (CLL) and many subjects with 
MCL and indolent NHL.  These data suggest the importance of the BCR pathway for survival in 
these diseases. 
 
 
1.1.2. 
JAK1 Inhibition in Oncology and Lymphoma 
Aberrant activation of JAKs, through production of cytokines and growth factors, has been 
associated with increased malignant cell proliferation and survival in a number of tumor types.  
Janus kinases activate a number of downstream pathways implicated in the proliferation and 
survival of malignant cells including the signal transducers and activators of transcription 
(STATs), a family of important latent transcription factors.  In DLBCL, JAK pathway activation 
occurs through both autocrine and paracrine mechanisms.  In the tumor cells, BCR signaling 
leads to increased interleukin (IL)-6 and IL-10 production through activation of the NF-κB 
pathway (Lam et al 2008).  A subset of DLBCLs has been characterized as having high 
expression of STAT3, IL-6, and/or IL-10 and it has been shown that JAK inhibition is cytotoxic 
in these DLBCL cell lines and synergizes with NF-κB inhibitors.  In addition to JAK/STAT 
pathway activation through autocrine pathways, the stromal compartment can also provide a 
source of these cytokines in a paracrine manner (Hodge et al 2005). 
Of clinical relevance, levels of serum IL-10 and IL-6, which signal through the JAKs, have been 
found to be elevated in subjects with DLBCL compared with normal controls (Gupta et al 2012).  
Further, subjects with high serum IL-10 levels were shown to have a shorter event-free survival 
(Gupta et al 2012).  Within the JAK family of kinases, JAK1 has been shown to cooperate with 
JAK2, JAK3, and tyrosine kinase 2 (TYK2) and to play a dominant role in mediating the 
signaling of a number of inflammatory cytokines including IL-6 and IL-10. 
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1.1.3. 
Targeting JAK1 in DLBCL and Rationale for Combining PI3Kδ and JAK 
Inhibition 
 
 
 
 
 
 Phase 1 studies with the 
PI3Kδ inhibitor idelalisib and the PI3Kδ γ inhibitor duvelisib demonstrated no responses in 
DLBCL, although 4 of 10 subjects treated with duvelisib showed stable disease (Flinn et al 2014, 
Horowitz et al 2013).  Similarly, early studies with the JAK2 inhibitor SB1518 showed 0 out of 
3 responses in relapsed/refractory DLBCL (Younes et al 2012). 
To test this hypothesis preclinically, a panel of DLBCL cell lines was grown in conditions to 
activate the JAK pathway.  These cells lines were exposed to the PI3Kδ inhibitor INCB040093, 
either alone or in combination with a panel of compounds that were shown to selectively inhibit 
JAK1 to examine their effects on cell proliferation and signaling.  The JAK pathway was not 
constitutively activated when grown in the absence of stromal conditioned media (SCM), IL-6, 
or IL-10 as assessed by the levels of phosphorylated STAT3 (pSTAT3), a direct downstream 
target of JAK proteins.  In addition, IL-6 or SCM, which contains predominantly IL-6, IL-8, and 
G-CSF, failed to activate the pathway in the majority of cell lines.  In contrast, IL-10 activated 
the JAK/STAT pathway in the majority of cell lines tested, consistent with previous reports 
(Gupta et al 2012). 
To test the effects of IL-10 on cell growth and sensitivity to BCR pathway inhibition, the Pfeiffer 
cell line was used as a model system of DLBCL.  Pfeiffer cells are of the germinal center B-cell 
like (GCB) subtype of DLBCL, have been shown to express PI3Kδ, are sensitive to PI3Kδ 
inhibition, and activate the JAK/STAT pathway in response to multiple cytokines as shown 
above.  Pfeiffer cells were treated for 3 days with various concentrations of a novel, selective 
inhibitor of the PI3Kδ kinase isoform, INCB040093, in the presence or absence of IL-10 and 
1 µM of a JAK1 inhibitor (INCB047986), and cell growth was measured using an ATP readout.  
As shown in Figure 1, the presence of IL-10 shifted the potency of INCB040093 by 
approximately 10-fold (half-maximal inhibitory concentration [IC50] = 0.67 µM, - IL-10; 
IC50 = 6.36 µM, + IL-10).  Addition of the JAK1 inhibitor reversed this effect so that the 
combination was approximately 50-fold more potent.  In this system, the JAK1 inhibitor 
compound alone had no effect (IC50 > 1 µM). 
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Figure 1: 
Synergistic Anti-Proliferative Activity of PI3Kδ and JAK Inhibition 
 
This model also showed that inhibition of PI3Kδ together with JAK signaling led to increased 
apoptosis whereas neither agent alone had a significant effect.   
Finally, to assess the effects on downstream signaling pathways, Pfeiffer cells were treated with 
INCB040093 +/- a JAK1 selective inhibitor and then stimulated with IL-10.  In this model, the 
combination of both compounds was required to block both pathways. 
Similar effects have been observed in other cell lines, including HBL-1 cells, which are of the 
ABC subtype of DLBCL, and with other JAK1 selective compounds.  
In summary, these data demonstrate that the presence of IL-10, a cytokine shown to be elevated 
in DLBCL subjects and to correlate with decreased survival, reduces the potency of a PI3Kδ 
inhibitor to block cell growth.  The addition of a JAK1 inhibitor, although it has no inhibitory 
effect as a single agent, reverses this effect.  The combination of both inhibitors demonstrates 
marked synergy in blocking cell growth and inducing apoptosis by inhibiting multiple signaling 
pathways.  Consistent with these findings, the early clinical data from studies of monotherapy 
BCR and JAK pathway inhibitors suggest only limited evidence of activity in relapsed/refractory 
DLBCL.  
 
 
 
Clinically the combination of PI3Kδ inhibition and JAK1 inhibition has been tested in Study 
INCB 40093-102.  Preliminary activity has been observed in subjects with NHL and HL 
receiving INCB040093 monotherapy and combination treatment (data on file). 
1.1.4. 
Rationale for Combining INCB050465 With the Chemotherapy Regimen R-ICE 
in DLBCL 
The combination chemotherapy regimen ICE (ifosfamide, carboplatin, and etoposide) was 
developed for use in relapsed aggressive NHL to induce a response while minimizing treatment 
toxicity with the goal of stem cell transplant, which may be a curative treatment.  Kewalramani 
et al (2004) explored whether adding rituximab to the ICE regimen would improve the CRR and 
therefore improve outcomes from stem cell transplant.  The CRRs of subjects with DLBCL who 
received R-ICE was 53%, which was an improvement from the 27% CRR historically observed 
(Kewalramani et al 2004).  The CORAL trial studied the salvage chemotherapy regimens R-ICE 
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and R-DHAP.  No difference was seen between these 2 regimens, and the ORR and CRR for the 
R-ICE regimen was 63% and 24%, respectively (Gisselbrecht et al 2010).  As R-ICE has become 
frequently used as salvage chemotherapy in this population, additional research has been 
performed to add noncytotoxic agents.  Lenalidomide was added to R-ICE in a study by Feldman 
et al (2014) with promising response rates in DLBCL subjects (60% CRR) after first relapse or 
with primary refractory disease.  Therefore, there is interest in combining the targeted agent 
INCB050465 with this salvage chemotherapy regimen to hopefully improve response rates seen 
with R-ICE alone and allow more subjects to become eligible for a potentially curative stem cell 
transplant. 
1.2. 
Overview of INCB050465 
Refer to the INCB050465 IB for current information on INCB050465. 
1.2.1. 
Pharmacology of INCB050465 
INCB050465 represents a novel, potent, and selective inhibitor of the Class IA PI3K enzymes, 
with selectivity for the delta isoform, which is proposed for development for treatment of 
hematological malignancies.  Because aberrant activation of PI3Kδ has been associated with 
increased malignant B-cell proliferation and survival, its inhibition may be therapeutic for the 
treatment of such conditions.  INCB050465 potently inhibits the PI3Kδ kinase 
(IC50 = 1.0 ± 0.5 nM), with ~ 20,000-fold selectivity for the other PI3K family members and 
> 300-fold selectivity against a broad panel of 192 other kinases.  INCB050465 also showed no 
significant cross-reactivity (defined as > 50% inhibition of specific binding) when screened 
in vitro at 0.1 and 1.0 μM against approximately 70 receptors, ion channels, transporters, and 
enzymes.  Moreover, INCB050465 is potent (IC50 values of ≤ 10 nM) in cell-based assays 
relevant to the pathogenesis of B-cell malignancies, such as PI3Kδ-mediated signaling and 
growth of human B-cell lines.  This effect is not due to general cytotoxicity, because 10 μM 
INCB050465 had no significant effect on the growth of nonlymphoid cell lines.  Compared to 
inhibition of B-cell proliferation, INCB050465 is similarly potent in blocking helper T-cell 
differentiation but is > 100 times less potent in assays that measure effects on human T-cell and 
natural killer cell proliferation or monocyte function.  These data suggest that the impact of 
INCB050465 on the human immune system will largely be restricted to B-cell and helper T-cell 
differentiation.  Similar results have been reported with the PI3Kδ inhibitor idelalisib (CAL-101, 
GS-1101) and duvelisib, although INCB050465 is significantly more potent in all of the assays 
examined (refer to the INCB050465 IB), suggesting that it may have more marked effects in the 
clinic due to more significant target inhibition throughout the dosing interval.  In vivo, the effects 
of oral INCB050465 were evaluated in mice in the Pfeiffer human tumor xenograft model of B-
cell malignancy.  In the Pfeiffer model of NHL, INCB050465 administration inhibited PI3Kδ 
signaling and tumor growth as a single agent in a dose-dependent manner. 
In a core battery of safety pharmacology studies, a single oral dose of INCB050465 produced no 
adverse effects on central nervous system or respiratory function in the rat, or cardiovascular 
function in telemeterized conscious dogs.  The IC50 for inhibition of human ether-à-go-go-related 
gene potassium current in stably transfected HEK293 cells was 188.0 μM (Hill 
coefficient = 1.0), which is > 8000-fold higher than the projected steady-state Cmax (0.023 μM 
unbound) after a 10 mg human dose. 
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INCB050465 had no effect on central nervous system function in rats; the no-observed-effect 
level was 100 mg/kg, the highest dose tested. 
Lower respiratory frequency and/or lower minute volume were observed in rats after 
administration of 30 and 100 mg/kg INCB050465.  These changes were not considered adverse 
based on relatively small magnitude (≤ 20% below controls) and short duration of the effects 
(resolved within 1-3 hours postdose).  The no-observed-adverse-effect level (NOAEL) for effects 
on respiratory function was 100 mg/kg, the highest dose tested. 
Slightly higher pulse pressure occurred in male dogs after administration of 15 mg/kg 
INCB050465 but was not considered to be adverse based on small magnitude (< 10% above 
controls) and short duration (resolved within 6 hours postdose).  The NOAEL for effects on 
cardiovascular function in this study was 15 mg/kg, the highest dose tested. 
The NOAELs for respiratory and cardiovascular function are well above the intended starting 
dose for this study and the anticipated therapeutic dose in humans.  Therefore, together with the 
planned monitoring of vital signs, the risk to subjects is expected to be low. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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1.2.3. 
Potential Risks of INCB050465 
1.2.3.1. 
Potential Risks of INCB050465 Based on Preclinical Safety 
Based on findings in repeat-dose toxicity studies of INCB050465 in rats and dogs, lymphoid 
depletion and resulting immunosuppression represents a potential risk for humans. 
 
 
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INCB050465 was not mutagenic or genotoxic in a bacterial reverse mutation assay, in vitro 
chromosomal aberrations study in human peripheral blood lymphocytes, or rat in vivo 
micronucleus assay. 
1.2.3.2. 
Potential Risks of PI3Kδ Inhibition Based on Other Agents in Class 
Idelalisib was approved by the FDA in July 2014 for treatment of relapsed/refractory follicular 
lymphoma and relapsed small lymphocytic lymphoma and for treatment of CLL in combination 
with rituximab.  Severe toxicities seen with the use of this agent include hepatotoxicity (fatal or 
serious occurring in 14%), fatal and/or serious diarrhea or colitis (14%), intestinal perforation,  
Pneumocystis jirovecii pneumonia (PJP), and pneumonitis.  Hepatotoxicity, colitis, and 
pneumonitis have also been reported in subjects treated with the PI3Kδ-inhibitor INCB040093.  
Subjects will be monitored closely for the development of these conditions and will have 
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treatment held and dose reduced as appropriate.  A standard PJP prophylaxis regimen will be 
required for all subjects receiving INCB050465 (see Section 5.8.2) either as monotherapy or in 
combination. 
Based on experience with idelalisib and INCB040093, hepatotoxicity is a risk with this class of 
agents.  Preclinically, hepatotoxicity with INCB050465 was only seen at plasma exposures 
> 65-fold higher than the projected clinical exposure at 10 mg QD.  The pharmacophore of 
INCB050465 is different from both idelalisib and INCB040093, which are similar to each other.  
Other PI3Kδ inhibitors with a different pharmacophore have not shown hepatotoxicity in early 
studies (Savona et al 2013).   
1.2.4. 
Clinical Summary of INCB050465 
As of 02 SEP 2016, data were available for 46 subjects who received INCB050465 administered 
orally at QD doses of 5 mg (n = 1), 10 mg (n = 3), 15 mg (n = 3), 20 mg (n = 15), 30 mg 
(n =  20), and 45 mg (n = 4).  The median duration of treatment was 104 days.  Adverse events 
observed in ≥ 20% of subjects were nausea, diarrhea, vomiting, neutropenia, fatigue, 
hypokalemia, and fever.  No ≥ Grade 3 treatment-related AEs were reported in ≥ 10% of 
subjects.  Serious AEs (SAEs) that occurred in ≥ 2 subjects included colitis (n = 3), diarrhea 
(n = 3), and pyrexia, pneumonia, dehydration, exfoliative dermatitis, and hypotension (n = 2 
each).  Eleven of the 46 subjects (24%) discontinued study treatment due to the following AEs:  
colitis, diarrhea, pneumonitis, rash, exfoliative dermatitis, psoriasis, neutropenia, pneumonia, and 
hypercalcemia.  All but 1 of these events occurred after the 9-week disease assessment.  No liver 
function test abnormalities > Grade 1 were reported while subjects were receiving study 
treatment.  No dose-limiting toxicities were identified, and the maximum tolerated dose was not 
reached. 
As of 02 SEP 2016, 20 objective responses as reported by investigators were observed at doses 
≥ 10 mg QD in 41 evaluable subjects.  Objective responses were observed in 5 subjects with 
DLBCL (n = 14), 6 subjects with follicular lymphoma (n = 6), 4 subjects with marginal zone 
lymphoma (n = 4); 3 subjects with mantle cell lymphoma (n = 4), 1 subject with  Hodgkin 
lymphoma (n = 8), and 1 subject with CLL (n = 5).  The objective response rate in evaluable 
subjects with NHL (n = 28) was 64%.  Among the 18 objective responses observed in subjects 
with NHL, 17 (94%) were observed by the time of the first disease assessment.  
Pharmacokinetics analysis showed the Tmax is 0.5 to 1 hour, the terminal half-life is 
approximately 8 to 12 hours, and exposure appeared to be dose-proportional between 5 mg QD 
and 45 mg QD at steady state.  The pharmacodynamic analyses demonstrated robust and 
sustained pathway inhibition at all dose levels tested.  Refer to the INCB050465 IB for further 
details. 
Food effect was assessed in Part 3 Cohort A.  Although coadministration of INCB050465 with a 
high-fat meal decreased 42% of dose-normalized Cmax compared with the fasted state, it had mild 
effect on dose-normalized AUC (10% decrease) based on data from 12 subjects.  The geometric 
mean ratio of AUC (fed vs fasted) and 90% confidence interval (CI) are 0.90 (0.68, 1.18), and 
INCB050465 may be administered without regard to meals (refer to the INCB050465 IB). 
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1.3. 
Overview of INCB039110 
INCB039110 is an inhibitor of the JAK family of protein tyrosine kinases with selectivity for 
JAK1.  Refer to the INCB039110 IB for current information on INCB039110. 
1.3.1. 
Pharmacology Summary 
INCB039110 represents a novel, potent, and selective inhibitor of the JAK family of protein 
kinases with selectivity for JAK1.  Because JAKs serve to transduce extracellular signals from a 
number of cytokines and growth factors that are upregulated and thought to be involved in the 
pathogenesis of cancer cachexia and cancer progression, inhibition of their signaling may be 
therapeutic for the treatment of such conditions.  JAK1 has been shown to cooperate with other 
JAKs to mediate the signaling of a number of inflammatory cytokines.  INCB039110 potently 
inhibits JAK1 (IC50 = 3.6 nM at 1 mM adenosine triphosphate concentration), with 22- to 
> 500-fold selectivity for the other JAK family members, JAK2, JAK3, and TYK2.  It does not 
significantly inhibit (< 30% inhibition) a broad panel of approximately 60 other kinases.  
Moreover, INCB039110 is potent (IC50 values of approximately 10-100 nM) in cytokine-driven 
cell-based assays, such as IL-2–stimulated phosphorylation of JAKs and STATs and IL-2–
induced proliferation of primary human T cells.  INCB039110 also inhibits the growth of the 
cytokine-dependent cell line INA-6.  This effect is not due to general cytotoxicity.  INCB039110 
potently inhibits the phosphorylation of STAT proteins and the production of proinflammatory 
factors (eg, IL-17, monocyte chemotactic protein-1) induced by other cytokines, such as IL-23 
and IL-6, with IC50 values in the range of approximately 30 to 100 nM.  In contrast, 
INCB039110 shows less inhibition in cell-based assays dependent on JAK2 (eg, thrombopoietin 
or prolactin-stimulated STAT phosphorylation) with IC50 values of approximately 1 μM or 
greater, suggesting that INCB039110 is JAK2-sparing in cells.  In in vivo models of 
JAK-dependent malignancy, INCB039110 impedes subcutaneous tumor growth of INA-6 cells 
expressing wild-type JAKs when administered by continuous infusion, achieving plasma 
concentrations well below those required to inhibit JAK2. 
INCB039110 did not demonstrate off-target activity nor was it active in a panel of approximately 
60 non-JAK family kinases.  Adverse findings in rat safety pharmacology studies, noted only at 
1000 mg/kg, included a transient decrease in locomotor activity, a slight decrease in body 
temperature, and suppression of respiratory function.  The IC50 for inhibition of the 
human-ether-a-go-go related gene channel was determined to be 65.3 μM.  In a cardiovascular 
evaluation of INCB039110 in dogs, ≥ 60 mg/kg produced a potentially adverse lowering of 
arterial pressure, compensatory higher heart rate, and an increase in core body temperature.  The 
NOAEL for the cardiovascular study was 30 mg/kg for both sexes.  
In summary, pharmacological data obtained in both in vitro and in vivo model systems support 
the potential utility of orally administered INCB039110 in the treatment of cancer and associated 
cachexia. 
1.3.2. 
Drug Disposition Summary 
The preclinical PK of INCB039110 was evaluated in rats, dogs, and monkeys.  INCB039110 
exhibits low-to-moderate systemic clearance, a low volume of distribution, and a short terminal 
elimination half-life.  The oral bioavailability was low in monkeys (< 20%), moderate in dogs 
(43%), and high in rats (82%).  INCB039110 is mainly cleared by metabolism and is a substrate 
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of CYP3A4 but does not significantly inhibit the activity of the major CYP enzymes, suggesting 
that the potential for INCB039110 to cause clinical drug-drug interactions through CYP 
inhibition is low. 
1.3.3. 
Nonclinical Toxicology Summary 
The toxicologic profile of INCB039110 was characterized in single- and multiple-dose oral 
studies of up to 3 months in duration in rats and dogs. 
 
  Pharmacology-related clinical pathology and anatomical alterations in 
multiple-dose rat studies included a reversible lowering of white blood cell count, primarily 
because of a lower circulating lymphocyte count, and reversible lymphoid depletion in lymphoid 
tissues and reduction in bone marrow cellularity.  
 
 
In repeat-dose studies in dogs, gastrointestinal inflammation was determined to be the DLT.  
 
 
 
 
 
 
  Clinical and histological evidence of JAK inhibition included 
decreased reticulocyte and/or lymphocyte counts, lymphoid depletion of lymphoid tissues, and/or 
reduction of bone marrow cellularity. 
 
INCB039110 was not genotoxic in the bacterial mutagenicity assay, the in vitro chromosome 
aberration assay in human lymphocytes, or the in vivo micronucleus assay in rats. 
INCB039110 also did not demonstrate off-target activity nor was it active in a panel of 
approximately 60 non-JAK family kinases.  Additional information on pharmacology, drug 
disposition, and nonclinical toxicology is available in the INCB039110 IB. 
1.3.4. 
Clinical Summary of INCB039110 
INCB039110 has been administered as monotherapy in clinical studies to healthy subjects and 
subjects with rheumatoid arthritis, chronic plaque psoriasis, and myelofibrosis.  INCB039110 is 
being administered in combination with gemcitabine and nab-paclitaxel to subjects with 
advanced solid tumors in an ongoing study (INCB 39110-116).  INCB039110 has also been 
administered in combination with INCB040093 in subjects with B-cell malignancies.  Additional 
information is available in the INCB039110 IB. 
1.3.5. 
Potential Risks of INCB039110 
INCB039110 is known to affect the immune system; therefore an increased incidence of 
infections could occur.  Strict clinical monitoring is indicated to identify and treat infections in 
study subjects should they occur, and a standard PJP prophylaxis regimen will be required for all 
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subjects receiving combination treatment with INCB050465 and INCB039110.  Refer to the 
INCB039110 IB for further details. 
INCB039110 has been shown to affect hematologic parameters.  In a study of INCB039110 in 
subjects with myelofibrosis, anemia, and thrombocytopenia occurred in > 30% of the 87 subjects 
enrolled (refer to the INCB039110 IB).  Subjects will have hematologic parameters closely 
monitored during this study. 
Hyperlipidemia has previously been noted in subjects receiving JAK inhibitors (Kontzias et al 
2012).  Ten subjects (18.2%) were observed to have an increase in blood cholesterol greater than 
the upper limit of normal (ULN) after receiving combination treatment with INCB040093 and 
INCB039110 while enrolled in the INCB 40093-102 study.  In the oncology population, 
monitoring and treatment of hyperlipidemia should be tailored as appropriate to individual 
subject characteristics, while exercising caution on study with cholesterol-lowering agents such 
as HMG-CoA reductase inhibitors that are associated with liver function abnormalities. 
1.4. 
Overview of the Combination of INCB050465 and INCB039110 
1.4.1. 
Nonclinical Pharmacokinetics and Drug Metabolism of the Combination 
Both INCB050465 and INCB039110 are metabolized predominately by CYP3A4, but neither 
appears to be an inducer or inhibitor of CYP3A4 at clinically relevant concentrations.  Also, 
INCB050465 is a P-gp inhibitor, while INCB039110 is a weak P-gp inhibitor.  While both 
INCB050465 and INCB039110 are P-gp substrates, their efflux transport via P-gp is likely to be 
saturated at the doses proposed for clinical evaluation and thus further inhibition of P-gp should 
have no effect on INCB050465 or INCB039110 absorption.  Therefore, a drug interaction 
between these compounds is unlikely in the setting of the proposed clinical study.  
Pharmacokinetics will be evaluated in this study to evaluate potential effect of INCB040093 on 
INCB039110 PK, with evaluation of INCB050465 PK in combination with INCB039110 
compared with INCB050465 monotherapy. 
1.4.2. 
Clinical Summary of Combination Treatment with INCB050465 and 
INCB039110 
As of 02 SEP 2016, 3 subjects had received the INCB050465 and INCB039110 combination 
therapy.  No SAEs were reported for these 3 subjects, and no AEs led to study treatment 
discontinuation.  Non−treatment-related AEs of spinal cord compression and pain led to study 
treatment interruption in 1 subject.  Among these 3 subjects, 2 partial responses (PRs) were 
reported in Hodgkin lymphoma and mantle cell lymphoma (n = 1 each). 
1.4.3. 
Clinical Summary of Combination Treatment With PI3Kδ Inhibition 
(INCB040093) and JAK Inhibition (INCB039110)  
Study INCB 40093-102 is an ongoing, open-label, dose escalation, safety and tolerability study 
of the PI3Kδ inhibitor INCB040093 as monotherapy and in combination with INCB039110.  As 
of 13 DEC 2015, 67 subjects had received treatment with the combination.  No evidence of any 
impact on the PK of the INCB040093 from coadministration of INCB039110 was apparent 
(INCB040093 IB). 
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1.4.4. 
Potential Risks of Combination Therapy of INCB050465 and INCB039110 
Incyte is proposing to study 2 investigational drugs INCB050465 and INCB039110 in 
combination for the treatment of relapsed/refractory B-cell malignancies.  The principle toxicity 
of inhibiting both PI3Kδ and JAK pathways is expected to be reversible effects on immune 
function.  Combined inhibition may adversely affect both B cell and T cell immune function with 
resultant increased risk of a variety of infections.  Subjects will be closely monitored for bacterial 
infections, viral reactivation, and opportunistic infections, and treatment will be interrupted for 
infections that can be easily managed with antibiotic therapy and discontinued for infections that 
are serious or require prolonged antibiotic therapy.  Study INCB 40093-102 is combining 
another PI3Kδ inhibitor, INCB040093 with INCB039110.  The most frequently reported SAE in 
this study was PJP (5 subjects, 7.5%).  The use of a standard Pneumocystis prophylaxis regimen 
is now mandated in subjects receiving combination therapy with INCB040093 and INCB039110.  
Since implementing this requirement, no additional cases of PJP have been observed in subjects 
receiving prophylaxis.  Therefore, all subjects receiving combination therapy with INCB050465 
and INCB039110 in this study must receive PJP prophylaxis.  Viral reactivation (ie, shingles) 
was observed in subjects receiving INCB040093 monotherapy and combination therapy with 
INCB039110. 
Effects on white blood cell, red blood cell, and platelet counts could result from JAK inhibition 
and result in infections, anemia, or thrombocytopenia requiring transfusions, which may be more 
likely in subjects with NHL that is refractory to recent therapy or transplantation. 
INCB039110 has been shown to affect hematologic parameters; however, cytopenias are not 
expected to be worse with combination PI3Kδ and JAK inhibition.  In the study combining 
INCB039110 with INCB040093 as of 13 DEC 2015, anemia has occurred in 14.9% of subjects 
receiving combination therapy.  Neutropenia has occurred in 28.4% of subjects receiving 
combination therapy; thrombocytopenia was reported in 31.3% of subjects receiving 
combination therapy (refer to the INCB039110 IB). 
Combined inhibition is not expected to increase the risk of hepatic toxicity and liver function 
testing will be monitored regularly.  Any hepatic toxicity is expected to be reversible.  These 
potential risks are considered acceptable in a population with relapsed/refractory lymphoid 
malignancies. 
1.5. 
Overview of Standard Therapies 
1.5.1. 
Rituximab 
1.5.1.1. 
Pharmacology Summary 
Rituximab (RITUXAN®) is a CD-20 cytolytic antibody that has been approved in the United 
States for the treatment of NHL, CLL, rheumatoid arthritis, and granulomatosis with polyangiitis 
and microscopic polyangiitis (Rituxan 2014).  Rituximab is used both as monotherapy and in 
combination with other agents in NHL.  
1.5.1.2. 
Potential Risks 
Boxed warnings for rituximab include fatal infusion reactions, severe mucocutaneous reactions, 
hepatitis B reactivations, and progressive multifocal leukoencephalopathy (PML).  Subjects 
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should be premedicated and will be monitored closely during rituximab infusion, and medical 
treatment should be performed as necessary for infusion reactions as described in the package 
insert.  Mucocutaneous reactions observed in patients receiving rituximab include 
Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal 
necrolysis.  Subjects who experience a severe mucocutaneous reaction should be discontinued.  
Hepatitis B virus reactivation can occur in patients receiving drugs classified as anti-CD20 
antibodies.  Subjects in this Protocol are screened for evidence of prior hepatitis B infection, 
which will mitigate the risk.  Progressive multifocal leukoencephalopathy should be considered 
in any subject with new-onset neurologic manifestations.  Evaluation should be performed as 
described in the package insert.   
Additional risks and precautions according to the package insert include tumor lysis syndrome 
infection (bacterial, fungal, and viral), cardiac events including arrhythmias, renal toxicities, and 
bowel obstruction and perforation.  Adverse reactions experienced by ≥ 30% of NHL subjects 
receiving monotherapy treatment with rituximab include fever, chills, infection, and 
lymphopenia.  A complete discussion of risks associated with rituximab can be found at 
http://dailymed.nlm.nih.gov/. 
1.5.2. 
R-ICE 
Rituximab is described in detail in Section 1.5.1. 
1.5.2.1. 
Ifosfamide 
1.5.2.1.1. Pharmacology Summary 
Ifosfamide is an alkylating agent that crosslinks DNA and results in cell death.  Ifosfamide 
requires breakdown of the parent compound to metabolites in the liver before it becomes active. 
1.5.2.1.2. Potential Risks 
The DLTs of ifosfamide are myelosuppression and urotoxicity.  Dose fractionation, vigorous 
hydration, and a protector such as mesna can significantly reduce the incidence of hematuria.  
Subjects enrolled into this study will receive mesna with the infusion of ifosfamide to protect 
against urotoxicity.  Adverse reactions occurring in > 10% of patients receiving ifosfamide 
include alopecia, nausea, vomiting, hematuria, gross hematuria, and CNS toxicity (IFEX 2015).  
A complete discussion of risks associated with ifosfamide can be found at 
http://dailymed.nlm.nih.gov/. 
1.5.2.2. 
Carboplatin 
1.5.2.2.1. Pharmacology Summary 
Carboplatin is a platinum compound that produced interstrand DNA cross-links in a manner that 
is cell-cycle nonspecific.  Carboplatin is generally felt to be less toxic than the earlier platinum 
agent, cisplatin. 
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1.5.2.2.2. Potential Risks 
Labeled warnings for carboplatin include bone marrow suppression, vomiting, and 
anaphylactic-like reactions.  Carboplatin should be administered under the supervision of a 
qualified physician for appropriate management of therapy and complications.  Bone marrow 
suppression is the DLT, and blood counts will be monitored before each dose of carboplatin in 
this study.  Supportive care including transfusions and G-CSF may be administered per the site's 
institutional policy.  Vomiting may be severe and the use of antiemetics prior to dose 
administration may reduce this risk and is allowed on study (Carboplatin 2015).  A complete 
discussion of risks associated with ifosfamide can be found at http://dailymed.nlm.nih.gov/. 
1.5.2.3. 
Etoposide 
1.5.2.3.1. Pharmacology Summary 
Etoposide is a topoisomerase II inhibitor that causes DNA strand breaks, which works to kill 
dividing cells by inhibiting DNA synthesis in the S phase.   
1.5.2.3.2. Potential Risks 
Etoposide is to be administered under the supervision of a qualified physician.  Etoposide can 
cause severe myelosuppression with resulting infection or bleeding.  Blood counts will be 
monitored closely per Protocol, and dose administration should be held if necessary to allow 
counts to sufficiently recover.  Other toxicities to be aware of include nausea and vomiting, 
which is generally mild to moderate and can be controlled with antiemetic therapy, hypotension 
following infusion, anaphylactic-like allergic reactions, and alopecia (Toposar 1998).  A 
complete discussion of risks associated with ifosfamide can be found at 
http://dailymed.nlm.nih.gov/. 
1.6. 
Study Rationale 
Lymphoid malignancies are the seventh leading cause of death in the United States, and their 
incidence has been increasing, with an estimated incidence of approximately 79,190 cases in 
2012, with 70,130 cases of NHL and 9,060 cases of HL (Siegel et al 2012).  Among these 
malignancies, the majority are derived from B-lymphocytes.  Although several therapeutic 
approaches such as combination chemotherapy, external beam irradiation, hematopoietic 
stem-cell transplantation, and molecular targeted agents, including B-lymphocyte–specific 
antibodies used alone or conjugated with radiopharmaceuticals or toxins, have significantly 
improved the prognosis of these patients, the annual mortality rate remains high, with 
20,130 patients dying from these malignancies in 2012. 
The recognition that aberrant signal transduction occurs in malignant B-lymphocytes via the 
PI3K pathways, resulting in disease progression, has led to a focus on agents that modulate these 
signaling pathways.  On 13 NOV 2013, the FDA granted accelerated approval to ibrutinib for the 
treatment of patients with MCL who have received at least 1 prior therapy.  The approval was 
based on the results of a multicenter, single-group study demonstrating a 66% ORR (95% CI:  
56.2, 74.5).  Idelalisib (a PI3K inhibitor) has been recently approved for the treatment of CLL in 
combination with rituximab, and as monotherapy for follicular lymphoma and small lymphocytic 
lymphoma.  The Phase 3 dose of idelalisib (150 mg twice daily [BID]) was shown to have a Cmin 
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of approximately 1 μM (Flinn et al 2014) and is therefore not expected to cover the IC90 for 
inhibiting Akt phosphorylation in whole blood (IC90 = 1.8 μM; refer to the INCB050465 IB) 
throughout the treatment interval.  As described in Section 1.2.1, INCB050465 is significantly 
more potent in all of the assays examined (refer to the INCB050465 IB), and based on its 
projected PK would be expected to cover > IC90 at Cmin, suggesting that it may have more 
marked effects than idelalisib in the clinic. 
Incyte is proposing to study 2 new investigational drugs (INCB050465 and INCB039110) in 
combination for the treatment of relapsed/refractory B-cell malignancies.  Both the JAK/STAT 
and PI3K pathways may contribute to driving tumor growth and survival in DLBCL as described 
above, and combination therapies that block both pathways may prove more beneficial in these 
diseases due to the central role that JAK-mediated cytokine signaling plays in augmenting 
BCR-mediated activation of the NF-κB pathway. 
In addition, Incyte is proposing to study INCB050465 in combination with a standard therapy in 
subjects with B-cell malignancies.  The therapy proposed is routinely used in subjects with 
DLBCL, and the addition of a PI3Kδ inhibitor may improve the activity of this therapy with 
limited additive toxicity from this targeted agent. 
1.7. 
Justification of Route, Dose Regimen, and Treatment Period 
1.7.1. 
INCB050465 
INCB050465 is being developed as a new investigational drug for oral administration.  Oral drug 
administration is generally the most convenient and cost-effective method of drug delivery for 
medications requiring continuous exposure.  INCB050465 tablets will be administered orally 
(QD, BID, or intermittently), as determined by emerging PK, pharmacodynamic (PD), and safety 
data.  INCB039110 will be administered orally QD.  One cycle of INCB050465 monotherapy 
will be defined as 21 days of treatment (eg, 21 continuous days of QD treatment, 21 days of 
once-weekly treatment); treatment for subjects in this study will consist of repeating 21-day 
cycles.  Combination regimens with standard agents may have different cycle lengths to 
accommodate standard regimens. 
Preclinical data suggest that the whole blood IC90 for INCB050465 is approximately 77 nM.  
Based on the preclinical PK profile of INCB050465, the clinical dose estimated to achieve IC90 
at trough is approximately 10 mg every 24 hours; unbound Cmax after this dose is projected to be 
approximately 0.023 μM, and unbound AUC is projected to be 0.37 μM·h.  Thus, it is reasonable 
to expect that full pharmacologic inhibition can be achieved with INCB050465 at a feasible 
clinical dose. 
Based on preclinical toxicology, the highest nonseverely toxic dose in the most sensitive species 
is 1 mg/kg per day in the dog.  This produces a human equivalent dose of 32 mg, and one-sixth 
of this dose indicates the estimated safe starting dose in oncology as 5.4 mg QD.  The NOAEL in 
the female dogs from the 28-day study (the most sensitive species) is 34.2 μM∙h (1.20 μM∙h 
unbound; refer to the INCB050465 IB).  The dose-related toxicities included changes in the 
lymphoid system consistent with pharmacological PI3Kδ inhibition (decrease in B-lymphocyte 
populations) by INCB050465.  The increase in incidence and/or severity of inflammatory 
changes was considered to be secondary to expected immunosuppression following PI3Kδ 
inhibition as inflammatory changes were noted in multiple tissues, secondary to putative loss in 
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antibody protection.  Upon cessation of administration of INCB050465, all of the inflammatory 
changes were reversed, with no histologic evidence of residual damage to the affected tissues. 
Based on this information, the initial dose will be 5 mg QD.  Based on preclinical models, 
INCB50465 has an IC50 of approximately 9 nM and IC90 of 77 nM.  The estimated plasma 
concentration in humans for a 5 mg QD dose exceeds the IC50 for 24 hours and the IC90 for 
approximately 12 hours. 
Dose escalation will be conducted with a 3 + 3 design, with the exception that the first cohort 
(dose level of 5 mg QD) will be a single subject cohort.  For each subsequent dose level, dose 
escalation will be conducted with a 3 + 3 dose titration design.  The initial cohort will consist of 
a single subject; and the initial dose will be 5 mg QD.  If a Grade 2 or greater AE is observed in 
the initial single subject cohort, the cohort will be expanded to 3 subjects.  Subsequent cohorts 
will have increases in the dose of INCB050465 limited to no more than 50%.  If a Grade 2 or 
greater AE is not observed, the dose of INCB050465 will be increased to 10 mg QD (or 5 mg 
BID depending on PK data) in the subsequent cohort, and dose escalation will be conducted 
using a 3 + 3 dose titration design.  After the 10 mg QD (or 5 mg BID) dose level cohort, 
subsequent increases in the dose of INCB050465 will be limited to no more than 50%.  Doses 
less than 5 mg QD may also be explored. 
Expansion cohorts of 15 to 30 subjects will be treated with the selected dose, either the 
maximum tolerated dose (MTD) or the PAD of INCB050465, as a single agent to further 
determine safety, tolerability, efficacy, PK, and PD in this population.  Part 3 Cohort A will 
study INCB050465 in subjects with refractory B-cell malignancies.  The subjects in Part 3 
Cohort A will also be used for an optional evaluation of food effect.  (Note that the food-effect 
study may be terminated based on emerging data before completing enrollment of Cohort A.)  If 
the dose selected for the expansion cohort was the MTD in the dose-escalation part of the study, 
on Cycle 1 Day 15 and Cycle 2 Day 1, the dose administered ONLY for these 2 doses will be 
1 dose level below the MTD (if the PAD is selected for the expansion cohort, there will be no 
alteration to the doses on Cycle 1 Day 15 or Cycle 2 Day 1). 
The sponsor may implement alternative regimens such as intermediate doses, intermittent dosing 
schedules, BID doses, or alternative formulations, depending on PK, PD, and safety results. 
Based on emerging efficacy and safety data from study INCB 50465-101 as of 02 SEP 2016, 
1 recommended regimen that will be evaluated in Parts 2, 3, and 6 is 20 mg QD for 9 weeks, 
followed by 20 mg once weekly.  The 20 mg QD dose provides exposure that is approximately 
2-fold greater than the IC90 (based on an in vitro whole-blood assay) at trough.  Furthermore, all 
11 NHL subjects who received 20 mg QD have achieved an objective response.  However, 24% 
of all 46 subjects in study INCB 50465-101 as of 02 SEP 2016 discontinued study treatment due 
to an AE.  Among the subjects with an objective response (n = 20), 7 (35%) discontinued study 
treatment due to an AE.  Consequently, after administration of 20 mg QD for 9 weeks, the dosing 
regimen will be reduced to 20 mg once weekly. This once-weekly regimen is proposed to 
maintain response while providing time off from pathway inhibition, which may reduce the 
frequency of AEs.  Pharmacodynamic data from INCB 50465-101 showed that a single dose of 
20 mg exhibited maximal inhibition of AKT in an ex vivo pharmacodynamic assay, and PK 
modeling suggests that 20 mg once weekly will 1) achieve maximal inhibition equivalent to 
approximately 10 × IC90, 2) exceed the IC90 for approximately 36 hours, and 3) have minimal to 
no inhibition for approximately half the dosing interval.  This once-weekly regimen is similar to 
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that of another PI3K inhibitor (copanlisib), which is administered intravenously on Days 1, 8, 
and 15 of a 28-day cycle, and which achieved 7 objective responses in 9 subjects with 
non-Hodgkin lymphoma (Patnaik et al 2016). Among the 51 subjects who received study drug, 
4 discontinued treatment due to an AE. There were 2 events of Grade 3 noninfectious 
pneumonitis, 1 event of Grade 3 diarrhea, and no events of colitis. 
1.7.2. 
INCB039110 
For Part 2, the initial starting dose for the other investigational agent, INCB039110, to be 
administered in combination with INCB050465, will be 300 mg QD.  Pharmacokinetic and 
safety data from prior studies in nononcologic indications support QD administration of 
INCB039110 in this study.  In the combination Phase 1 study INCB 40093-102, the MTD of 
INCB039110 was not reached when given at doses up to 600 mg QD in combination with 
another PI3Kδ inhibitor, INCB040093.  However, based on an increased incidence of 
thrombocytopenia and neutropenia in subjects receiving a dose of 600 mg QD, the dose of 
INCB039110 was reduced to 400 mg in combination with INCB040093 for use in the expansion 
cohort.  Although this combination is tolerated, emerging PK and PD data indicate that inhibition 
of the JAK/STAT pathway at this dose exceeds the target (approximately 50%-60%).  As the 
probability of some AEs, such as cytopenias and infections, may correspond to the level of 
inhibition of INCB039110, 300 mg QD is considered an appropriate dose level for chronic 
administration and will be the starting dose of INCB039110 in combination with INCB050465.  
Alternative dose regimen strategies may be explored based on the aggregate safety, PK, PD, and 
clinical activity data.  For instance, if INCB039110 300 mg QD is not tolerated, then 
INCB039110 200 mg QD will be combined with INCB050465 (see Section 1.3.4). 
1.7.3. 
R-ICE in Combination With INCB050465 
In Part 6 of the study, INCB050465 will be administered at a starting dose approximately 25% 
(rounded down to the nearest tablet size combination) below the recommended dose determined 
in Part 1 in combination with the R-ICE chemotherapy regimen at the following doses for three 
21-day cycles: 
• Rituximab 375 mg/m2 given on Day 1 and Day 2 of Cycle 1 and on Day 1 of Cycles 2 
and 3. 
• Ifosfamide 5000 mg/m2 continuous IV infusion over 24 hours on Day 3. 
− Mesna should be added to ifosfamide infusion. 
• Carboplatin area under the curve (AUC) = 5 mg/mL (maximum dose 800 mg) IV 
infusion on Day 3. 
• Etoposide 100 mg/m2 IV on Days 3 to 5. 
Note:  As an alternative to the Protocol-specified dose and schedule, R-ICE may also be 
administered per institutional practice with medical monitor approval. 
If tolerated, the dose of INCB050465 will be escalated to the recommended dose in combination 
with R-ICE.  The selected doses of the components of R-ICE have been administered to subjects 
with DLBCL in a number of clinical studies (Zelenetz et al 2003, Kewalramani et al 2004, 
Gisselbrecht 2010, Feldman et al 2014, Matasar et al 2013).  The 21-day cycle was used by 
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Gisselbrecht et al (2010) in the CORAL study as well as by Matasar et al (2013) and was chosen 
here to allow subjects the maximum time to recover from any toxicities including 
myelosuppression.  INCB050465 may be administered continuously or intermittently. 
2.
STUDY OBJECTIVES AND PURPOSE
2.1. 
Primary Objective
•
To assess the safety and tolerability of the planned study treatments and select doses
for further evaluation.
2.2. 
Secondary Objectives
•
To assess preliminary efficacy by assessing the ORR of the planned study treatments.
•
To assess the PK of the planned study treatments and assess the effect of food on the
PK of INCB050465 monotherapy.
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3. 
SUBJECT ELIGIBILITY 
3.1. 
Study Population 
The study will include individuals diagnosed with B-cell malignancies (excluding Burkitt's 
lymphoma and precursor B-lymphoblastic leukemia/lymphoma) who have failed or are 
refractory to available treatments. 
3.2. 
Subject Inclusion Criteria 
The following criteria are required for inclusion in the study: 
1. Aged 18 years or older with lymphoid malignancies of B-cell origin including the 
following: 
a. Indolent/aggressive B-cell NHL 
− EXCLUDING:  Burkitt's lymphoma and precursor B-lymphoblastic 
leukemia/lymphoma 
− INCLUDING:  any non-Hodgkin's B-cell malignancy such as CLL and rare 
non-Hodgkin's B-cell subtypes such as hairy cell leukemia, Waldenström 
macroglobulinemia (WM), MCL, and transformed NHL histologies. 
b. Hodgkin's lymphoma 
2. For Part 3, Expansion Cohort B, subjects must have relapsed/refractory HL. 
3. For Part 3, Expansion Cohort C, and Part 6, Cohort L, subjects must have 
relapsed/refractory DLBCL.  Note:  DLBCL subtype (eg, GCB) should be known at 
study entry. 
4. Life expectancy of ≥ 12 weeks. 
5. Subject must have received ≥ 1 prior treatment regimen(s). 
6. The subject must not be a candidate for potentially curative therapy, including 
hematopoietic stem-cell transplantation, except where one of the standard therapy 
regimen combinations (such as R-ICE) may be used prior to transplantation per standard 
medical practice. 
7. Women who are either postmenopausal for at least 1 year with documented 
follicle-stimulating hormone (FSH) > 30 IU/L or are surgically sterile for at least 
3 months, or who agree to take appropriate precautions to avoid pregnancy (with at least 
99% certainty) from screening through follow-up if of childbearing potential.  
(Note:  Permitted methods that are at least 99% effective in preventing pregnancy 
[Appendix A] should be communicated to the subjects and their understanding 
confirmed).  For all women, the pregnancy test result must be negative at screening. 
8. Men must agree to take appropriate precautions to avoid fathering a child (with at least 
99% certainty) from screening through follow-up.  (Note:  Permitted methods that are at 
least 99% effective in preventing pregnancy [Appendix A] should be communicated to 
the subjects and their understanding confirmed). 
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9. Ability to comprehend and willingness to sign an informed consent form (ICF). 
10. For Part 3 Expansion, Cohort D, subjects must have relapsed/refractory indolent  
lymphoma.  Indolent lymphoma is defined as histologically confirmed follicular 
lymphoma Grade 1, 2, or 3a, or histologically confirmed marginal zone lymphoma. 
11. For Part 6, subjects must be CD20-positive (assessed at the site) and must be currently 
eligible to receive rituximab. 
3.3. 
Subject Exclusion Criteria 
If met, any of the following criteria will lead to subject exclusion from the study: 
1. Pregnant or breastfeeding women. 
2. Received an investigational study drug within 28 days or 5 half-lives (whichever is 
longer) before receiving the first dose of study drug or with medical monitor approval. 
3. Received any approved anticancer medications within 21 days or 5 half-lives (whichever 
is longer) before receiving the first dose of study drug(s) (42 days for nitrosoureas) 
EXCEPT steroids at ≤ 10 mg prednisone daily (or equivalent), or with medical monitor 
approval. 
4. Any unresolved toxicity ≥ Grade 2 from previous anticancer therapy except for stable 
chronic toxicities (≤ Grade 2) not expected to resolve, such as stable Grade 2 peripheral 
neurotoxicity. 
5.  History of brain metastases or spinal cord compression (unless treated, asymptomatic, 
and stable on most recent imaging and enrolling in an expansion cohort), or lymphoma 
involving the central nervous system (permitted in Expansion Cohorts A and E). 
6. ECOG performance status of ≥ 3 (≥ 2 during dose escalation) (Appendix C). 
7. Received allogeneic hematopoietic stem-cell transplant within the last 6 months, or has 
active graft-versus-host disease following allogeneic transplant, or is currently receiving 
immunosuppressive therapy following allogeneic transplant. 
8. Received autologous hematopoietic stem-cell transplant within the last 3 months. 
9. Laboratory parameters: 
a. Any of the following laboratory values at screening, unless directly resulting from the 
bone marrow infiltration of the underlying malignancy.  Screening values must be 
independent of blood product or hematopoietic growth factor support.  All of the 
following laboratory tests should be performed within 14 days of treatment initiation. 
Laboratory 
Parameter 
For Monotherapy 
Cohorts (No Bone 
Marrow Involvement) 
For Combination Therapy 
Cohorts (No Bone Marrow 
Involvement) 
Bone Marrow Infiltration of 
the Underlying Malignancy 
(for Any Cohort) 
Hemoglobin 
≤ 8.0 g/dL 
≤ 9.0 g/dL 
≤ 8.0 g/dL 
Platelet count 
≤ 50 × 109/L 
≤ 100 × 109/L 
≤ 50 × 109/L 
Absolute neutrophil 
count (ANC) 
≤ 1.0 × 109/L 
≤ 1.5 × 109/L 
≤ 1.0 × 109/L 
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b. Any of the following laboratory results at screening irrespective of causality: 
− Total bilirubin ≥ 1.2 × ULN (if total bilirubin is ≥ 1.2 × ULN then direct bilirubin 
must by < 1.2 × ULN) 
− Alkaline phosphatase (ALP) ≥ 2.5 × ULN (or ≥ 5 × ULN if bone metastases are 
present and hepatic parenchymal metastases are absent) 
− Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
≥ 2.0 × ULN. 
− Creatinine clearance ≤ 50 mL/min measured or calculated by Cockroft-Gault 
equation or estimated glomerular filtration rate ≤ 50 mL/min/1.73 m2 using the 
modification of diet in renal disease formula. 
10. Current or recent history (< 30 days before screening and/or < 45 days before study drug 
administration) of a clinically meaningful bacterial, fungal, parasitic, or mycobacterial 
infection. 
11. Current, clinically active viral infection. 
12. Known human immunodeficiency virus infection, or hepatitis B virus (HBV) or 
hepatitis C virus (HCV) viremia or at risk for HBV or HCV reactivation.  Hepatitis B 
virus DNA and testing for HCV RNA must be undetectable.  At risk for HBV 
reactivation is defined as HBSAg positive or anti-HBc antibody positive.  At risk for 
HCV reactivation is defined as HCV antibody positive. 
13. History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's 
opinion, is clinically meaningful.  Screening QTc interval > 450 milliseconds is excluded 
(corrected by Fridericia).  In the event that a single QTc is > 450 milliseconds, the subject 
may enroll if the average QTc for the 3 ECGs is < 450 milliseconds.  For subjects with an 
intraventricular conduction delay (QRS interval > 120 milliseconds), the JTc interval may 
be used in place of the QTc with sponsor approval.  The JTc must be < 340 milliseconds 
if JTc is used in place of the QTc. Subjects with left bundle branch block are excluded. 
14. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months from Day 1 of study drug administration, 
New York Heart Association Class III or IV congestive heart failure, and arrhythmia 
requiring therapy. 
15. History of major stomach or intestinal surgery, or malabsorption syndrome (eg, Crohn's 
disease or chronic pancreatitis) that would, by clinical judgment, affect the absorption of 
study drug. 
16. Use of any potent CYP3A4 inhibitor (Appendix G) or inducer within 14 days or 
5 half-lives (whichever is longer) of the first dose of study drug. 
17. Prior treatment with a PI3Kδ inhibitor or pan-PI3K inhibitors (excluded in Part 1 and 
Part 3 Expansion Cohorts A, B, C, and D only, or with medical monitor approval). 
18. Radiation treatment within the previous 4 weeks.  Palliative radiation treatment to 
nonindex or bone lesions may be considered with medical monitor approval. 
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19. Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the 
administration schedule and study evaluations. 
20. Any serious medical condition that, in the opinion of the investigator, would pose a 
significant risk to the subject or interfere with the interpretation of study data. 
21. Prior treatment with a JAK inhibitor (excluded in Part 2 and Part 3 Cohort E only). 
22. Known hypersensitivity to any of the active substances or any of their excipients, 
including INCB050465 or INCB039110. 
23. For Part 2 and Part 3 (Cohort E) subjects only:  Any ≤ Grade 2 immune-related AEs from 
prior immunotherapy must have complete resolution and must have resolved at least 2 
weeks before Cycle 1 Day 1.  Subjects with a history of a Grade 3 or 4 immune-related 
AE or any grade ocular immune-related AE from prior immunotherapy are excluded. 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Study Drugs 
The investigational drugs in this study include INCB050465 and INCB039110.  All study 
subjects will receive these study drugs in an open-label manner, as oral, self-administered agents.  
INCB050465 will be administered in all parts of the study.  INCB039110 will only be 
administered in Part 2 and Part 3 Expansion Cohorts E. 
4.2. 
Overall Study Design 
The study consists of 4 parts.  The overall study design is shown in Figure 2.  Monotherapy dose 
escalation (Part 1) will determine recommended dose(s) to be explored further.  The 
recommended dose(s) will be defined as dose(s) at least equivalent to the PAD (a dose that 
produced substantial pharmacologic target inhibition) and no higher than the MTD. 
Part 2 will evaluate the combination of INCB050465 and INCB039110 to determine the 
recommended dose(s) of the combination. 
Expansion (Part 3), which consists of 5 cohorts, will evaluate the recommended dose(s) of 
INCB050465 as monotherapy and in combination with INCB039110.  The monotherapy 
dose-expansion cohorts will evaluate INCB050465 in subjects with B-cell malignancies, indolent  
lymphoma, DLBCL, and HL.  Note that expansion cohorts for INCB050465 monotherapy may 
explore more than 1 recommended dose and schedule to obtain long-term safety data on multiple 
dose levels and schedules.  The combination expansion cohorts will evaluate the chosen 
combination dose of INCB050465 and INCB039110 in subjects with B-cell malignancies.   
Part 6 will include a safety assessment of INCB050465 in combination with the chemotherapy 
regimen R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) in subjects with B-cell 
malignancies, followed by an expansion cohort in DLBCL.  Timing for the initiation of Part 6 
will be determined by the sponsor based on emerging data from Parts 1 and 3 of the study.  Note, 
for purposes of consistency and database completion, this will remain Part 6. 
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Note:  With Amendment 10, Protocol-required procedures have been reduced for ongoing 
subjects. 
Figure 2: 
Study Design 
 
4.2.1. 
Part 1 – Monotherapy Dose Escalation of INCB050465 
Dose escalation will be conducted with a 3 + 3 design, with the exception that the first cohort 
(dose level of 5 mg QD) will be a single subject cohort.  There will be an observation period of 
21 days before enrollment of the next cohort and administration of the next dose level.  Subjects 
who receive at least 17 days of INCB050465 at the level assigned to that cohort will be 
considered evaluable for determining tolerability of dose.  Subjects enrolling but not meeting 
these criteria may be replaced in order to fill the cohort. 
• The initial cohort will consist of a single subject (the cohort may include an additional 
subject to ensure completion of 1 evaluable subject through Day 21); the initial dose 
will be 5 mg QD. 
− If a Grade 2 or greater AE is observed, the cohort will be expanded to 3 subjects.  
If the initial cohort is expanded to 3 subjects, the safety assessment will follow the 
3 + 3 design.  Subsequent cohorts will have increases in the dose of INCB050465 
limited to no more than 50%. 
− If a Grade 2 or greater AE is not observed, the dose of INCB050465 will be 
increased to 10 mg QD (or 5 mg BID depending on PK data) in the subsequent 
cohort, and dose escalation will be conducted using a 3 + 3 dose titration design.  
After the 10 mg QD (or 5 mg BID) dose level cohort, subsequent increases in the 
dose of INCB050465 will be limited to no more than 50%. 
− If the MTD has been exceeded or the PAD has been achieved in the initial cohort, 
this cohort may be expanded to at least 3 subjects and a lower dose of 
INCB050465 (eg, 2.5 mg QD) may be explored. 
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• With the 3 + 3 design, each cohort will enroll a minimum of 3 subjects.  If no DLTs 
are observed in the initial 3 subjects, the next cohort will begin enrollment.  If 1 DLT 
is observed in the first 3 subjects, 3 additional subjects will be enrolled in the cohort.  
If DLTs occur in > 1 of the first 3 subjects or the total cohort of 6 subjects, then the 
MTD will be deemed to have been exceeded and the next lower tolerable dose level 
will be deemed to be the MTD. 
• If the dose increment has been 100% and deemed exceeding the MTD, an 
intermediate dose level may be explored (eg, from 10 mg QD to 7.5 mg QD). 
• Dose increases will occur using 1 of 2 options:  1) increasing the number of tablets 
taken at each QD administration, or 2) increasing the dose frequency to BID.  For 
example, based on safety in a cohort receiving 5 mg QD, the total daily dose might be 
increased 2-fold in the next cohort by using a 5 mg BID regimen or by using a 10 mg 
QD regimen, depending on emerging PK data.  The dose regimen will be designed to 
maintain a suitable peak-to-trough ratio and minimize accumulation. 
If a dose level is reached that provides a suitable profile of pharmacologic target inhibition 
(PAD) before reaching the MTD, then this dose may be deemed a recommended dose(s) and 
used to move to Part 3 monotherapy dose expansion, as well as taken to Part 2 for testing in the 
combination.  Dose escalation of the monotherapy may continue at doses above the PAD until 
the MTD is reached or dose escalation is stopped.  In the event that the half-life suggests 
alternative schedules will provide optimum target inhibition, additional cohorts may be evaluated 
(eg, BID administration). 
4.2.2. 
Part 2 – Dose Escalation With the Combination of INCB0504065 and 
INCB039110 
Dose escalation will proceed using a 3 + 3 design with a starting dose of INCB050465 
approximately 25% (rounded down to the nearest tablet size combination) below the 
recommended dose determined in Part 1 followed by escalation of INCB050465 in combination 
with INCB039110 300 mg QD.  Escalation of the dose of INCB050465 will continue in 
combination with INCB039110 300 mg QD until the recommended dose is determined.  If the 
starting dose of INCB050465 cannot be combined safely with INCB039110 300 mg QD, 
INCB039110 at 200 mg QD will be tested.  If that combination is tolerated, escalation of 
INCB050465 will proceed with INCB039110 200 mg QD.  Additional dose de-escalation may 
occur with INCB050465 if DLTs occur with a causality that can be reasonably assigned to 
INCB050465.  Additional dose escalation or de-escalation of INCB039110 and/or INCB050465 
may be considered if supported by emerging safety, PK, 
 data in this combination.   
4.2.3. 
Part 3 – Expansion 
Monotherapy Expansion Cohorts A, B, C, and D will open when the recommended dose(s) is 
chosen from Part 1, independently from Part 2.  Recommended dose(s) will be at least equivalent 
to the PAD and no higher than the MTD (or the highest dose tested).  Expansion Cohort A will 
enroll subjects with B-cell malignancies, Cohort B will enroll subjects with HL, Cohort C will 
enroll subjects with DLBCL, and Cohort D will enroll subjects with indolent lymphoma.  Note 
that expansion cohorts for INCB050465 monotherapy may explore more than 1 recommended 
dose and schedule to obtain long-term safety data on multiple dose levels and schedules. 
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When the recommended dose for Phase 2 combination therapy has been determined from Part 2, 
enrollment will proceed simultaneously for Expansion Cohort E, which will enroll subjects with 
B-cell malignancies.  Details regarding the dose expansion cohorts are described in Table 1. 
If ≥ 5 subjects in the first 15 subjects of any cohort, cumulatively, (or more than 33% of subjects 
in cohorts larger than 15 subjects) experience DLTs during Cycle 1, then further enrollment to 
the cohort will be stopped, and a lower dose level may be explored.  Based on emerging data, the 
sponsor may decide on the number of subjects with a specific subtype of an indication to be 
enrolled into each expansion cohort (eg, non-GCB or GCB in DLBCL) or specific tumor types to 
be enrolled in Cohorts A and E (eg, mantle cell lymphoma). 
Table 1: 
Part 3 Expansion Cohorts 
Part Cohort 
Population 
# of Subjects 
Treatment 
3 
A 
B-cell malignancies 
15-30 
INCB050465 monotherapy 
B 
HL 
≤ 15 
C 
DLBCL
a 
≤ 15 
D 
Indolent lymphoma 
≤ 30 
E 
B-cell malignancies 
≤ 15 
INCB050465 + INCB039110 
a Based on emerging data, the sponsor may decide on the number of subjects with a specific subtype of an 
indication to be enrolled (eg, non-GCB or GCB). 
4.2.4. 
Part 6 – Dose Evaluation and Expansion With the Combination of INCB050465 
and R-ICE 
Initiation of Part 6 dose evaluation will be dependent on preliminary data from Parts 1 and 3 of 
the study.  Dose evaluation would proceed in subjects with DLBCL using a 3 + 3 design with a 
starting dose of INCB050465 approximately 25% (rounded down to the nearest tablet size 
combination) below the recommended dose determined in Part 1 in combination with the 
chemotherapy components at the following doses in a 21-day cycle for a total of 3 cycles: 
• Rituximab 375 mg/m2 given on Day 1 and Day 2 of Cycle 1, and on Day 1 of 
Cycles 2 and 3. 
• Ifosfamide 5000 mg/m2 continuous IV infusion over 24 hours on Day 3. 
− Mesna should be added to ifosfamide infusion. 
• Carboplatin AUC = 5 mg/mL (maximum dose 800 mg) IV infusion on Day 3. 
• Etoposide 100 mg/m2 IV on Days 3 to 5. 
Note:  As an alternative to the Protocol-specified dose and schedule, R-ICE may be administered 
according to institutional practice with medical monitor approval. 
If tolerated, the dose of INCB050465 will be escalated to the recommended dose in combination 
with R-ICE.  INCB050465 will be given daily or intermittently and may be continued until a 
criterion is met for treatment discontinuation.  If the starting dose of INCB050465 cannot be 
combined safely with R-ICE at the schedule described above, the dose of INCB050465 will be 
reduced to 25% below the dose first administered in combination with R-ICE.  Additional dose 
de-escalation may occur with INCB050465 if DLTs occur with a causality that can be reasonably 
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assigned to INCB050465.  Additional dose de-escalation of INCB050465 and intermittent 
schedules may be considered if supported by emerging safety, PK, 
 data in this 
combination.  Following the identification of a tolerable dose of the combination of 
INCB050465 and R-ICE (a dose less than or equal to the MTD), expanded Cohort L will be 
opened to further evaluate the safety, efficacy, PK, 
 as described in Table 2. 
Table 2: 
Part 6 Expansion Cohort 
Part 
Cohort 
Population 
# of Subjects 
Treatment 
6 
L 
DLBCL
a 
~15 
INCB050465 + R-ICE 
a Based on emerging data, the sponsor may decide on the number of subjects with a specific subtype of an 
indication to be enrolled (eg, non-GCB or GCB). 
If ≥ 5 subjects in Cohort L experience DLTs during Cycle 1, further enrollment to the cohort will 
be stopped, and a lower dose level may be explored. 
4.2.5. 
Crossover to Combination Therapy After Monotherapy Treatment 
For subjects who discontinue INCB050465 monotherapy for a reason described in Section 5.7.1, 
the investigator may feel that the best option for the subject is to enroll in a combination therapy 
offered in this Protocol.  Prior use of a PI3K inhibitor is not prohibited per the 
inclusion/exclusion criteria for combination cohorts.  Therefore, subjects who discontinue 
INCB050465 may be allowed to cross over to combination therapy.  In these cases, the subject 
must meet the eligibility criteria for the cohort they will cross over to, and the sponsor must 
approve the crossover.   
4.3. 
Study Endpoints 
4.3.1. 
Primary Endpoint 
• Safety and tolerability of the planned study treatments as assessed by summary of 
AEs, clinical laboratory assessments, physical examination results, and 12-lead 
ECGs. 
4.3.2. 
Secondary Endpoints 
• Efficacy as measured by ORR, defined as the sum of subjects achieving a minor 
response (MR, only among subjects with WM), PR, very good partial response 
(VGPR, only among subjects with WM), and CR to the planned study treatments 
based on: 
− International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for 
CLL (Hallek et al 2008, Cheson et al 2012). 
− VIth International Workshop on Waldenström macroglobulinemia response 
assessment for subjects with Waldenström macroglobulinemia (Owen et al 2013)  
− Revised response criteria for lymphoma for HL and NHL (Cheson et al 2014). 
• Cmax, Tmax, Cmin,  AUC0-t, and AUC0-τ at Cycle 1 Day 15 of INCB039110 in 
combination with INCB050465. 
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• Cmax, Tmax, Cmin, AUC0-t, and AUC0-τ of INCB050465 as monotherapy and in 
combination with INCB039110. 
4.4. 
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. 
4.5. 
Number of Subjects 
Up to approximately 150 subjects are planned for enrollment at approximately 15 sites.  The 
number of subjects may vary due to the number of cohorts required to determine the tolerated or 
recommended dose. 
4.6. 
Study Termination 
If a PAD (eg, trough plasma concentration of ≥ IC90) cannot be reached in a cohort with less than 
one-third of the subjects experiencing a DLT as monotherapy or combination therapy, the study 
will be terminated. 
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 institutional review 
boards and independent ethics committees (IRBs/IECs), and regulatory bodies of the decision 
and the reason for termination of the study.   
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB or IEC in writing of 
the study's completion or early termination, and send a copy of the notification to the sponsor or 
sponsor's designee and retain 1 copy for the site study regulatory file. 
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5. 
TREATMENT OF SUBJECTS 
5.1. 
Treatment Groups and Administration of Study Drug 
5.1.1. 
INCB050465 Monotherapy 
Subjects will self-administer INCB050465 using an oral daily QD, BID, or intermittent regimen, 
as instructed by the investigator.  INCB050465 should be administered in the clinic on Days 1, 8, 
and 15 of Cycle 1.  Subjects enrolled in Part 3 Cohort A participating in the food-effect study 
will also have INCB050465 administered in clinic on Cycle 2 Day 1.  INCB050465 will be taken 
orally with water without regard to food.  If QD or once-weekly intervals are used, INCB050465 
should be taken at approximately the same time each day. 
5.1.2. 
INCB050465 and INCB039110 Combination Therapy 
In Part 2 and Part 3 (Cohort E), subjects will concomitantly receive INCB039110 (administered 
QD) with INCB050465.  INCB050465 and INCB039110 should be administered in the clinic on 
Days 1, 8, and 15 of Cycle 1.  INCB039110 will be given after all INCB050465 PK sampling is 
complete on Day 1.  At other designated visits where INCB039110 is administered at the site, it 
can be given with INCB050465.  For either drug, if a dose of is missed, the subject should skip 
the dose and take the next scheduled dose at the usual time.   
If BID doses are used, INCB050465 should be taken morning and evening, at approximately 
12-hour intervals.  For QD administration, if a dose is missed by more than 12 hours, the subject 
should skip the dose and take the next scheduled dose at the usual time.  For BID administration, 
if the morning or evening dose is missed by more than 4 hours, the subject should skip that dose 
and take next scheduled dose at the usual time.  For once-weekly dosing, if the dose is missed by 
more than 2 days, the subject should skip the dose and take the next scheduled dose. 
One cycle will be defined as 21 days of treatment; subjects will receive treatment in continuous 
cycles.  All subjects will attend study visits weekly during the first cycle, and at the beginning of 
each 21-day cycle thereafter.  
5.1.3. 
INCB050465 and R-ICE Combination Therapy 
Subjects enrolled into Part 6 of the study will receive INCB050465 continuously in 21-day 
cycles.  INCB050465 should be administered in the clinic on Days 1 and 15 of Cycle 1.  The 
R-ICE chemotherapy regimen will be administered as described below for 3 cycles, which will 
be 21 days each.  INCB050465 may be continued until a criterion is met for treatment 
discontinuation. 
• Rituximab 375 mg/m2 given on Day 1 and Day 2 of Cycle 1 and on Day 1 of Cycles 2 
and 3. 
• Ifosfamide 5000 mg/m2 continuous IV infusion over 24 hours on Day 3 of each cycle. 
− Mesna will be infused with ifosfamide. 
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• Carboplatin area under the curve = 5 (maximum dose 800 mg) IV infusion on Day 3 
of each cycle. 
• Etoposide 100 mg/m2 IV on Days 3 to 5 of each cycle. 
Note:  As an alternative to the Protocol-specified dose and schedule, R-ICE may be administered 
per institutional practice with medical monitor approval. 
5.2. 
Treatment Compliance 
Subjects should be counseled by the investigator to maintain strict adherence to the study 
regimen as prescribed and to keep a record of any missed doses.  Subject diaries will be provided 
for the purposes of keeping accurate documentation of study drug administration and treatment 
compliance.  The subject will be instructed to bring all unopened, empty, and opened/partially 
used bottles of study drug to each study visit, at which time compliance will be assessed. 
5.3. 
Randomization and Blinding 
Not applicable. 
5.4. 
Duration of Treatment and Subject Participation 
Subjects in Parts 1, 2, and 3 will be treated in continuous 21-day cycles indefinitely; this may 
include temporary interruptions described in Section 5.6.  Subjects in Part 6 will be treated in 
21-day cycles.  INCB050465 may continue indefinitely, but R-ICE will only be given for 
3 cycles. 
Subjects who have evidence of objective clinical benefit, regardless of dose level, may continue 
to be treated at that dose level.  Dose and schedule changes may be implemented for ongoing 
subjects based on emerging tolerability data.  If study drug is permanently discontinued (for 
reasons, see Section 5.6.2.1) the subject will be withdrawn from the study.  Treatment duration 
will vary among subjects, but is expected to average approximately 6 months. 
5.5. 
Rationale for Dose Modification 
Selections and modifications to the dosage of study drug are planned for dose-escalation cohorts.  
Also, dose interruptions and modifications may occur for individual study subjects.  The 
identification of DLTs will define the doses used in planned cohorts.  Further, the occurrence of 
DLTs and other toxicities will guide decisions for treatment interruptions and discontinuation for 
individual subjects. 
Subjects enrolled in lower doses 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 provided the criteria specified 
in Section 5.6.1 are met. 
5.5.1. 
Dose-Limiting Toxicity 
A DLT is any AE noted in Table 3.  DLTs include all AEs of the specified grades, regardless of 
investigator attribution of relatedness.  AEs occurring during Cycle 1 of the dose-escalation 
portion of the study will be considered to be DLTs if they are not clearly related to the 
underlying disease, its progression, a comorbidity, concomitant medication, or transient 
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(≤ 72 hours) abnormal laboratory values without associated clinically significant signs or 
symptoms based on investigator determination.  Events not meeting these precise criteria may be 
considered DLTs as determined during review by the Incyte medical monitor and principal 
investigators. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with INCB050465; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the MTD or recommended dose of INCB050465, 
decisions will be made based on events deemed to be DLTs that are observed from the first day 
of INCB050465 administration through and including the final day of Cycle 1 (Day 21 or Day 28 
depending on the part of the study that the subject has been enrolled to); in addition, all safety 
data available to date will be considered. 
Each dose cohort in this study will be reviewed before dose escalation by the Incyte medical 
monitor and principal investigators.  Telephone conferences will be scheduled by the sponsor 
with all investigators in order to review cohort-specific data and overall safety data from prior 
cohorts (if applicable), and to agree on dose escalation and the recommended dose for Phase 2 
per DLT rules defined in this section. 
Dose-limiting toxicities will be assessed by the investigator using the current CTCAE version 
4.03 criteria.  All toxicities will be graded based on the highest grade that is actually reached, 
rather than the level that might have been reached if left untreated.  A DLT will be defined as 
any AE that is new in onset or worsening in severity and meets any of the criteria listed in 
Table 3. 
Table 3: 
Definition of Dose-Limiting Toxicity 
Nonhematologic: 
• 
≥ Grade 3 nonhematologic toxicity, excluding nausea, vomiting, diarrhea. 
• 
≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal antiemetic/antidiarrheal therapy 
lasting > 48 hours. 
• 
Any toxicity considered a DLT in the opinion of the investigator and medical monitor. 
Hematologic:  
• 
Grade 4 neutropenia lasting ≥ 7 days. 
NOTE:  INCB039110 is suspected to cause transient decreases in white blood cells due to 
margination, therefore, DLT rules require neutropenia to persist after holding INCBC039110 for 
2 to 3 days.  Where the clinical status of the subject allows, investigators are encouraged to wait 
24 hours before starting growth factors, to determine if white blood cell margination is 
contributing to the degree of neutropenia.   
• 
Febrile neutropenia (ANC < 1.0 × 109/L with a single temperature of > 38.3°C (101°F) or a 
sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour). 
• 
Grade 3 thrombocytopenia associated with clinically significant bleeding (clinically significant as 
determined by the investigator or resulting in the need for a transfusion of red blood cells). 
• 
Grade 4 thrombocytopenia lasting > 7 days. 
• 
Grade 4 anemia. 
General: 
• 
Any specific AE that results in a dose delay or reduction in > one-third of subjects. 
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5.5.2. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 4 weeks.  During follow-up subjects should be seen as often as medically indicated 
to assure safety. 
5.5.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases investigators are free to employ any measures or concomitant medications, following 
discussion with sponsor, necessary to optimally treat the subject. 
5.6. 
Dose Adjustment of Study Drug 
5.6.1. 
Planned Dose Adjustments 
Cohort dose escalation is described in Section 4.1.  Intrasubject dose escalation of INCB050465 
will be allowed during dose escalation, provided that the following criteria are met: 
• The Protocol inclusion criteria are met. 
• The subject has received 4 cycles of study drug and has not had a related or possibly 
related toxicity ≥ Grade 2. 
• The next dose level has been determined to be safe based on DLT rules (eg, no DLTs 
during Cycle 1). 
• The subject is willing to submit to all visits and procedures as in Cycle 1 per the 
Protocol, except the PK
sampling will only be done as on Cycle 1 Day 15 (Day 1 
and Day 8 PK
sampling will not be done). 
• In the opinion of the investigator, the subject does not have any concurrent condition 
or circumstance that would complicate the dose escalation or PK sampling, or pose 
increased risk to the subject. 
• The intrasubject dose escalation has been approved by the sponsor. 
5.6.2. 
Criteria and Procedures for Dose Interruptions and Dose Reductions of 
INCB050465 and INCB039110 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of 
adverse experiences that may have an unclear relationship to study drug.  Treatment with 
INCB050465, the combination with INCB039110, or the combination with standard therapies 
may be delayed up to 2 weeks to allow for resolution of toxicity.  If treatment needs to be 
interrupted in subjects receiving the combination of INCB050465 and INCB039110 for toxicities 
with unknown causality, both study medications should be held.  However, based on the 
evolving experience with the study treatments, the suspected causal agent only may be held 
(while the other study treatment continues) until resolution of toxicity following consultation and 
approval with the medical monitor.  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's medical monitor to discuss the case of any subject whose treatment has been delayed 
for more than 14 days before treatment with INCB050465 or the combination of INCB050465 
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and INCB039110 may be restarted (see Table 4).  Dose reductions of 1 or both (as applicable for 
subjects on combination therapy) study treatments may be necessary as described in Table 4.  
For subjects who start on the 300 mg QD dose of INCB039110, the first dose reduction would be 
to 200 mg QD.  If subjects start at a 200 mg QD dose of INCB039110, the combination of 
INCB050465 with INCB039110 at a lower dose (eg, 100 mg QD) will be subject to discussion 
with the sponsor.  Alternatively, INCB039110 may be discontinued if dose reduction is 
indicated, and subjects may continue on INCB050465 monotherapy if they continue to receive 
benefit. 
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.  
Individual decisions regarding dose reduction should be made using clinical judgment and in 
consultation with the sponsor's medical monitor, taking into account relatedness of the AE to the 
study drug and the subject's underlying condition.  Subjects receiving dose reductions (but not 
meeting DLT criteria) during the first cycle will not be considered evaluable for the purposes of 
determining the MTD. 
Table 4: 
Guidelines for Interruption and Restart of Study Drug 
TOXICITY/NCI CTCAE GRADE 
ACTION TAKEN 
Chemistries: 
 
• Total bilirubin > 3.0 × ULN  
• AST and/or ALT > 3.0 × ULN 
• ALP ≥ 2.5 × ULN  
Note:  For ALP increases in subjects with 
bone metastasis-related ALP elevation at 
baseline, contact sponsor to discuss clinical 
management and possible dose reductions. 
Step 1:  Interrupt study drug(s) up to 2 weeks (14 days) until the 
toxicity has resolved to ≤ Grade 1 except ALT/AST elevations, 
which may require 4 weeks (28 days) to resolve. 
Step 2:  Restart study drug(s) at next lower dose (or 
INCB050465 at 25% reduction if in expansion cohorts, rounded 
down to the nearest pill strength); monitor as clinically 
indicated.
a   
Dose reductions may be made solely to the suspected agent if 
the causality can be reasonably assigned to that agent based on 
existing data (refer to the INCB050465 IB and INCB039110 IB) 
with approval of the medical monitor. 
Hematologic: 
 
• ANC < 1.0 × 109/L for subjects who 
enrolled with ANC > 1.5 × 109/L 
• ANC < 0.5 × 109/L for subjects who 
enrolled with ANC ≤ 1.5 × 109/L 
• Platelet count is 50 to < 75 × 109/L for 
subjects who enrolled with platelets > 100 × 
109/L 
• Platelet count is < 50 × 109/L for subjects 
who enrolled with platelets ≤ 100 × 109/L 
Step 1:  Interrupt study drug(s) up to 2 weeks (14 days) until the 
toxicity has resolved to ≤ Grade 1 or pretherapy baseline. 
Step 2:  Restart study drug(s) and monitor as clinically 
indicated. 
Dosing interruption may be made solely to the suspected agent 
if the causality can be reasonably assigned to that agent based on 
existing data (refer to the INCB050465 IB and INCB039110 IB) 
with approval of the medical monitor. 
• Grade 4 ANC (< 0.5 × 109/L) lasting 7 days 
• ≥ Grade 3 ANC with an oral temperature of 
at least 38.5°C OR with ≥ Grade 3 infection 
• Platelet count is < 50 × 109/L for subjects 
who enrolled with platelets > 100 × 109/L 
• Platelet count is < 25 × 109/L for subjects 
who enrolled with platelets ≤ 100 × 109/L 
Step 1:  Interrupt study drug(s) up to 2 weeks (14 days) until the 
toxicity has resolved to ≤ Grade 1.   
Step 2:  Restart study drug(s) at next lower dose (or 
INCB050465 at 25% reduction if in expansion cohorts) and 
monitor as clinically indicated.a   
Dose reductions may be made solely to the suspected agent if 
the causality can be reasonably assigned to that agent based on 
existing data (refer to the INCB050465 IB and INCB039110 IB) 
with approval of the medical monitor. 
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Table 4: 
Guidelines for Interruption and Restart of Study Drug (Continued) 
TOXICITY/NCI CTCAE GRADE 
ACTION TAKEN 
Other drug-related toxicities or toxicities not 
attributable to other causes: 
 
Diarrhea/colitis (Grade 1) 
Step 1:  Treat with antimotility agents (eg, 4 mg loperamide 
followed by 2 mg every 4 hours or after every unformed stool) 
and initiate supportive care (see Section 5.6.2.1).  If not 
improved after 48 hours, treat per guidance for ≥ Grade 2. 
Diarrhea/colitis (≥ Grade 2) 
Step1:  Interrupt INCB050465.  Perform work-up for infection 
(including CMV, C. difficile, etc).  Initiate or continue 
supportive care (see Section 5.6.2.1).  Consider colonoscopy 
with biopsy for ≥ Grade 3. 
Step 2:  If infection is ruled out, start oral steroids, or consider 
IV steroids if subject is being given IV fluids.  If no 
improvement with oral steroids, switch to IV steroids. 
When diarrhea resolves to ≤ Grade 1, continue supportive care 
and taper steroids over 4 weeks.  When taper is complete and 
diarrhea is ≤ Grade 1, restart INCB050465 at next lower dose in 
consultation with the medical monitor. 
If  ≥ Grade 2 diarrhea reoccurs, permanently discontinue 
INCB050465.  
Pneumonitis (Grade 1) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved.   
Step 2:  Restart INCB050465 at next lower dose.  Monitor as 
clinically indicated. 
Pneumonitis (Grade  ≥ 2) 
Permanently discontinue INCB050465. 
Skin toxicity (eg, rash, pruritus, etc, unless 
otherwise specified) (Grade 2-3) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved to 
≤ Grade 1. 
Step 2: Restart INCB050465 at same dose.  If assessed as 
related to INCB050465, restart at next lower dose in 
consultation with the medical monitor. 
Exfoliative dermatitis (Grade 1) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved. 
Step 2:  Restart INCB050465 at next lower dose.  Monitor as 
clinically indicated. 
Exfoliative dermatitis (≥ Grade 2) 
Permanently discontinue INCB050465. 
Intestinal perforation (any grade) 
Permanently discontinue INCB050465. 
Pneumocystis jiroveci pneumonia infection 
Interrupt INCB050465.  Permanently discontinue INCB050465 
if Pneumocystis jiroveci pneumonia infection is confirmed. 
CMV infection 
Subjects with CMV viremia without associated clinical signs of 
CMV infection should be carefully monitored.  Consider 
interrupting INCB050465 for subjects with CMV viremia and 
clinical signs of infection until the infection has resolved.  
Restart INCB050465 reduced by 1 dose level if approved by the 
medical monitor. 
Varicella zoster infection 
Interrupt INCB050465.  Restart INCB050465 only by approval 
of the medical monitor. 
Any Grade 1 or 2 toxicity unless otherwise 
specified 
Continue study drug treatment(s); monitor as clinically 
indicated. 
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Table 4: 
Guidelines for Interruption and Restart of Study Drug (Continued) 
TOXICITY/NCI CTCAE GRADE 
ACTION TAKEN 
Any Grade 2 or 3 toxicity, if clinically 
significant and not manageable by supportive 
care unless otherwise specified 
Step 1:  Interrupt study drug(s) up to 2 weeks (14 days) until 
toxicity resolves to ≤ Grade 1 or medical monitor approval. 
Step 2:  Restart study drug(s) at next lower dose for events 
considered to be drug-related (or 25% reduction if in expansion 
cohort, rounded down to the nearest pill strength); monitor as 
clinically indicated.a 
Dose reductions may be made solely to the suspected agent if 
the causality can be reasonably assigned to that agent based on 
existing data (refer to the INCB050465 IB and INCB039110 IB) 
with approval of the medical monitor. 
Any recurrent Grade 2 or 3 toxicity after 2 dose 
reductions 
Discontinue study drug treatment(s) and follow-up per Protocol. 
Any other Grade 4 toxicity 
Discontinue study drug(s) and follow-up per Protocol.  
However, if toxicity resolves to ≤ Grade 1 within 2 weeks, may 
restart treatment at 1 dose level lower with medical monitor 
approval. 
CMV = cytomegalovirus; IV = intravenous. 
a Note:  Only 2 dose reductions due to AEs are permitted. 
5.6.2.1. 
Supportive Care Guidelines for Diarrhea/Colitis 
Subjects should be informed to immediately report to the investigator any event of diarrhea.  
Subjects should receive appropriate supportive care measures as deemed necessary by the 
investigator.  For any Grade ≥ 1 diarrhea, subjects should be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  Subjects should try to eat 5 to 6 small meals per day; low-fat, high-
protein foods; and cooked instead of raw vegetables.  Subjects may supplement their diet with 
bananas, rice, applesauce, and toast to reduce the number of bowel movements, and may also try 
crackers, gelatin, noodles, or oatmeal.  Subjects should avoid fried, fatty, greasy, or spicy foods; 
milk, milk products, and acidic drinks; high-fiber foods and foods that cause gas; and alcohol, 
caffeine, and herbal supplements (Coutré et al 2015). 
For each occurrence, attempts should be made to rule out other causes, such as metastatic disease 
or bacterial or viral infection (including CMV), which might require additional supportive care. 
It may be necessary to perform conditional procedures such as colonoscopy with biopsy as part 
of evaluation of the event.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain or cramping, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
5.6.2.2. 
Dose Interruptions for Standard Therapies 
Dose interruptions and adjustments for standard therapy in Part 6 of the study will be at the 
discretion of the investigator, in accordance with the individual product package insert and 
applicable treatment guidelines (eg, NCCN Guidelines).   
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5.6.3. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity will require that the study drug be permanently 
discontinued.  Unacceptable toxicity is defined as: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
subject's ability to continue study-specific procedures or is considered to not be in the 
subject's best interest. 
• Toxicity requiring more than 2 dose reductions of INCB050465 or the combination of 
INCB050465 and INCB039110 or the standard therapy.  Subjects enrolled in Part 6 
who require > 2 reductions of the standard therapy may remain on INCB050465 
monotherapy with medical monitor approval. 
• Persistent toxicity requiring a delay of therapy for more than 2 weeks (14 days), 
except ALT/AST elevation, which may require 4 weeks (28 days) to resolve, unless 
approved by the medical monitor. 
• Prolongation of QTc by > 60 milliseconds or to > 500 milliseconds confirmed by 
repeat ECG. 
• Recurrent toxicity despite 2 dose reductions. 
If study drug is permanently discontinued, the subject will be withdrawn from the study. 
5.7. 
Withdrawal of Subjects From the Study 
5.7.1. 
Withdrawal Criteria 
Subjects must be withdrawn from the study for the following reasons: 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The subject becomes pregnant. 
• Consent is withdrawn. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB or IEC. 
• Unacceptable toxicity has occurred (see Section 5.6.2.1). 
• Disease progression has occurred (see Appendix D, Appendix E, or Appendix F for 
definition) 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, or  
− if progression is observed on a once-weekly schedule after an objective response 
was observed on a QD schedule, a subject may be returned to the QD schedule if 
it is determined to be in the subject's best interest by the investigator (eg, no better 
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alternative) and agreed by both the subject and the medical monitor. The subject 
should be withdrawn when a subsequent radiological assessment demonstrates 
further deterioration or sooner based on clinical signs and symptoms. 
− Note:  Subjects receiving INCB039110 monotherapy study treatment may receive 
combination therapy with INCB039110 and INCB050465 as described in 
Section 4.2.  
A subject may be withdrawn from the study 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.  Refer to Section 11.3, 
Protocol Adherence. 
• If a subject is noncompliant with study procedures or study drug administration in the 
opinion of the investigator, the sponsor should be consulted for instruction on 
handling the subject. 
5.7.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the subject will 
be withdrawn from the study and the end-of-treatment (EOT) visit should be conducted.  
Reasonable efforts should be made to have the subject return for a follow-up visit.  These visits 
are described in Section 5.10.  The last date of the last dose of study drug will be recorded in the 
case report form (CRF), and the reason for subject withdrawal will be recorded. 
If a subject is withdrawn from the study: 
• 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 CRF. 
• The EOT visit should be performed. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longer. 
5.8. 
Concomitant Medications and Measures 
All concomitant medications and treatments must be recorded in the CRF.  Any prior medication 
received up to 30 days before enrollment (Cycle 1 Day 1) will be recorded in the CRF.  
Concomitant treatments and/or procedures that are required to manage a subject's medical 
condition during the study will also be recorded in the CRF. 
5.8.1. 
Supportive Care Measures 
Supportive care should be administered to subjects as per the institutional policy at the site for 
the standard therapy that the subject will receive.  Additional information may be available in the 
appropriate package inserts.  This includes the use of prophylactic growth factors should be 
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based on American Society of Clinical Oncology guidelines for the use of white blood cell 
growth factors (Smith et al 2006) and the investigator's clinical judgment. 
5.8.2. 
Pneumocystis jirovecii Pneumonia Prophylaxis 
All subjects in this study  are required to receive a standard PJP prophylaxis regimen determined 
by the investigator.  Examples of standard PJP prophylaxis therapies for this population include 
trimethoprim-sulfamethoxazole, atovaquone, dapsone with or without pyrimethamine, and 
pentamidine (NCCN 2014).  Due to reports of cross-sensitivity between sulfonamides and 
dapsone, all subjects who have a known or suspected allergy to sulfonamides must receive either 
inhaled pentamidine or atovaquone (Mepron®) for PJP prophylaxis.  Prophylaxis should be given 
while subjects are receiving study treatment and continue for at least 2 to 6 months after the last 
dose of study drug. 
5.9. 
Restricted Medications and Measures 
• Use of systemic corticosteroid doses ≤ 10 mg/day prednisone (or equivalent) is 
permitted but discouraged from the screening visit through the EOT visit. 
• Use of weak or moderate inducers or inhibitors of CYP3A4 (Appendix G) is 
discouraged, and investigators should seek other options where possible. 
• P-glycoprotein substrates of clinical relevance should be used with caution  
• Aspirin in doses exceeding 81 mg/day is not permitted.  Low-dose aspirin 
(≤ 81 mg/day) is permitted.  Acetaminophen and nonsteroidal anti-inflammatory 
agents (NSAIDs, eg, ibuprofen) may be used.  Due to the risk of liver injury with the 
use of high doses of acetaminophen, subjects should be advised to stay within the 
recommend daily dose of acetaminophen. 
• If concomitant administration of an anticoagulant/antiplatelet medication is indicated, 
caution and enhanced monitoring are required.  History of thrombocytopenia and any 
concurrent INCB039110-related thrombocytopenia should be a factor in the choice of 
anticoagulant and dose.  Aspirin use should be carefully considered because of the 
potential for gastric irritation in subjects with concomitant bleeding risk. 
5.10. 
Prohibited Medications and Measures 
• Use of potent inducers and inhibitors of CYP3A4 are prohibited (Appendix G).  
Based on the low overall bioavailability of topical ketoconazole, there are no 
restrictions on topical ketoconazole. 
• Use of any anticancer medications other than the study medications from 21 days 
before Day 1 through the 30-day follow-up is prohibited. 
• Use of systemic corticosteroid doses > 10 mg/day prednisone (or equivalent) is not 
permitted from the screening visit through the EOT visit. 
• Any concomitant use of another JAK inhibitor (Part 2 and Part 3 Cohort E only). 
• Administration of live virus vaccines within 30 days of rituximab treatment 
(applicable to Part 6 of the study only). 
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6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedules of assessments (Table 5 
and Table 7) and schedules of laboratory assessments (Table 6 and Table 8).  Required analytes 
for laboratory assessments are provided in Table 11.  The order of assessments is suggested by 
the order of mention within the schedules.  For instructions on each assessment, see Section 7. 
Note:  Upon implementation of Protocol Amendment 10, only study assessments indicated 
in Table 9 and Table 10 will be performed. 
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Table 5: 
Schedule of Assessments for Parts 1, 2, and 3 
Note:  Upon implementation of Protocol Amendment 10, the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other 
Cycles 
EOT 
Follow-Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 8  
(± 3 Days) 
Day 15  
(± 3 Days) 
Day 1  
(± 3 Days) 
EOT +  
30-37 Days 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
Review inclusion and 
exclusion criteria 
3 
X 
X 
 
 
 
 
 
 
Demography and 
medical history 
7.3 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.3.2 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination/body 
weight, height 
7.4.2 
X* 
X 
X 
X 
X 
X 
X 
* Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
screening only. 
Vital signs  
7.4.4 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
7.4.5 
X 
X* 
 
X* 
X 
X 
X 
* Timed triplicate ECGs (separated 
by 5 minutes) at predose and 2 and 
4 hours postdose. 
Laboratory tests 
7.4.6 
X 
X 
X 
X 
X 
X 
X 
 
ECOG status 
7.6 
X 
X 
X 
X 
X 
X 
X 
 
CT or MRI 
7.5.1 
X 
 
 
 
X* 
X 
 
* Every 9 weeks (3 cycles) or at a 
frequency consistent with the 
standard of care for the subject's 
disease.  Performed only if 
measurable disease is present. 
FDG-PET scan 
7.5.2 
X 
 
 
 
X* 
X 
 
If performed per standard of care.  
Applicable for lymphomas only (see 
Section 7.5.2). 
* Every 9 weeks (3 cycles) or at a 
frequency consistent with the 
standard of care for the subject's 
disease. 
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Table 5: 
Schedule of Assessments for Parts 1, 2, and 3 (Continued) 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other 
Cycles 
EOT 
Follow-Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 8  
(± 3 Days) 
Day 15  
(± 3 Days) 
Day 1  
(± 3 Days) 
EOT +  
30-37 Days 
Bone marrow 
examination 
7.5.3 
X* 
 
 
 
X* 
 
 
* At baseline and if confirming CR. 
For exceptions to this requirement, 
see Section 7.5.3. 
Review AEs 
7.4.1 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
dispensing 
7.10.1.2 
 
X 
 
 
X 
 
 
 
Administer 
INCB050465 at site 
7.10.1.1 
 
X 
X 
X* 
X* 
 
 
Subject to withhold AM dose of 
study drug on days it will be 
administered at the site. 
* For subjects in Part 3 Cohort A, 
study drug will be administered at 
the site on Cycle 1 Day 15 and 
Cycle 2 Day 1 as part of the 
food-effect study.  If the dose 
selected for the expansion cohort 
was the MTD in the dose-escalation 
part of the study, on Cycle 1 Day 15 
and Cycle 2 Day 1, the dose 
administered ONLY for these 2 
doses will be 1 dose level below the 
MTD (if the PAD is selected for the 
expansion cohort, there will be no 
alteration to the doses on Cycle 1 
Day 15 or Cycle 2 Day 1). 
Administer 
INCB039110 at site 
7.10.1.4 
 
X* 
X 
X 
 
 
 
Part 2 and Part 3 Cohort E only. 
* INCB039110 is administered after 
INCB050465 PK sampling is 
complete on Cycle 1 Day 1. 
Assess compliance 
7.10.1.3 
 
 
 
 
X 
X 
 
 
Distribute reminders 
7.10.2 
X 
X 
X 
X 
X 
X 
 
 
CT = computed tomography; PET = positron emission tomography. 
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Table 6: 
Schedule of Laboratory Assessments for Parts 1, 2, and 3 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Local Laboratory 
Tests 
Protocol 
Section 
Screening 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
D1 All 
Other 
Cycles 
EOT 
Follow-
Up 
Details 
Serum chemistries 
7.4.6.1 
X* 
X** 
X 
X 
X 
X 
X 
X 
* Required within 14 days of treatment 
initiation. 
** May be performed within 3 days of the 
first dose. 
Hematology 
7.4.6.2 
X* 
X** 
X 
X 
X 
X 
X 
X 
* Required within 14 days of treatment 
initiation. 
** May be performed within 3 days of the 
first dose. 
Coagulation panel 
7.4.6.4 
X* 
 
 
 
X 
X^ 
X 
 
* Required within 14 days of treatment 
initiation. 
^ Only at Cycles 4, 7, 10, etc. 
Hepatitis screening 
7.4.6.7 
X 
 
 
 
 
 
 
 
 
Urinalysis 
7.4.6.3 
X 
 
 
 
X 
X* 
 
 
* Only at Cycles 4, 7, 10, etc. 
Serum pregnancy  
7.4.6.6 
X 
 
 
 
 
 
 
X 
All female subjects of childbearing potential. 
FSH  
7.4.6.5 
X 
 
 
 
 
 
 
 
To document hormonal menopause. 
Immunophenotyping 
7.5.4 
X 
 
 
 
X* 
 
 
 
*CLL:  Cycle 2 and to confirm CR. 
IgM (subjects with 
WM only) 
7.5.5 
 
X** 
 
 
 
X* 
 
 
* To be performed at least every 9 weeks or 
more frequently as clinically indicated. 
** May be performed within 3 days of the 
first dose. 
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Table 6: 
Schedule of Laboratory Assessments for Parts 1, 2, and 3 (Continued) 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Central Laboratory 
Samples 
Protocol 
Section 
Screening 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
D1 All 
Other 
Cycles 
EOT 
Follow-
Up 
Details 
PK plasma (predose) 
7.7.1 
 
X 
X 
X 
X* 
 
 
 
Collect before morning dose of study drug. 
*Cycle 2 Day 1 PK is only required for 
subjects in the monotherapy expansion 
Cohort A. 
PK plasma TIMED 
(postdose) 
7.7.1 
 
X* 
 
X*,** 
X*,** 
 
 
 
* Collect at 0.5, 1, 2, 4, 6, 8, and, if possible, 
12 hours postdose of INCB050465 on 
Cycle 1 Days 1 and 15. 
** Subjects in the monotherapy expansion 
cohort (Part 3 Cohort A) who participate in 
the food-effect study will be required to 
undergo PK sampling to test food effect on 
Cycle 1 Day 15 after fasted 
administration and on Cycle 2 Day 1 after 
fed administration of INCB050465.  The 
sampling on Cycle 2 Day 1 will be identical 
to the PK testing on Cycle 1 Day 15, except 
dose administration will be within 5 minutes 
of completing a high-fat meal.  Subjects may 
be excused from the food-effect portion of 
the study if they are unable to consume the 
meal. 
Urine PK (postdose) 
7.7.2  
 
 
 
X 
 
 
 
 
Provide a complete urine output collection 
from hour 0 (after morning dose) through 
8 hours; or 12 hours postdose if 12-hour 
postdose PK sample is being collected. 
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Table 6: 
Schedule of Laboratory Assessments for Parts 1, 2, and 3 (Continued) 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Central Laboratory 
Samples 
Protocol 
Section 
Screening 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
D1 All 
Other 
Cycles 
EOT 
Follow-
Up 
Details 
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Table 7: 
Schedule of Assessments for Part 6 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other Cycles 
EOT 
Follow-Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 
2 
Day 
3 
Days  
4-5 
Day 
15 
Day 1 
(± 3 Days) 
Days 
3-5
a 
EOT +  
30-37 Days 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
Review inclusion 
and exclusion 
criteria 
3 
X 
X 
 
 
 
 
 
 
 
 
 
Demography and 
medical history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.3.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination/ body 
weight, height 
7.4.2 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
screening only. 
Vital signs  
7.4.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
7.4.5 
X 
X* 
X 
X 
X 
X* 
X 
X 
X 
X 
* Timed triplicate ECGs (separated 
by 5 minutes) at predose and 2 and 
4 hours postdose. 
Laboratory tests 
7.4.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG status 
7.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CT or MRI 
7.5.1 
X 
 
 
 
 
 
X* 
 
X 
 
* Every 9 weeks (3 cycles) or at a 
frequency consistent with the 
standard of care for the subject's 
disease.  Performed only if 
measurable disease is present. 
FDG-PET scan 
7.5.2 
X 
 
 
 
 
 
X* 
 
X 
 
If performed per standard of care.  
Applicable for lymphomas only 
(see Section 7.5.2). 
* Every 9 weeks (3 cycles) or at a 
frequency consistent with the 
standard of care for the subject's 
disease.  Performed only if 
measurable disease is present. 
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Table 7: 
Schedule of Assessments for Part 6 (Continued) 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other Cycles 
EOT 
Follow-Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 
2 
Day 
3 
Days  
4-5 
Day 
15 
Day 1 
(± 3 Days) 
Days 
3-5
a 
EOT +  
30-37 Days 
Bone marrow 
examination 
7.5.3 
X* 
 
 
 
 
 
 
 
 
 
* At baseline and if confirming CR. 
For exceptions to this requirement, 
see Section 7.5.3. 
Review AEs 
7.4.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
INCB050465 
dispensing 
7.10.1.2 
 
X 
 
 
 
 
X 
 
 
 
 
Administer 
INCB050465 at site 
7.10.1.1 
 
X 
 
 
 
X 
 
 
 
 
Subject to withhold AM dose of 
study drug on days it will be 
administered at the site. 
Administer standard 
therapy 
7.10.1.7 
 
X 
X 
X 
X 
 
X 
X 
 
 
Rituximab will be given on Day 1 
and Day 2 of Cycle 1 and Day 1 of 
Cycles 2 and 3 
Ifosfamide and carboplatin will be 
administered on Day 3 of each 
cycle. 
Etoposide will be administered on 
Days 3 to 5 of each cycle. 
Note: As an alternative to the 
Protocol-specified dose and dose 
schedule, R-ICE may be 
administered according to 
institutional practice with medical 
monitor approval. 
Assess compliance 
7.10.1.3 
 
 
 
 
 
 
X 
 
X 
 
 
Distribute reminders 
7.10.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a Subjects who continue to receive INCB050465 after the 3 cycles of R-ICE plus INCB050465 are not required to have Protocol-specified assessments performed on Days 3 to 5 
of Cycle 4 and subsequent cycles unless clinically indicated. 
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Table 8: 
Laboratory Assessments for Part 6 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other Cycles 
EOT 
Follow-
Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 
2  
Day 
3 
Days  
4-5 
Day 
15 
Day 
1 
(± 3 
Days) 
Days 
3-5
a 
EOT +  
30-37 
Days 
Local Laboratory 
Tests 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistries 
7.4.6.1 
X* 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
* Required within 14 days of 
treatment initiation. 
** May be performed within 3 days 
of the first dose. 
Hematology 
7.4.6.2 
X* 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
* Required within 14 days of 
treatment initiation. 
** May be performed within 3 days 
of the first dose. 
Coagulation panel 
7.4.6.4 
X* 
 
 
 
 
 
X^ 
 
X 
 
* Required within 14 days of 
treatment initiation. 
^ Only at Cycles 2, 4, 7, 10, etc. 
Hepatitis screening 
7.4.6.7 
X 
 
 
 
 
 
 
 
 
 
* Comprehensive examination at 
screening, targeted physical 
examination thereafter.  Height at 
screening only. 
Urinalysis  
7.4.6.3 
X 
 
 
 
 
 
X^ 
 
 
 
^ Only at Cycles 2, 4, 7, 10, etc. 
Serum pregnancy 
7.4.6.6 
X 
 
 
 
 
 
 
 
 
X 
All female subjects of childbearing 
potential. 
FSH 
7.4.6.5 
X 
 
 
 
 
 
 
 
 
 
 
Immunophenotyping 
7.5.4 
X 
 
 
 
 
 
 
 
 
 
 
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Table 8: 
Laboratory Assessments for Part 6 (Continued) 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other Cycles 
EOT 
Follow-
Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 
2  
Day 
3 
Days  
4-5 
Day 
15 
Day 1 
(± 3 
Days) 
Days 
3-5a 
EOT +  
30-37 
Days 
Central 
Laboratory 
Samples 
 
 
 
 
 
 
 
 
 
 
 
 
PK plasma 
(predose) 
7.7.1 
 
X 
 
 
 
X 
 
 
 
 
Collect before morning dose of 
study drug. 
PK plasma TIMED 
(postdose) 
7.7.1 
 
X 
 
 
 
X 
 
 
 
 
Collect at 0.5, 1, 2, 4, 6, 8, and, if 
possible, 12 hours postdose of 
INCB050465 on Cycle 1 Days 1 
and 15. 
Urine PK (postdose) 
7.7.2 
 
 
 
 
 
X 
 
 
 
 
Provide a complete urine output 
collection from hour 0 (after 
morning dose) through 8 hours; or 
12 hours postdose in 12-hour 
postdose PK sample is being 
collected. 
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Table 8: 
Laboratory Assessments for Part 6 (Continued) 
Note:  Upon implementation of Protocol Amendment 10, only the schedules of assessments in Table 9 and Table 10 should be 
followed. 
Procedure 
Protocol 
Section 
Screening 
Phase 
Cycle 1 
Other Cycles 
EOT 
Follow-
Up 
Notes 
Days 
-30 to -1 
Day 
1 
Day 
2  
Day 
3 
Days  
4-5 
Day 
15 
Day 1 
(± 3 
Days) 
Days 
3-5a 
EOT +  
30-37 
Days 
a Subjects who continue to receive INCB050465 after the 3 cycles of R-ICE plus INCB050465 are not required to have Protocol-specified assessments performed on Days 3 to 5 
of Cycle 4 and subsequent cycles unless clinically indicated. 
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Table 9: 
Schedule of Assessments for Ongoing Subjects in All Cohorts Upon Implementation of Protocol Amendment 10 
Procedure 
Section 
At Least Every 12 Weeks 
in Clinic
a 
EOT 
Follow-Up 
Notes 
EOT + 30-37 Days 
Prior/concomitant medications 
7.3.2 
X 
X 
X 
Review to ensure no prohibited medications are 
being used.  Provide data to sponsor in regard to 
SAEs only. 
Study drug dispensing 
7.10.1 
X 
 
 
 
Assess compliance 
7.10.1.3 
7.10.1.6 
X 
X 
 
 
Distribute reminders 
7.10.2 
X 
X 
 
 
Laboratory tests 
Table 10  
X 
X 
X 
Performed at each site as per standard of care and 
monitored per investigator discretion. 
AEs/SAEs 
7.4.1  
X 
X 
X 
AEs that lead to the discontinuation of study 
treatment and all SAEs must be recorded in the 
CRFs, regardless of the causal relationship. 
Radiographic tumor assessments 
7.5.1  
 
 
 
Performed per standard-of-care guidelines. 
a Information related to concomitant medications and adverse events may also be collected between the required clinic visits (eg, by phone or email). 
Table 10: 
Schedule of Laboratory Assessments for Ongoing Subjects in All Cohorts Upon Implementation of Protocol 
Amendment 10 
Local Laboratory Tests 
Section 
At Least Every 12 Weeks 
in Clinic 
EOT 
Follow-Up 
Details 
EOT + 30-37 Days 
Serum chemistries 
N/A 
X 
X 
X 
Performed at each site as per standard of care and 
monitored per investigator discretion. 
Hematology 
N/A 
X 
X 
X 
Performed at each site as per standard of care and 
monitored per investigator discretion. 
 
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Table 11: 
Local Laboratory Tests:  Required Analytes (Not Applicable After Implementation of Protocol Amendment 10) 
Serum Chemistries 
Hepatitis Screening 
Hematology 
Urinalysis 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Blood urea nitrogen 
Calcium 
Bicarbonate 
Chloride 
Creatinine 
Glucose 
CRP (normal range) 
LDH 
Magnesium 
Phosphate  
Potassium  
Sodium  
Total bilirubin  
Direct (conjugated) bilirubin 
(required only if total bilirubin 
is abnormal) 
HBs Ag 
Anti-HB core total 
HCV antibody 
HCV-RNA 
HBV-DNA 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
Differential cell count: 
• Basophils 
• Eosinophils 
• Lymphocytesa 
• Monocytes 
• Neutrophilsa 
 
Color/appearance 
pH 
Specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Blood 
Protein 
Microscopic analysis 
PT 
PTT 
INR 
Females Only 
FSH 
Serum pregnancy 
Serum Chemistries 
Immunophenotyping 
Total serum protein 
Total cholesterol 
Pre-albumin 
 
Immunophenotyping 
(see Section 7.5.4) 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based upon emerging safety data. 
a Absolute values must be provided for lymphocytes and neutrophils. 
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6.1. 
Screening Phase 
The screening phase is the interval between the signing of the ICF and the day the subject is 
enrolled in the study (Cycle 1 Day 1).  Informed consent must be obtained before performing any 
study-specific procedures.  Assessments that are required to demonstrate eligibility may be 
performed over 1 or more days during this phase.  The maximum screening period is 30 days. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment/administration of study drug.  Tests with results that fail eligibility requirements may 
be repeated once during the screening phase if the investigator believes the results to be in error 
or not representative.  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).  Subjects will be assigned a new subject ID. 
Additionally, the screening phase will be used to determine the baseline assessments of clinical 
condition and disease status.  Tumor assessments appropriate to the type of malignancy will be 
performed and recorded in the CRF. 
6.2. 
Treatment Phase 
The treatment phase begins on the day the subject is enrolled in the study and receives the first 
dose of study drug; this is defined as Cycle 1 Day 1.  Dates for subsequent study visits will be 
determined based on this day and should occur within 3 days (±) of the scheduled date unless 
delayed for safety reasons.  At Cycle 1 Day 1, results from screening visit evaluations should be 
reviewed to determine if the subject continues to meet the eligibility requirements as specified in 
the Protocol. 
During the treatment phase, regular study visits (physician visits) will occur as described in the 
schedule of assessments for the appropriate part of the study. 
At certain study visits as indicated in the laboratory assessment tables above, subjects will attend 
the study visit having fasted overnight, having recorded the time of the prior study drug 
administration, and having withheld the morning dose of the study drug.  At these visits, PK 
 
 sampling will be conducted. 
6.3. 
End of Treatment 
If a decision is made that the subject will withdraw from study participation, the EOT visit 
should be conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT visit in the 
CRF.  The subject should be encouraged to return for the follow-up visit. 
6.4. 
Follow-Up Phase 
The follow-up phase is the interval between the EOT visit and the scheduled follow-up visit, 
which should occur 30 to 37 days after the EOT visit (or after the last dose of study drug if the 
EOT visit was not performed).  Adverse events and SAEs must be reported up until at least 
30 days after the last dose of study drug, until the date of the follow-up visit, or until study 
drug-related toxicities resolve, return to baseline, or are deemed irreversible, whichever is longer.  
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Reasonable efforts should be made to have the subject return for the follow-up visit, and report 
any AEs that may occur during this phase. 
Subjects are required to remain on PJP prophylaxis for at least 2 to 6 months after the last dose 
of study drug (see Section 5.8.2) and should be reminded of this at the safety follow-up visit.  
Sites should follow up with subjects to confirm that they have been compliant with the 
prophylactic treatment for the duration of this period. 
6.5. 
Unscheduled Visits 
Unscheduled visits may occur at any time as medically warranted.  Visits where study drug is 
held are considered unscheduled visits.  Any assessments performed at those visits should be 
recorded in the CRF. 
6.6. 
Early Termination 
Not applicable. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Required assessments/procedures listed here will be captured on the CRF.  Subjects ongoing 
after implementation of Protocol Amendment 10 will only have assessments performed as 
indicated in Table 9 and Table 10 and at a frequency determined by the investigator as guided by 
the standard of care.  Unless noted below, procedures listed in this section are not required to 
be performed or collected on the CRF after implementation of Amendment 10. 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures.  The granting of informed consent for study participation must be 
documented in writing using an ICF that contains all of the 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; a copy of the signed ICF must be provided to the study subject.  Subjects of 
childbearing potential must agree to take appropriate measures to avoid pregnancy in order to 
participate in the study (Appendix A). 
7.2. 
Interactive Response Technology Procedure 
Not applicable. 
7.3. 
Demography, Medical History, Medication Usage 
7.3.1. 
Demographics and Medical History 
Demographic data and a complete medical and medication history will be collected at screening.  
This will include complete documentation of the history of medical or surgical treatment for the 
malignancy under study.  Note:  For subjects with DLBCL, the DLBCL subtype (eg, GCB) 
should be known at study entry and will be collected at screening. 
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7.3.2. 
Prior/Concomitant Medications 
Prior and/or ongoing medications will be reviewed during screening to determine study 
eligibility and will continue to be recorded throughout the duration of the study.  The medication 
record will be maintained after enrollment as a documentation of concomitant medications, 
including any changes to the dose or regimen.  Prior/concomitant medications include any 
prescription, over-the-counter, or natural/herbal preparations taken or administered during 
30 days before Cycle 1 Day 1 and throughout the study period. 
Upon implementation of Amendment 10, use of concomitant medications should be monitored to 
verify that subjects are not taking any concomitant medication prohibited per Protocol 
(Section 5.10). 
7.4. 
Safety Assessments 
Upon implementation of Amendment 10, only safety assessments (including laboratory analytes) 
that are consistent with standard of care and monitoring should be performed per the 
investigator's discretion.  Subjects must be taken off study treatment if, in the opinion of the 
investigator, an unacceptable toxicity develops. 
7.4.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs informed consent.  Subjects 
will be instructed to report all AEs during the study and subjects 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 CRFs 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. 
Upon implementation of Amendment 10, AEs that lead to the discontinuation of study treatment 
and all SAEs must be recorded in the CRFs, regardless of the assumption of a causal relationship 
with the study drug(s). 
7.4.2. 
Comprehensive Physical Examination 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, Physician's Assistants, or an advanced Registered Nurse Practitioner, as local law 
permits. 
The comprehensive physical examination will include the following organ or body system 
assessments:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen 
(liver, spleen); extremities, lymph nodes, and a brief neurological examination.  The screening 
physical examination should also include a measurement of height and body weight. 
7.4.3. 
Targeted Physical Examination 
A targeted physical examination must include a measurement of the subject's body weight, 
examination of the abdomen (liver, spleen), and evaluation of any AEs or any previously 
reported symptoms or prior physical examination findings. 
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7.4.4. 
Vital Signs 
Vital sign measurements (blood pressure, heart rate, and body temperature) will be taken with 
the subject in the recumbent, semirecumbent, or sitting position after 5 minutes of rest. 
7.4.5. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest.  The 12-lead ECGs will be interpreted by the investigator at the site and 
will be used 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 
Meaningful" is the responsibility of the investigator, in consultation with the sponsor's medical 
monitor, as appropriate. 
7.4.5.1. 
Timed Electrocardiograms 
Timed triplicate (separated by 5 minutes) ECGs will be performed at Cycle 1 Day 1 and Cycle 1 
Day 15.  ECGs will be conducted predose and will be conducted in conjunction with the 2-hour 
and 4-hour PK timepoints (Section 7.7.1).  ECGs should be conducted before but within 
30 minutes of the PK blood draw at the corresponding timepoint.  The specified postdose 
timepoint may be adjusted based on emerging PK data. 
7.4.6. 
Laboratory Assessments 
A laboratory local to the study site and subject will perform all clinical laboratory assessments 
for safety.  The investigative site will enter the laboratory results and laboratory normal ranges 
into the CRF.  Hematology, serum chemistry, and urinalysis should be performed using standard 
procedures on the days indicated in Table 6 and Table 8 where required tests are shown. 
Upon implementation of Amendment 10, laboratory assessments (Table 10) only need to be 
performed in accordance with standard of care at each investigational site and monitored as per 
the investigator’s discretion.  Laboratory results do not need to be reported in the CRF, but all 
laboratory results corresponding with an SAE must be reported on the SAE form. 
7.4.6.1. 
Chemistry 
A panel of serum chemistries will be performed as indicated in Table 6 and Table 8; analytes 
required for this panel are listed in Table 11. 
7.4.6.2. 
Hematology 
Hematology will be performed as indicated in Table 6 and Table 8; required analytes are listed in 
Table 11. 
7.4.6.3. 
Urinalysis 
Complete urinalysis will be performed at screening and as indicated in Table 6 and Table 8; 
required analyses are listed in Table 11. 
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7.4.6.4. 
Coagulation Panel 
A coagulation panel will be run as indicated in Table 6 and Table 8.  Required analytes are listed 
in Table 11. 
7.4.6.5. 
Fertility Testing 
Female subjects who report being amenorrheic for ≥ 1 year will have FSH tested to confirm 
hormonal menopause; a result of > 30 IU/L will be considered confirmatory.  Female subjects 
must be either confirmed postmenopausal or surgically sterile, OR must be advised on acceptable 
methods that have been determined to be more than 99% effective in avoiding pregnancy 
(Appendix A). 
7.4.6.6. 
Pregnancy Testing 
A serum pregnancy test will be required for all female subjects of childbearing potential at 
screening and follow-up.  Pregnancy tests will be conducted only as medically indicated during 
study treatment. 
7.4.6.7. 
Hepatitis Screening 
Hepatitis screening assessments will be performed at the screening visit (Table 6 and Table 8) to 
rule out hepatitis infection; required analytes are shown in Table 11.  Additional tests may be 
performed if clinically indicated. 
7.5. 
Efficacy Assessments 
An objective assessment of disease status is required at baseline (screening) using a method that 
is appropriate for disease subtype, per established and modified guidelines (Hallek et al 2008, 
Cheson et al 2014, Cheson et al 2012, Owen et al 2013).  Disease status will be assessed by the 
site every 9 weeks (3 cycles) after Cycle 1 Day 1 or at a frequency consistent with the standard 
of care for the subject's disease.  For subjects in Part 3 Expansion Cohorts, the sponsor may also 
have disease status assessed by a central imaging vendor. 
7.5.1. 
CT Scan or MRI 
Subjects with applicable disease types will undergo CT or magnetic resonance imaging (MRI) to 
evaluate measurable disease during the screening phase.  If CT/MRI 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 CRF in lieu of a study-specific assessment.  
On-treatment assessments (for subjects with disease measurable by CT or MRI) should be 
performed at least every 9 weeks (3 cycles) after Cycle 1 Day 1 or at a frequency consistent with 
the standard of care for the subject's disease.  Investigators may have subjects assessed for 
response earlier than the every-9-week frequency if clinically indicated in discussion with the 
sponsor. 
Upon implementation of Amendment 10, CT/MRI assessments are only required to be 
performed as per standard of care guidelines and monitored.  Subjects must be taken off study if, 
in the opinion of the investigator, the disease has progressed and the subject is no longer having 
clinical benefit from the study treatment. 
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7.5.2. 
FDG-PET or Combined PET-CT 
If positron emission tomography (PET) using [18 F] fluorodeoxyglucose (FDG) 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 (eg, in subjects with HL or DLBCL), the results obtained during 
any study phase will be captured in the CRF. 
7.5.3. 
Bone Marrow Examination 
Bone marrow examination is required as a baseline assessment for subjects with disease subtypes 
that utilize bone marrow histology as part of the objective criteria for disease staging except in 
the following circumstances or with approval of the medical monitor: 
• Subject had a bone marrow examination performed as per standard of care prior to 
60 days of the first dose of study drug. 
• Subject had a bone marrow examination performed after the last treatment for the 
lymphoid malignancy and the results showed involvement of the bone marrow. 
• Baseline PET scan shows that the subject does have FDG-avid disease in the bone 
marrow (PET + bone marrow). 
Subsequently, bone marrow biopsy will be performed only to confirm CR or as clinically 
indicated.  If the bone marrow does not have lymphoma involvement at baseline, a repeat bone 
marrow examination is not required to confirm indication of CR on imaging. 
Data from the pathology report result from the bone marrow examination will be captured in the 
CRF.  Results of assessments performed under standard of care before the signing of the ICF 
may be used as the baseline assessment in lieu of a study-specific procedure IF performed within 
60 days of the first dose of study drug (Cycle 1 Day 1). 
All bone marrow examinations should include a unilateral aspiration and biopsy, when feasible.  
Subjects may be enrolled based on a biopsy only, when a "packed marrow" precludes aspiration.  
An aspiration only may be performed at the discretion of the investigator. 
7.5.4. 
Immunophenotyping 
Immunophenotyping results for all subjects will be collected at baseline.  For subjects with CLL 
or other B-cell malignancy with circulating tumor cells, lymphocyte immunophenotyping 
(Table 6) will be conducted by flow cytometry at the local laboratory at screening and Cycle 2 
Day 1, and at subsequent times only as part of confirmation of CR.  Results will be captured in 
the CRF. 
7.5.5. 
Immunoglobulin M Monitoring 
Subjects with WM should have their disease assessed by IgM monitoring of blood serum at 
baseline (C1D1) and at least every 9 weeks for response assessment per the response criteria 
defined by Owen et al (2013).  This assessment should be performed locally. 
7.6. 
Performance Status 
Eastern Cooperative Oncology Group performance status (Appendix C) must be assessed by a 
medically qualified individual and recorded in the CRF at visits indicated in Table 5. 
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7.7. 
Pharmacokinetic Assessments 
7.7.1. 
Blood Sample Collection 
Pharmacokinetic samples will be obtained at the visits indicated in Table 6 and Table 8 
(Laboratory Assessments) for all subjects enrolled in this study; collection times and windows 
are described below.  The exact date and time of the PK blood draws will be recorded in the CRF 
along with the date and time of the last dose of study drug preceding the blood draw and the time 
of the most recent meal.  Instructions for sample preparation and shipping will be provided in the 
Laboratory Manual.  Subjects will receive reminder cards in advance of the study visit providing 
instruction to hold the morning dose of study drug on the day of the visit, and a place to record 
the time of the prior dose of study drug, and time of the most recent meal or snack consumed. 
On Cycle 1 Day 1, study subjects should have fasted overnight; the clinic visit should be 
scheduled in the morning.  For subjects receiving INCB050465 monotherapy only, a predose PK 
sample will be taken, followed by administration of the INCB050465 only.  For subjects 
receiving the combination with INCB050465, administration of INCB039110 should be started 
on Day 1 after INCB050465 PK sampling is complete in Part 2 and Part 3 Cohort E.  On Cycle 1 
Day 1, subjects should arrive at the clinical after an overnight fast; the clinic visit should be 
scheduled in the morning.  Pharmacokinetic blood samples will be obtained at the times shown 
in Table 12. 
On Cycle 1 Day 8 (only for Parts 1, 2, and 3), subjects will refrain from taking study drug in the 
morning before arriving at the research unit.  A trough (predose) PK sample will be taken, 
followed by administration of the study drug.  Overnight fasting is not required. 
On Cycle 1 Day 15, subjects will refrain from taking the study drug in the morning before 
arriving at the research unit.  Subjects should have fasted overnight; the clinic visit should be 
scheduled in the morning, and a trough PK sample should be drawn early in the study visit.  The 
initial schedule for timed postdose samples is shown in Table 12. 
In the 15-subject expansion Cohort A, if the dose selected was the MTD in the dose-escalation 
part of the study, on Cycle 1 Day 15 and Cycle 2 Day 1, the dose administered ONLY for these 
2 doses will be 1 dose level below the MTD.  If the PAD is selected for the expansion cohort, 
there will be no alteration to the doses on Cycle 1 Day 15 or Cycle 2 Day 1. 
Table 12: 
Pharmacokinetic Blood Sampling Schedule 
  
Predose 
Postdose 
0.5 hr 
1 hr  
± 15 min 
2 hr 
± 15 min 
4 hr 
± 15 min 
6 hr 
± 30 min 
8 hr 
± 30 min 
12 hr 
± 30 min 
(if possible) 
C1D1 
X 
X 
X 
X 
X 
X 
X 
X 
C1D8
a 
X 
 
 
 
 
 
 
 
C1D15 
X 
X 
X 
X 
X 
X 
X 
X 
C2D1
b 
X 
X 
X 
X 
X 
X 
X 
X 
a Cycle 1 Day 8 only required for subjects enrolled in Parts 1, 2, and 3. 
b Cycle 2 Day 1 only required for subjects enrolled in the food-effect expansion cohort. 
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On Cycle 2 Day 1, study subjects in the expansion Cohort A only will be required to undergo PK 
testing after fed administration on Cycle 2 Day 1 only. 
• PK testing conducted on Cycle 2 Day 1 will be similar to that on Cycle 1 Day 15 in 
respect to the timing of sample collection and evaluations.  Subjects may be excused 
from the food-effect portion of the study if they are unable to consume the meal or 
feel they are unable to consume the meal. 
• Subjects receiving INCB050465 in the fed state 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 
− and 8 oz whole milk 
• Alternative menus with the same caloric and fat content may be substituted with the 
prior approval of the study sponsor. 
For fasting subjects, a single dose of the study medication will be taken with 240 mL of water.  
Subjects will remain fasting and sitting or semirecumbent for 3 hours postdose, after which point 
a meal may be served.  Subjects will abstain from water for 1 hour postdose. 
Adjustments to the timing of blood sampling postdose may be made based on emerging PK data; 
however, no more than 8 postdose timepoints will be used, and the maximum scheduled 
timepoint will be no greater than 12 hours postdose.  If possible, food should be withheld until 
1 hour after study drug administration.  
 
  Subjects 
who meet criteria in Section 5.6.1 for intrasubject dose escalation must agree to perform full PK 
sampling during the first cycle treated at the higher dose level on Day 15. 
7.7.2. 
Urine Sample Collection 
Urine will be collected from each subject on Cycle 1 Day 15 after morning dose and a predose 
void.  A complete urine output collection will be collected from hour 0 (after morning dose) 
through  8 hours after the first dose of study drug or through 12 hours after the morning dose if a 
12-hour postdose PK sample is being performed.  The time period and cumulative volume will 
be recorded and 2 aliquots will be provided to the sponsor according to the instructions provided 
in the Laboratory Manual.  Urine output will be stored under refrigeration (5ºC) during the 
collection interval. 
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7.7.3. 
Bioanalytical Methodology and Analysis 
The plasma and urine samples will be analyzed for INCB050465 and INCB039110 by a 
validated assay and will be collected from all subjects enrolled in this study. 
 
 
 These samples will be analyzed by Incyte Corporation 
(Wilmington, DE) or its designee. 
For each subject who completes study participation, PK parameters will be calculated from the 
plasma concentrations of INCB050465 and INCB039110 according to the model independent 
approach.  Refer to Appendix B for a detailed list and description of the PK parameters. 
7.7.4. 
Pharmacokinetic Analysis 
The PK 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 > 5 minutes for 
samples collected up to 4 hours after administration and greater than 15 minutes for samples 
collected more than 4 hours after administration; in these cases, actual time will be used for PK 
analysis.  Additional details of analyses will be described in the Statistical Analysis Plan. 
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7.10. 
Other Study Procedures 
7.10.1. 
Drug Administration 
After implementation of Amendment 10, subjects will be dispensed the appropriate amount of 
medication to self-administer study drug as per protocol until their next scheduled visit 
(scheduled no more than 12 weeks later).  Subjects will continue to self-administer study 
medication, and compliance will continue to be assessed for INCB050465 and INCB039110. 
7.10.1.1. Administration of INCB050465 
Based on emerging PK and food-effect data (see Section 1.2.4 and the INCB050465 IB), 
subjects will self-administer INCB050465 tablets orally with water without regard to food, as 
directed by the investigator.  For QD or once-weekly intervals, INCB050465 should be taken , at 
approximately the same time each day.*  If BID doses are used, INCB050465 should be taken 
morning and evening at approximately 12-hour intervals. 
* NOTE:  Updated advice will be provided if emerging PK and food-effect data suggest that 
an improved PK profile may be achieved by administering INCB050465 with food or if food 
does not have a significant effect on the INCB050465 PK. 
INCB050465 will be administered in the study clinic on days indicated in Table 5 and Table 7, 
and in Section 7.7.1.  Subjects will attend the study visit having fasted overnight (for Cycle 1 
Day 1 and Cycle 1 Day 15 for all subjects and also at Cycle 2 Day 1 for subjects participating in 
the food-effect study in Part 3 Expansion Cohort A), recorded the time of the prior 
administration of INCB050465 and time and content of prior meal, and having withheld the 
morning dose of INCB050465.  At this visit, PK 
 sampling will be conducted. 
7.10.1.2. Dispensing of INCB050465 
An initial bulk supply of INCB050465 tablets will be provided to investigative sites before 
enrollment of the first subject.  Thereafter, the site staff will contact the sponsor for resupply of 
INCB050465.  When dispensing to subjects, the investigator or designee will remove the 
appropriate quantity of INCB050465 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 
Pharmacy Manual. 
7.10.1.3. Assessment of Compliance With INCB050465 
The study subject will return to the clinic with full, empty, and partially full bottles of 
INCB050465 tablets at the beginning of each treatment cycle or at routine visits or every 
12 weeks or as defined by standard of care, and a compliance check (tablet count) will be 
performed by the clinic staff.  Appropriate steps should be taken to optimize compliance. 
7.10.1.4. Administration of INCB039110 
Subjects will self-administer INCB039110 orally, with water, according to a QD regimen as 
directed by the investigator.  INCB039110 should be taken on an empty stomach if possible 
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(refrain from food consumption during the period 2 hours before and 1 hour after INCB039110 
administration) and can be administered at the same time as INCB050465.  INCB039110 should 
be administered in the morning. 
INCB039110 will be administered in the study clinic as indicated in Table 5; subjects will attend 
the study visit having fasted, recorded the time of the prior administration of INCB039110 and 
prior meal, and having withheld the morning dose of INCBC039110.  At this visit, PK 
 
sampling will be conducted.  INCB039110 dose administration will be started on Cycle 1 Day 1 
after INCB050465 PK sampling is complete. 
7.10.1.5. Dispensation of INCB039110 
For subjects enrolled in either Part 2 or Part 3 Expansion Cohort E, an initial bulk of 
INCB039110 will be provided to investigative sites prior to enrollment of the first subject.  
Thereafter, the site staff will contact the sponsor for resupply of INCB039110.  When dispensing 
to subjects, the investigator or designee will remove the appropriate quantity of INCB039110 
from their stock, dispense the medication, and enter the amount dispensed into the CRF and drug 
accountability log.  Full details will be provided in the Study Manual. 
7.10.1.6. Assessment of Compliance With INCB039110 
For subjects enrolled in either Part 2 or Part 3 Expansion Cohort E the study subject will return 
to the clinic with full, empty, and opened/partially used bottles of INCB039110 at the beginning 
of each treatment cycle or at routine visits or every 12 weeks or as defined by standard of care, 
and a compliance check (tablet count) will be performed by the clinic staff.  Appropriate steps 
should be taken to optimize compliance. 
7.10.1.7. Sourcing and Administration of Standard of Care Agents 
The standard of care agents described above will be supplied by the site.  These agents are all 
administered by intravenous infusion in clinic. 
7.10.1.8. Assessment of Compliance With Standard of Care Agents 
The site will document the amount of infusion administered to the subject at each appropriate 
visit.  This information will be captured in the eCRF. 
7.10.1.9. Administration of Supportive Care 
Supportive care, including GCSF for treatment of chemotherapy-induced neutropenia, will be 
supplied by the institution's pharmacy and administered according to the package insert and 
institutional guidelines. 
7.10.2. 
Distribution of Subject Reminder Cards/Subject Diaries 
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.  Reminder cards will include instructions specific 
for Day 8 and Day 15 study visits, at which time the subject will refrain from taking the study 
drug at home in the morning before the clinic visit.  All necessary instructions, such as 
administration instructions for study drug, concomitant medications, and reminders of visits to 
conduct laboratory tests, should be provided to the subject in writing on this reminder card, or on 
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accompanying written materials.  Subject diaries will be provided for the purpose of 
documenting study drug administration and AEs.  The subject diary will have an area on which 
the date and time of the last dose taken before each visit will be recorded as well as the time (and 
content if applicable to the visit) of the last meal. 
After implementation of Amendment 10, subjects will receive reminder cards that will include 
the date and time of the next visit and instructions for study treatment administration. 
8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions and Reporting 
For the purposes of this Protocol, an AE is defined as the appearance of (or worsening of any 
pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occur 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). 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events page of the CRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History page of the CRF.  Adverse event monitoring 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. 
Adverse events will be assessed according to the CTCAE version 4.03.  The CTCAE severity 
Grade 5 (death) will not be used in this study; rather, information about deaths will be collected 
as an outcome of the event.  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.   
As far as possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Reasonable possibility that the AE is related to the study treatment:  unrelated (no) or 
related (yes). 
− NOTE: for subjects receiving combination therapy, causality assessment for 
each agent administered per study must be indicated. 
• Start and end dates, unless unresolved at final examination. 
• Action taken with respect to study drug (eg, none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable). 
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• Outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• Whether it is serious, as per serious adverse event (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 a concomitant medication or nondrug therapy is 
given, this action should be recorded on the AE and Prior/Concomitant medications pages of the 
CRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
Disease progression should not be regarded or reported as an AE itself, unless it is associated 
with a separate AE. 
Upon implementation of Amendment 10, AEs leading to treatment discontinuation and all SAEs 
regardless of causal relationship must be reported on the AE CRF. 
8.2. 
Laboratory Test Abnormalities 
8.2.1. 
Definitions and Reporting 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug), should be recorded on the AE page of the CRF.  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, as per CTCAE, does not automatically indicate an SAE unless it 
meets the definition of serious, as defined in Section 8.3.1, and/or per the investigator's 
discretion.  A dose interruption or adjustment for the laboratory abnormality may be required 
(see Section 5.6) and should not contribute to the designation of a laboratory test abnormality as 
an SAE. 
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8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
A SAE is defined as an event that meets 1 of the following criteria: 
• Is fatal or life-threatening (ie, immediate risk of dying). 
• Results in persistent or significant disability or incapacity. 
• Constitutes a congenital anomaly or birth defect. 
• Is clinically meaningful (ie, defined as an event that jeopardizes the subject or 
requires potential medical or surgical intervention to prevent 1 of the outcomes listed 
above).  Considered meaningful by the investigator as an important medical event 
that may not result in death, be life-threatening, or require hospitalization, but may be 
considered a SAE when, based upon appropriate medical judgment, it may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the 
outcomes listed in this definition. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition 
− Elective or preplanned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF. 
− Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 
− Social reasons and respite care, in the absence of any deterioration in the subject's 
general condition. 
− Any SAEs that are expected due to the condition being treated, including if the 
SAE is a primary outcome measure, or where there has been a clear agreement 
with regulators not to consider these as SAEs, provided the information is 
collected elsewhere. 
8.3.2. 
Reporting 
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has signed the ICF and up to the last study visit, or up to 30 days after the subject has 
stopped study treatment, whichever is later, must be reported to the sponsor (or designee) within 
24 hours of learning of its occurrence.  Any SAEs experienced after this period should be 
reported to the sponsor (or designee) only if the investigator suspects a causal relationship to the 
study drug.  Recurrent episodes, complications, or progression of the initial SAE must be 
reported as the follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information.  An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new event.  
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Previously planned (before providing informed consent) surgeries should not be reported as 
SAEs unless the underlying medical condition worsens over the course of the study. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form.  The investigator must assess and record the relationship of each SAE to each specific 
study drug (if there is more than 1), complete the SAE Report Form in English, and send the 
completed, signed form by fax within 24 hours to the sponsor or its designee.  The investigator 
must assess if there is a reasonable possibility that the SAE is related to the study treatment:  
unrelated (no) or related (yes). 
Serious AEs related to unblinded comparator drugs or concomitant medications/drug delivery 
systems are reported directly to the manufacturers of those drugs/devices in accordance with the 
package insert. 
The telephone and facsimile number of the sponsor's contact persons, specific to the study, are 
listed in the investigator folder provided to each site.  The original copy of the SAE Report Form 
and the fax confirmation sheet must be kept with the CRF documentation at the study site. 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report.  Each recurrence, complication, or progression of 
the original event should be reported as a follow-up to that event regardless of when it occurs.  
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the subject continued or withdrew from study participation, or if 
study drug was interrupted or discontinued. 
If the SAE is not previously documented in the IB for the study drug (new occurrence) and is 
thought to be related to the sponsor's study drug, a sponsor's associate may urgently require 
further information from the investigator for reporting to health authorities. 
The sponsor or its designee may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same drug that this SAE has been reported.  
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC, or as per national regulatory requirements in participating countries. 
Upon implementation of Amendment 10, all SAEs regardless of causal relationship will be 
reported as described above. 
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, the following procedures should occur: 
• The investigator must notify the sponsor or its designee immediately. 
• The study drug must be discontinued immediately. 
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• The subject must be withdrawn from the study. 
• The EOT visit evaluations must be performed. 
• The investigator must complete and submit the Pregnancy Initial and Follow-Up 
Report forms to the sponsor or its designee. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
(The serum test should be performed at the investigative site to ensure the test will be 
performed promptly and the result available immediately for review.) 
If a negative serum test does not confirm the urine pregnancy test result, then: 
• The investigator will use his or her expert judgment, based on an assessment of the 
potential benefit/risk to the subject, to determine if it is in the subject's best interest to 
resume study drug and continue participation in the study. 
To ensure subject safety, each pregnancy in a subject during maternal or paternal 
exposures to study drug must be reported within 24 hours of learning of its occurrence.  
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up to each pregnancy should be conducted 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 Study Pregnancy 
Form and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the sponsor's study drug of any pregnancy outcome and follow-up to the first 
well-baby visit.  Any SAE experienced during pregnancy must be reported on the SAE 
Report Form and to the sponsor or its designee. 
8.6. 
Warnings and Precautions 
No evidence available at the time of the approval of this study Protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided IB.  Additional 
safety information collected between IB updates will be communicated in the form of 
Investigator Notifications (INs).  Any important new safety information should be discussed with 
the subject during the study as needed.  If new, significant risks are identified, they will be added 
to the ICF. 
8.7. 
Data Monitoring Committee 
A formal Data Monitoring Committee will not be used for this study.  The sponsor will 
continuously monitor safety through frequent contact with the treating investigators, review of 
the clinical data, and formal study meetings.  Routine teleconferences will be held among 
participating study sites to provide subject-by-subject updates on current study status, interim 
toxicities reported, and any other pertinent information.  Adverse event and laboratory data 
entered into the clinical database will be reviewed periodically for trends and evolving safety 
signals.  Lastly, formal review meetings will be conducted with investigators during the study to 
establish consensus on the safety and tolerability of a given dose. 
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8.8. 
Adverse Events of Special Interest 
INCB050465 is a potent and selective PI3Kδ inhibitor, which is a key target in the BCR survival 
pathway in normal and malignant B-lymphocytes.  In animal studies, lymphoid depletion was 
observed and may also occur in humans.  This may result in infections, fever, or cytokine release 
resulting in fever, chills, hypotension, wheezing, and/or rash.  Reversible minimal to mild 
hypospermatogenesis was observed in rats at doses that exceed the intended starting clinical dose 
and anticipated therapeutic dose in humans.  For additional information on the risks of treatment 
with INCB050465 and INCB039110, see Sections 1.2.3, 1.3.5, and 1.4.4.  
8.9. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint and any associated AEs via email or other written communication to the 
Incyte contact. 
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: 
• Intent-to-treat (ITT) population/safety population:  Subjects enrolled in the study 
who received at least 1 dose of INCB050465, INCB039110, rituximab, ifosfamide, 
carboplatin, and/or etoposide. 
• Per-Protocol (PP) population:  Subjects in the ITT/safety population who are 
sufficiently compliant with the Protocol.  Details will be provided in the SAP.  
• PK
population:  Subjects in the ITT/safety population who had PK
data. 
The ITT/safety population will be used for the summary of baseline, disposition, efficacy, and 
safety analyses.  The PP population may be used in the sensitivity analysis of efficacy endpoints.  
The PK
population will be used in the summary of all PK
data. 
9.2. 
Selection of Sample Size 
The total sample size estimate is up to approximately 150 subjects in this study.  Approximately 
20 subjects will be enrolled in Part 1 monotherapy dose escalation, and approximately 
12 subjects will be enrolled in Part 2 combination dose escalation.  Expansion Cohort A will 
enroll between 15 and 30 subjects, and Cohorts B, C, D, and E will enroll up to 15 subjects each.  
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In Part 6, up to 12 subjects will be enrolled in the safety evaluation followed by an expansion 
cohort of up to15 subjects.  The exact number of subjects treated will depend on the number of 
subjects required per dose level and the number of dose levels studied.  During the 3 + 3 dose 
escalation in Part 1 and Part 2, the probabilities of dose escalation from that dose level for 
various DLT rates are given in Table 13. 
Table 13: 
Probability of Dose Escalation for Specific Dose-Limiting Toxicity Rates 
During 3 + 3 Dose Escalation 
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% 
Note that if escalation occurs at the highest dose level during the study, then the MTD is at or 
above the last dose level.  If the study stops at the first dose, then the MTD is below the first dose 
level.  In either of these cases, the prescribed doses may need to be altered in order to determine 
the MTD. 
In the expansion cohorts the evaluation of 15 subjects, each will provide a ≥ 90% chance of 
identifying a toxicity with a true event rate of 15%.   
9.3. 
Level of Significance 
No hypothesis is being tested in the study.  All CIs will be 95%. 
9.4. 
Statistical Analyses 
9.4.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; Version 9 or later) will be 
used for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
Data will be summarized overall and by treatment cohorts based on the dose regimen initially 
assigned.  In the event that several dose regimens tested are deemed substantially below the 
MTD, these doses may be combined for summary purposes. 
9.4.2. 
Efficacy Analyses 
The efficacy endpoints will be analyzed using the ITT and the PP populations. 
Response status per investigator's assessment will be categorized at each response assessment 
visit as CR, very good partial response (VGPR; only among subjects with WM), partial response 
(PR), minor response (MR; only among subjects with WM), stable disease (SD), progressive 
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disease, or not evaluable (NE) per published criteria for lymphoma (Cheson et al 2014, 
Owen et al 2013 for WM) and CLL (Hallek et al 2008, Cheson et al 2012).  In the unlikely 
situation that the subject does not have any disease at baseline, the best response will be denoted 
as no disease (ND). 
Best overall response is the best response recorded during the study treatment before and 
including the first progressive disease, in the order of CR, PR, SD, progressive disease, NE, and 
ND. 
A subject is considered an objective responder if they have a best overall response of CR or PR 
for lymphoma or CR, VGPR, PR, or MR for WM.  The ORR is the proportion of objective 
responders.  Subjects who do not have sufficient baseline or on-study response assessment 
information to be adequately assessed for response status will be included in the denominators in 
the calculation of ORR.  ORR will be estimated with 95% CI, which will be calculated based on 
the exact method for binomial distributions.  Best overall response will also be summarized. 
For subjects with CLL, changes in peripheral blood leukemic cells from baseline to each 
post-treatment assessment will be summarized with mean, median, standard error, and 95% CIs. 
For subjects with measurable lesions, target lesion sizes will be measured by sum of product of 
diameters (SPD).  The best percent change from baseline, defined as the largest decrease in SPD 
during study will also be summarized, and a waterfall plot of best percent change will be 
generated.  Note that for subjects who only have increases in SPD from baseline, the smallest 
increase will be considered as the best change from baseline. 
9.4.3. 
Safety Analyses 
The clinical safety data (vital signs, ECGs, routine laboratory tests, physical examinations, and 
AEs) will be summarized using descriptive statistics (eg, mean, frequency) using the safety 
population. 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique preferred terms reported on 
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relatively few subjects.  Unless otherwise stated, table summaries will be limited to AEs 
occurring within 30 days of the last administration of study medication. 
9.4.3.1. 
Adverse Events 
A treatment-emergent AE (TEAE) 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 TEAEs, but 
data listings will include all AEs regardless of their timing to study drug administration. 
Unresolved missing onset date, causality, or severity will be handled according to the following 
rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
• A unresolved missing onset date will be considered treatment-emergent, with the 
following examples illustrating exceptions: 
− If the stop/resolution date is before the first dose date on Day 1, then the AE will 
be considered as not being treatment-emergent. 
− If both the month and day are missing, and the last day of the year is before the 
first dose date on Day 1, then the AE will not be considered treatment-emergent. 
− If only the day is missing, and the last day of the month is before the first dose 
date on Day 1, then the AE will not be considered treatment-emergent. 
− If only the day is missing, and the first day of the month is after the first dose date 
on Day 1, then the AE will be considered treatment-emergent. 
Adverse events will be coded to system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA®) coding dictionary.  Severity of AEs will be 
based on the NCI CTCAE version 4.03. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, the AE will be considered to be treatment-related. 
The number of subjects with DLTs during the first cycle of study medication and the type of 
DLT will be listed. 
An overall summary of AEs will include number (%) of subjects reporting any TEAEs, any 
DLTs in Cycle 1, any SAEs, any Grade 3 or 4 TEAEs, any treatment-related TEAEs, any fatal 
TEAE, any TEAEs leading to dose interruption/reduction/discontinuation, and any TEAEs 
leading to study discontinuation. 
Number (%) of subjects reporting any TEAEs, any SAEs, any Grade 3 or 4 TEAEs, any 
treatment-related TEAEs, any treatment-related SAEs, any treatment-related Grade 3 or 4 
TEAEs, any fatal TEAE, any TEAEs leading to dose interruption/reduction/discontinuation, and 
any TEAEs leading to study discontinuation will be tabulated by system organ class and 
preferred term.  Number (%) of subjects reporting any TEAEs and any treatment-related TEAEs 
will be tabulated by preferred term in decreasing order of frequency in the overall column, and 
by system organ class, preferred term, and maximum severity. 
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9.4.3.2. 
Clinical Laboratory Tests 
The SI unit will be used for all 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 assessed for severity based on NCI CTCAE version 4.03.  For specific 
laboratory parameters requiring clinical intervention to grade, the classification according to the 
quantitative component will be provided. 
For numeric laboratory values, baseline value, postbaseline value, change from baseline, and 
percent change from baseline will be summarized by visit. 
Shift summaries will be presented showing number and percentage of subjects with the 
laboratory values being low, normal, and high at baseline and at each of the scheduled 
postbaseline visits.  The denominator for the percentage calculation will use the number of 
subjects in the baseline category (ie, low, high, normal, missing). 
For the laboratory parameters that have CTCAE grading, shift tables will also be presented 
showing change in CTCAE severity grade from baseline to worst grade postbaseline.  Separate 
tables will be provided for selected laboratory tests that have grading criteria in both high and 
low directions.  All postbaseline values occurring within 30 days of last dose of study drug will 
be included when summarizing worst postbaseline grade.  The denominator for the percentage 
calculation will be the number of subjects in the baseline category. 
Categorical laboratory data will be tabulated by visit at baseline and postbaseline visits when 
necessary. 
9.4.3.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, heart rate, and body temperature) at each assessment time.  Criteria for clinically 
notable vital sign abnormalities are defined in Table 14.  The abnormal values for subjects 
exhibiting clinically notable vital sign abnormalities will be listed. 
Alert vital signs are defined as an absolute value outside the defined range and absolute 
percentage change greater than 25%.  The abnormal values for subjects exhibiting alert vital sign 
abnormalities will be listed. 
Table 14: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure  
> 155 mm Hg 
< 85 mm Hg 
Diastolic blood pressure  
> 100 mm Hg 
< 40 mm Hg 
Heart rate  
> 100 bpm 
< 45 bpm 
Temperature  
> 38°C 
< 35.5ºC 
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9.4.3.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Average of all values before the first dose of study drug will be used as 
the baseline value.  Criteria for clinically notable ECG abnormalities are defined in Table 15.  
The abnormal values for subjects exhibiting clinically notable ECG abnormalities will be listed. 
Alert ECG values are defined as an absolute value outside the defined range and absolute 
percentage change > 25% (30% for QRS) interval.  The abnormal values for subjects exhibiting 
alert vital sign abnormalities will be listed. 
Outliers of QT, QTcB, and QTcF, defined as absolute values > 450 milliseconds or change from 
baseline > 30 milliseconds, will also be listed. 
Table 15: 
Criteria for Clinically Notable ECG Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
9.4.4. 
Other Analyses 
 
 
 
  
 
 
 
• The PK parameters of INCB050465 and INCB039110 will be summarized by 
descriptive statistics by dose group and cohort.  The log-transformed PK parameters 
of INCB050465 will be compared among the dose levels by using a 1-factor analysis 
of variance (ANOVA).  Dose-dependent parameters (Cmax and AUC) will be 
normalized to the lowest common dose before statistical comparisons.  Cmax and AUC 
will be evaluated using a power model, eg, AUC = α∙(doseβ) or equivalently, 
log(AUC) = log(α) + β∙log(dose), where linear dose proportionality is accepted if β is 
not significantly different from 1.  Attainment of steady state will be assessed 
separately for each cohort by comparing trough plasma concentrations on Days 8 and 
15 during Cycle 1. 
• For the food-effect portion of the study, the log-transformed PK parameters of 
INCB050465 will be compared between the fed and fasted treatments using an 
ANOVA 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. 
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9.5. 
Data Monitoring Committee 
Not applicable. 
9.6. 
Interim Analysis 
Not applicable. 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Investigational Product Description – INCB050465 
10.1.1. 
Packaging, Labeling, and Preparation of Study Drug 
INCB050465 tablets are provided in high-density polyethylene bottles; no preparation is 
required.  All bottles of Incyte investigational product contain the following language:  "Caution:  
New Drug—Limited by Federal Law to Investigational Use." 
10.1.2. 
Formulation and Chemical Properties of INCB050465 
Physical and chemical properties of INCB050465 are summarized in the INCB050465 IB.  
INCB050465 is formulated as 2.5 and 5 mg tablets (free-base equivalent).  A tablet strength of 
20 mg may also be used depending on the dose escalation of INCB050465.   
10.1.3. 
Storage and Stability of INCB050465 
INCB050465 drug product should be stored under ambient conditions at 15°C to 30°C (59°F to 
86°F). 
10.2. 
Investigational Product Description – INCB039110 (Comedication 
for Part 2 and Expansion Cohort E) 
10.2.1. 
Packaging, Labeling, and Preparation of INCB039110 
INCB039110 is provided in high-density polyethylene bottles of 35 tablets; no preparation is 
required.  All bottles of Incyte investigational product contain the following language:  "Caution:  
New Drug—Limited by Federal Law to Investigational Use." 
10.2.2. 
Formulation and Chemical Properties of INCB039110 
Physical and chemical properties of INCB039110 are summarized in the INCB039110 IB.  
INCB039110 is formulated as 100 mg (free-base equivalent) SR tablets.  (The 100 mg 
formulation is referred to in the INCB039110 IB as SR3.) 
10.2.3. 
Storage and Stability of INCB039110 
The bottles of tablets should be stored under ambient conditions at 15°C to 30°C (59°F to 86°F).   
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10.3. 
Accountability, Handling, and Disposal of Study Drug 
Responsibility for drug accountability at the study site rests with the investigator; however, the 
investigator may assign some of the drug accountability duties 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 will be expected to collect and retain all used, unused, and partially 
used containers of study drug until the end of the study.  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. 
These records should include dates, quantities, batch or serial numbers (if available), and the 
unique code numbers (if available) assigned to the investigational product and study 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 correct 
study drug specified. 
Completed accountability records will be archived by the site.  At the completion 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 site destruction of investigational supply, prior written approval 
must be obtained from Incyte. 
11. 
STUDY ADMINISTRATION 
11.1. 
Data Management 
11.1.1. 
Data Collection 
The investigator will be provided with a CRF for each subject.  Entries made in the CRF must be 
verifiable against source documents; any discrepancies should be explained and documented.  
The investigator will be responsible for reviewing all data and CRF entries and will sign and date 
the designated pages in each subject's CRF, verifying that the information is true and correct.  
The investigator is responsible for the review and approval of all responses. 
11.1.2. 
Data Management 
Data management will be performed from CRFs.  All CRF data will be entered into a validated 
database.  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. 
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11.2. 
Study Monitoring 
Qualified representatives of the sponsor or its designee, "study monitors," will monitor the study 
according to a predetermined monitoring plan.  Monitoring visits provide the sponsor with the 
opportunity to: 
• Evaluate the progress of the study. 
• Verify the accuracy and completeness of CRFs. 
• Assure that all Protocol requirements, applicable laws and/or regulations, and 
investigator's obligations are being fulfilled. 
• Resolve any inconsistencies in the study records. 
The investigator must allow the study monitors to periodically review, at mutually convenient 
times during the study and after the study has been completed, all CRFs and office, hospital, and 
laboratory records supporting the participation of each subject in the study.  The CRFs and other 
documentation supporting the study must be kept up-to-date by the investigator and the research 
staff at the investigative site.  These study materials must be available for review by the study 
monitor, and/or other qualified representatives of the sponsor or its designee, at each monitoring 
visit. 
The study monitor will review the various records of the study (CRFs, subject medical and 
laboratory records, and other pertinent data).  The study monitor will verify the CRF data against 
original source documentation for accuracy and completeness.  The study monitor will identify 
data discrepancies and collaborate with the investigator and research staff to resolve the 
discrepancies in a timely manner.  Protocol deviations will also be identified and recorded on a 
"Protocol Deviation Log."  The study monitor will follow an "Issue Escalation" plan in order to 
ensure that each issue identified during a monitoring visit is appropriately documented, reported, 
and resolved in a timely manner in accordance with the plan's requirements. 
11.3. 
Protocol Adherence 
The principal investigator must obtain IRB or IEC approval for the investigation.  Initial IRB or 
IEC approval and all materials approved by the IRB or IEC for this study including the subject 
ICF and recruitment materials must be maintained by the investigator and made available for 
inspection. 
Each investigator must adhere to the Protocol as described in this document and agree that 
changes to the Protocol, with the exception of medical emergencies, must be discussed and 
approved, firstly, by the sponsor or its designee and, secondly, by the IRB or IEC.  Each 
investigator is responsible for enrolling subjects who have met the Protocol inclusion and 
exclusion criteria.  The IRB or IEC that granted original approval, or the IRB or IEC currently 
responsible for overseeing the conduct of the study, must be notified of all changes in and 
deviations from the Protocol that may increase risk to the subject, and/or that may adversely 
affect the rights of the subject or validity of the investigation.  The investigator must send a copy 
of the approval letter from the IRB or IEC to the sponsor or its designee and retain the original in 
the site study regulatory file. 
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Major eligibility deviations must be reported to the IRB or IEC in accordance with the IRB or 
IEC requirements.  During the course of the study, the monitor must notify the sponsor or its 
designee of subjects found not to have met eligibility criteria.  The medical monitor, in 
collaboration with the investigator, will determine if the subject should be withdrawn from the 
study. 
11.4. 
Financial Disclosure 
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, are 
required before study initiation to submit a completed clinical investigator Financial Disclosure 
Request 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.  These requirements 
apply to both US and foreign clinical investigators conducting covered clinical studies. 
Any new investigators or subinvestigators added to the covered clinical study during its conduct 
must also submit a completed clinical investigator Financial Disclosure Request 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 obligation to report to the 
sponsor or its designee any changes to the financial information previously reported.  The 
clinical investigators will also be reminded that they must report any changes in their financial 
information for a period of 1 year after completion of the covered clinical study. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1. 
Sponsor Audits 
At some point during the study, individuals from the sponsor's Quality Assurance department 
and/or their authorized representative may visit the investigator's site to conduct an audit of the 
study.  The purpose of this visit will be to determine the investigator's adherence to the Protocol, 
applicable regulations, and the sponsor's procedures, in addition to assessing the accuracy of the 
study data.  Before initiating this audit, the investigator will be contacted by the sponsor to 
arrange a convenient time for this visit.  The investigator and staff are expected to cooperate with 
the auditors and allow access to all subject records supporting the CRFs and other study-related 
documents. 
12.2. 
Inspection by Regulatory Authorities 
At some point during the investigational product's development program, a regulatory authority 
may visit the investigator to conduct an inspection of the study and the site.  The investigator and 
staff are expected to cooperate with the inspectors and allow access to all source documents 
supporting the CRFs and other study-related documents.  The investigator must immediately 
notify the sponsor when contacted by any regulatory authority for purposes of conducting an 
inspection. 
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13. 
ETHICS 
13.1. 
Ethical Conduct of the Study 
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, GCPs as defined in 
Title 21 of the US CFR Parts 50, 54 56, 312, and Part 11, as well as ICH GCP consolidated 
guidelines (E6) and applicable regulatory requirements. 
13.2. 
Written Informed Consent 
Informed consent documentation that includes both information about the study and the ICF will 
be prepared and given to the subject.  This document will contain all elements required by the 
ICH E6 Guideline for GCP and any additional elements required by local regulations.  The 
document must be in a language understandable to the subject and must specify who informed 
the subject.  Where required by local law, the person who informs the subject must be a 
physician. 
The principal investigator at each center will ensure that the subject is given full and adequate 
verbal and written information about the nature, purpose, and the possible risk and benefit of the 
study.  Subjects must also be notified that they are free to discontinue study drug and withdraw 
from the study at any time.  The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
The subject's signed and dated ICF must be obtained before conducting any study procedures.  
The principal investigator must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject.  The investigator should inform the subject's primary physician 
about the subject's participation in the study if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
Preparation of the ICF is the responsibility of the investigator and must include all elements 
required by the ICH GCP, and applicable regulatory requirements, and must adhere to the ethical 
principles that have their origin in the Declaration of Helsinki.  A template will be provided by 
the sponsor or its designee.  The sponsor or its designee must review and approve all changes to 
site-specific ICFs.  The ICF must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to subject records.  Before the beginning of the study, 
the IRB or IEC must provide the investigator with written approval/favorable opinion of the 
written ICF and any other information to be provided to the subjects. 
13.3. 
Ethics Review 
It is the responsibility of the investigator to assure that all aspects of the ethics review are 
conducted in accordance with the Declaration of Helsinki as described in the ICH E6:  Guideline 
for GCP, and/or local laws, whichever provides the greatest level of protection for the study 
participants.  The Protocol and any information supplied to the subject to obtain informed 
consent, including written ICFs, subject recruitment procedures (eg, advertisements), and written 
information to be provided to subjects (information leaflets), must be reviewed and approved by 
a qualified IRB/IEC before enrollment of participants in the study.  Before initiation of the study, 
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the sponsor or its designee must receive documentation of the IRB or IEC approval, which 
specifically identifies the study/protocol, and a list of the committee members. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
Protocol in accordance with local requirements.  Protocol amendments and revisions to the ICF 
must be submitted to and approved by the IRB or IEC. 
Investigators must submit progress reports to the IRB or IEC in accordance with the IRB or IEC 
requirements and local regulations.  Annual re-approval of the study must be obtained.  Copies 
of progress reports and annual re-approvals must be sent to the sponsor or its designee. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The sponsor or its designee will provide this information to the principal investigator. 
When the sponsor or its designee provides the investigator with a safety report, the investigator 
must promptly forward a copy to the IRB or IEC. 
After completion or termination of the study, the investigator must submit a final report to the 
IRB or IEC and to the sponsor or its designee. 
The investigator, as part of the records retention requirements for the study, must maintain 
documentation of all submissions, correspondence, and approvals to and from the IRB or IEC. 
Each clinical investigator is responsible to conduct the study in accordance with the Protocol, all 
applicable laws, regulations, and GCP according to ICH guidelines. 
13.4. 
Data Privacy 
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. 
14. 
DATA HANDLING AND RECORDKEEPING 
14.1. 
Inspection of Records 
The sponsor or its designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The investigator agrees to allow the monitor 
to inspect the drug storage area, study drug stocks, drug accountability records, subject charts 
and study source documents, and other records relative to study conduct. 
The investigator must ensure that all records pertaining to the conduct of the clinical study (as 
listed above) are adequately maintained for a period of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal termination of 
clinical development of the investigational product. 
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14.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved, 2 years following the 
termination of the test article for investigation.  If it becomes necessary for the sponsor or the 
regulatory authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
The investigator must not destroy any records associated with the study without receiving 
approval from Incyte.  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. 
Whenever possible, an original recording of an observation must be retained as the source 
document.  However, a photocopy of a record is acceptable, provided it is legible and is a 
verified copy of the original document. 
All CRF 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 CRF data and 
audit trail. 
14.3. 
Confidentiality 
Subject names will not be supplied to the sponsor or its designee if applicable.  Only the subject 
number and subject's initials will be recorded in the CRF, 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. 
15. 
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.  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.  The signed agreement is 
retained by the sponsor or its designee. 
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16. 
REFERENCES 
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Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-1657. 
Carboplatin [package insert]. Lake Forest, IL: Hospira, Inc.; 2015. 
http://www.hospira.com/en/images/434650_tcm81-7956.pdf. Accessed October 4, 2015. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
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Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end 
points in chronic lymphocytic leukemia. J Clin Oncol 2012;30:2820-2822. 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 15, 2014. http://www.hma.eu/ctfg.html. Accessed 
November 11, 2015. 
Coutré S, Barrientos JC, Brown JR, et al. Management of adverse events associated with 
idelalisib treatment: expert panel opinion. Leuk Lymphoma 2015;56:2779-2786. 
Feldman T, Mato AR, Chow KF, et al. Addition of lenalidomide to rituximab, isofamide, 
carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell 
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Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 
3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 
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Food and Drug Administration (FDA). Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. May 2007. 
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Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for 
relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010;28:4184-4190. 
Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed 
indolent lymphoma. N Engl J Med 2014;371:1008-1018. 
Gupta M, Han JJ, Stenson M, et al. Elevated serum IL-10 levels in diffuse large B-cell 
lymphoma: a mechanism of aberrant JAK2 activation. Blood 2012;119:2844-2853. 
Gururajan M, Jennings CD, Bondada S. Cutting edge: Constitutive B cell receptor signaling is 
critical for basal growth of B lymphoma. J Immunol 2006;176:5715-5719. 
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic 
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Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eu J 
Cancer 2005;41: 2502-2512. 
Horowitz SM, Flinn I, Patel MR, et al. Preliminary safety and efficacy of IPI-145, a potent 
inhibitor of phosphoinositide-3-kinase0δγ, in patients with relapsed/refractory lymphoma.  J Clin 
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https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=14898. Accessed 
October 2, 2015. 
INCB039110 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
INCB040093 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
INCB050465 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
Kahl BS, Spurgeon SE, Furman RR, et al. A phase 1 study of the PI3Kδ inhibitor idelalisib in 
patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 2014;123:3398-3405. 
Kang S, Bader AG, Vogt PK.  Phosphatidylinositol 3-kinase mutations identified in human 
cancer are oncogenic. Proc Natl Acad Sci U S A 2005;102:802-807. 
Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before 
autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell 
lymphoma. Blood 2004;103:3684-3688. 
Kontzias A, Kotlyar A, Laurence A, Changelian P, O'Shea JJ. Jakinibs: a new class of kinase 
inhibitors in cancer and autoimmune disease. Curr Opinion Pharmacol 2012;12:464-470. 
Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K. Survival of resting mature B lymphocytes 
depends on BCR signaling via the Igα/β heterodimer. Cell 2004;117:787-800. 
Lam LT, Wright G, Davis RE, et al. Cooperative signaling through the signal transducer and 
activator of transcription 3 and nuclear factor- κB pathways in subtypes of diffuse large B-cell 
lymphoma. Blood 2008;111:3701-3713. 
Matasar MJ, Czuczman MS, Rodriguez MA, et al. Ofatumumab in combination with ICE or 
DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood 
2013;122:499-506. 
Meadows SA, Vega F, Kashishian A, et al. PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates 
pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in 
cellular models of Hogdkin lymphoma. Blood 2012;119:1897-1900. 
Monti S, Savage KJ, Kutok JL, et al. Molecular profiling of diffuse large B-cell lymphoma 
identifies robust subtypes including one characterized by host inflammatory response. Blood 
2005;105:1851-1861. 
National Comprehensive Cancer Network (NCCN). NCCN Guidelines for the Prevention and 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Owen RG, Kyle RA, Stone MJ, et al. Response assessment in Waldenström 
macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 
2013;160:171–176. 
Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib 
(BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients 
with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol 2016;27:1928-1940. 
Rituxan [package insert]. South San Francisco, CA: Genentech, Inc; 2014. 
http://www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed October 1, 2015. 
Savona M, Gutierrez M, Lanasa M, et al. A phase I dose escalation study of TGR-1202, a novel 
PI3K-δ Inhibitor, for patients with relapsed or refractory hematologic malignancies. Blood 
2013;122:Abstract 4373. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29. 
Smith TC, Khatcheressian J, Lyman GH, et al. 2006 Update of ASCO Practice Guideline 
Recommendations for the use of white blood cell growth factors: guideline summary. J Clin 
Oncol 2006;24:3187-3205. 
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https://www.pfizer.com/files/products/uspi_toposar.pdf. Accessed October 4, 2015. 
Wang M, Rule SA, Martin P, et al.   Interim Results of an International, Multicenter, Phase 2 
Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or 
Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer 
Follow-up.  Blood (ASH Annual Meeting Abstracts) 2012;120:Abstract 904. 
Younes A, Romaguera J, Fanale M, et al. Phase I study of a novel oral Janus kinase 2 inhibitor, 
SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in 
multiple lymphoma subtypes. J Clin Oncol 2012;30:4161-4167.  
Zelenetz AD, Hamlin P, Kewalramani T, et al. Ifosfamide, carbopolatin, etoposide (ICE)-based 
second-line chemotherapy for the management of relapsed and refractory aggressive 
non-Hodgkin’s lymphoma.  Annals of Oncology 2003;14 Suppl 1:i5-i10. 
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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 INCB050465 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, Mountain View, CA).  Additional details of analyses will 
be described in the Statistical Analysis Plan. 
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APPENDIX C. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE 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. RESPONSE CRITERIA FOR LYMPHOMA 
LYMPHOMA RESPONSE CRITERIA – The Lugano Classification (Cheson et al 2014) 
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. 
 
 
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Site 
PET–Based Response 
CT/MRI-Based Response 
 
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. 
 
Progressive metabolic disease: 
Progressive disease (requires at least one 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 
 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. 
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APPENDIX E. RESPONSE CRITERIA FOR CLL 
CLL- DEFINITION OF RESPONSE, RELAPSE AND REFRACTORY DISEASE MODIFIED 
FROM IWGCLL (Hallek et al 2008, Cheson et al 2012) 
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 
Patients 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). 
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APPENDIX F. 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 baselinea 
• 
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 baselinea 
• 
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 baselinea 
• 
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 G. PROHIBITED AND RESTRICTED MEDICATIONS 
In Vivo CYP3A4 Inhibitors 
 
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In Vivo CYP3A Inducers 
 
 
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