An Open-Label Phase I/II Safety and Efficacy Study of Itacitinib In Combination With Everolimus In Subjects With Relapsed/Refractory Classical Hodgkin Lymphoma
Phase: PHASE1
Conditions: Classical Hodgkin Lymphoma
Sponsor: University of Pennsylvania

 
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AN OPEN-LABEL PHASE I/II SAFETY AND EFFICACY STUDY OF 
ITACITINIB IN COMBINATION WITH EVEROLIMUS IN SUBJECTS 
WITH RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA 
Principal Investigator: 
Jakub Svoboda, MD 
Department of Medicine 
Division Hematology-Oncology 
Hospital of the University of Pennsylvania 
3400 Civic Center Blvd. 
Philadelphia, PA 19104 
Tel: 215-614-1846 
Regulatory Sponsor: 
University of Pennsylvania 
3400 Spruce Street 
Philadelphia, PA 19104  
Medical Director: 
 
3400 Civic Center Blvd.,  
PCAM-10th Floor, South Pavilion 
Philadelphia, PA 19104 
Statistician 
 
Investigational Products: 
Itacitinib adipate 
Everolimus 
Protocol Number: 
UPCC #: 45418 
IRB Number: 
831774 
IND Number: 
 
NCT Identified Number:  
NCT03697408 
Original Protocol Date: 
22 May 2018 
Version: 
11.0 
Date: 
V1.0 - 22 May 2018 
V2.0 - 15 Aug 2018 
V3.0 - 07 Sep 2018 
V4.0 - 14 Sep 2018 
V5.0 - 23 Oct 2018 
V6.0 - 06 Dec 2018 
V7.0 – 05 Mar 2019 
V8.0 – 01 Aug 2019 
V9.0 – 22 Jan 2021 
V10.0 – 14 Feb 2022 
V11.0 – 22 Jun 2022 
 

 
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TABLE OF CONTENTS 
Study Summary ............................................................................................................................11 
1 
Background and Study Rationale .......................................................................................16 
1.1 
Background and Relevant Literature ............................................................................16 
1.2 
Description of the Investigational Products ..................................................................18 
1.2.1 
Itacitinib adipate ........................................................................................................18 
1.2.2 
Everolimus ..................................................................................................................18 
1.3 
Nonclinical Data ...............................................................................................................18 
1.3.1 
Itacitinib ......................................................................................................................18 
1.3.2 
Everolimus ..................................................................................................................19 
1.4 
Clinical Data to Date ........................................................................................................20 
1.4.1 
Itacitinib ......................................................................................................................20 
1.4.2 
Everolimus ..................................................................................................................21 
1.5 
Combination of Itacitinib and Everolimus Safety ........................................................22 
1.6 
Dose Rationale for the Combination of Itacitinib and Everolimus .............................23 
2 
Study Objectives ...................................................................................................................23 
2.1 
Phase I ...............................................................................................................................23 
2.1.1 
Primary Objective ......................................................................................................23 
2.1.2 
Secondary Objective ..................................................................................................23 
2.1.3 
Exploratory Objective ...............................................................................................24 
2.2 
Phase II .............................................................................................................................24 
2.2.1 
Primary Objective ......................................................................................................24 
2.2.2 
Secondary Objective ..................................................................................................24 
2.2.3 
Exploratory Objective ...............................................................................................24 
3 
Investigational Plan ..............................................................................................................24 
3.1 
General Design .................................................................................................................24 
3.1.1 
Screening Phase ..........................................................................................................24 
3.1.2 
Study Intervention Phase I ........................................................................................24 
3.1.3 
Study Intervention Phase II ......................................................................................26 
3.1.4 
Follow Up Phase .........................................................................................................26 
3.1.5 
Allocation to Interventional Group ..........................................................................27 
3.2 
DLT Definition .................................................................................................................27 
3.3 
Primary Study Endpoints ...............................................................................................28 
3.3.1 
Phase I .........................................................................................................................28 
3.3.2 
Phase II .......................................................................................................................29 
4 
Study Population and Duration of Participation ...............................................................29 
4.1 
Inclusion Criteria .............................................................................................................29 
4.2 
Exclusion Criteria ............................................................................................................31 
4.3 
Subject Recruitment ........................................................................................................31 
4.4 
Duration of Study Participation .....................................................................................32 
4.5 
Total Number of Subjects and Sites ...............................................................................32 
4.6 
Vulnerable Populations ...................................................................................................32 
4.7 
Telemedicine Visits ..........................................................................................................32 
5 
Treatment ..............................................................................................................................32 

 
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5.1 
Itacitinib ............................................................................................................................32 
5.1.1 
Description of Itacitinib .............................................................................................32 
5.1.2 
Intervention Regimen ................................................................................................32 
5.1.3 
Receipt .........................................................................................................................33 
5.1.4 
Storage ........................................................................................................................33 
5.1.5 
Preparation .................................................................................................................33 
5.1.6 
Administration and Accountability ..........................................................................33 
5.2 
Everolimus ........................................................................................................................34 
5.2.1 
Description of Everolimus .........................................................................................34 
5.2.2 
Intervention Regimen ................................................................................................34 
5.2.3 
Receipt .........................................................................................................................34 
5.2.4 
Storage ........................................................................................................................34 
5.2.5 
Preparation .................................................................................................................34 
5.2.6 
Administration and Accountability ..........................................................................34 
5.3 
Overdose ...........................................................................................................................35 
5.4 
Subject Compliance Monitoring .....................................................................................35 
5.5 
Return or Destruction of Investigational Product ........................................................35 
5.6 
Modifications after DLT period .....................................................................................35 
5.6.1 
Dose Modification for Hematologic and Non-Hematologic Toxicities ..................36 
5.6.2 
Adverse Events Described with Everolimus and Management .............................38 
6 
Study Evaluations and Procedures .....................................................................................40 
6.1 
Screening ...........................................................................................................................40 
6.2 
Concomitant Medications ...............................................................................................41 
6.3 
Diet/Activity/Other Considerations ................................................................................43 
6.3.1 
Diet ..............................................................................................................................43 
6.3.2 
Contraception .............................................................................................................43 
6.3.3 
Use in Nursing Women ..............................................................................................44 
6.4 
Study Intervention Phase ................................................................................................44 
6.4.1 
Cycle 1 Day 1 ..............................................................................................................44 
6.4.2 
Cycle 1 Day 8 (+/- 3 Days) .........................................................................................44 
6.4.3 
Cycle 1 Day 15 (+/- 3 Days) .......................................................................................45 
6.4.4 
Cycle 1 Day 22 (+/- 3 days) ........................................................................................45 
6.4.5 
Cycles 2-24 Day 1 (+/- 7 days) ...................................................................................45 
6.4.6 
End of Treatment Visit (EOT) ..................................................................................46 
6.4.7 
Safety Assessments .....................................................................................................46 
6.4.8 
Follow-up Phase .........................................................................................................47 
6.5 
Physical Examination ......................................................................................................48 
6.6 
Laboratory Assessment ...................................................................................................48 
6.7 
Radiographic Evaluations ...............................................................................................49 
6.8 
Unscheduled Visits ...........................................................................................................49 
6.9 
Subject Withdrawal .........................................................................................................49 
6.9.1 
Treatment Discontinuation .......................................................................................49 
7 
Statistical Plan .......................................................................................................................53 
7.1 
Sample size ........................................................................................................................53 
7.2 
Statistical Methods ...........................................................................................................53 

 
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7.2.1 
Interim Efficacy Analysis ..........................................................................................53 
7.2.2 
Interim Safety Analyses .............................................................................................53 
7.3 
Subject Population for Analysis – Phase I .....................................................................54 
7.4 
Primary Analyses .............................................................................................................54 
7.5 
Secondary Analyses .........................................................................................................54 
7.6 
Other Analyses .................................................................................................................54 
7.7 
Subject Population for Analysis – Phase II ...................................................................55 
8 
Safety and Adverse Events ...................................................................................................55 
8.1 
Definitions .........................................................................................................................55 
8.2 
Expected Adverse Events ................................................................................................56 
8.3 
Recording of Adverse Events ..........................................................................................56 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated 
Problems ...........................................................................................................................57 
8.5 
Pregnancy .........................................................................................................................58 
8.6 
Protocol Exceptions and Deviations ...............................................................................58 
8.7 
Stopping Rules (safety and efficacy) ..............................................................................59 
8.8 
Monitoring ........................................................................................................................59 
8.9 
Auditing and Inspecting ..................................................................................................59 
9 
Study Administration, Data Handling and Record Keeping ............................................60 
9.1 
Confidentiality ..................................................................................................................60 
9.2 
Source Documents ............................................................................................................60 
9.3 
Case Report Forms ..........................................................................................................60 
9.4 
Data Collection and Management ..................................................................................61 
9.5 
Records Retention ............................................................................................................61 
10 Ethical Considerations .........................................................................................................61 
10.1 
Risks ..................................................................................................................................62 
10.2 
Benefits ..............................................................................................................................62 
10.3 
Risk Benefit Assessment ..................................................................................................62 
10.4 
Informed Consent Process / HIPAA Authorization .....................................................62 
10.5 
Conflict of Interest ...........................................................................................................62 
11 Publication Plan ....................................................................................................................62 
12 References ..............................................................................................................................63 
13 Appendix ................................................................................................................................65 
13.1 
FACT-Lym Questionnaire ..............................................................................................65 
13.2 
Concomitant Medications/Products not to be taken.....................................................68 
13.3 
ECOG Performance Status Scores .................................................................................69 
13.4 
Revised Criteria for Response Assessment of Malignant Lymphoma[19] .................70 
13.5 
New York Heart Association (NYHA) Functional Classification................................72 
13.6 
Regimens for Pneumocystis Pneumonia Prophylaxis ...................................................72 
 

 
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TABLE OF TABLES 
Table 1: Dose Cohort Design ......................................................................................................25 
Table 2: DLT defining toxicities .................................................................................................27 
Table 3: Guidelines for Interruption and Restarting Study Drugs due to AEs 
suspected to result from itacitinib or everolimus ................................................36 
Table 4: Guidelines for Interruption and Restarting Study Drugs due to AEs 
suspected to result from everolimus .....................................................................37 
Table 5: Guidelines for Dose Reductions for Itacitinib ............................................................38 
Table 6: Guidelines for Dose Reductions for Everolimus ........................................................38 
Table 7: Recommended Dosage Modifications for Concurrent Use of a P-gp 
substrate or CYP3A4 Inhibitor .............................................................................42 
Table 8: Recommended Dosage Modifications for Concurrent Use of a P-gp 
substrate or CYP3A4 Inducer ...............................................................................42 
Table 9: Schedule of Study Procedures .....................................................................................51 
 
TABLE OF FIGURES 
Figure 1: Dose Cohort Design .....................................................................................................26 
 

 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
ABVD 
adriamycin-bleomycin-vinblastine-dacarbazine 
ACC 
Abramson Cancer Center 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
ASH 
American Society of Hematology 
AST 
aspartate aminotransferase 
ASCT 
autologous stem cell transplant 
AUC 
area under curve 
AVD 
adriamycin, vinblastine, dacarbazine 
BCL 
B-cell lymphoma 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
Complete Blood Count 
CRF  
case report form 
CD  
cluster of differentiation 
CFR 
Code of Federal Regulations 
cHL 
classical Hodgkin lymphoma 
CNS 
central nervous system 
CI 
confidence interval 
CPK 
creatine phosphokinase  
CR 
complete response 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTSRMC  
Clinical Trials Scientific Review and Monitoring Committee 
CYP 
cytochrome P450 
DFS 
disease-free survival 

 
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DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DOCM  
Department of Compliance and Monitoring 
DSMC  
Data Safety Monitoring Committee 
EBV  
Epstein-Barr virus 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS  
event free survival 
EOT 
end of treatment 
EMR 
electronic medical record 
FACT-G  
Functional Assessment of Cancer Therapy - General 
FACT-Lym 
Functional Assessment of Cancer Therapy - Lymphoma 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FLT3 
FMS-like tyrosine kinase-3 
G-CSF  
granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GFR  
glomerular filtration rate 
GI 
gastrointestinal 
GM-CSF  
granulocyte macrophage colony 
GVHD 
graft-versus-host disease 
HBsAb  
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hCG 
human chorionic gonadotropin  
HDC 
high-dose chemotherapy 
HDL 
high-density lipoprotein 

 
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HDT  
high-dose chemotherapy 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV  
human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HMG 
3-hydroxy-3-methyl-glutaryl 
HR 
heart rate 
HRQOL 
Health-Related Quality of Life During Therapy  
HRS 
Hodgkin Reed-Sternberg 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IL 
interleukin 
ILD 
interstitial lung disease 
IN 
Investigator Notification 
INCB039110 Itacitinib 
INR 
international normalized ratio 
IPI 
International Prognostic Index 
IR  
immediate-release 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IVRS 
Interactive Voice Response System 
IV 
intravenous  
HDAC 
Histone deacetylases 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
LDi 
longest transverse diameter of lesion 
LDL 
low-density lipoprotein 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 

 
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MF 
myelofibrosis 
MPN 
myeloproliferative neoplasm 
MRI 
magnetic resonance imaging 
MTD  
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MYD88 
myeloid differentiation primary response 88 
N/A  
not applicable 
N/D  
not done 
NCI 
National Cancer Institute 
NCCN  
National Comprehensive Cancer Network 
NCT 
National Clinical Trial 
NHL  
non-Hodgkin lymphoma 
NF-κB 
nuclear factor kappa light chain enhancer of activated B cells 
NOAEL 
no-observed-adverse-effect-level 
ORR 
objective response rate 
OS 
overall survival 
PCR  
polymerase chain reaction 
PCP  
Pneumocystis pneumonia 
PD  
progressive disease 
PET 
positron emission tomography 
PET/CT 
positron emission tomography/computed tomography 
PFS  
progression free survival 
Pg 
prostaglandin 
PgP 
P-glycoprotein 
PHI  
protected health information 
PI3K 
Phosphatidylinositol-4,5-bisphosphate 3-kinase 
PI3Kδ 
PI3K delta isoform 
PI 
principal investigator 
PK 
pharmacokinetics 
PI3K 
Phosphatidylinositol 3-kinase 
PO 
by mouth 

 
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PR  
partial response 
QD 
once daily 
QOL 
quality of life 
R  
rituximab 
RA 
rheumatoid arthritis 
RP2D 
recommended Phase II dose 
RT  
radiation therapy 
SAE  
serious adverse event 
SCT 
stem cell transplant 
SOCS1  
suppressor of cytokine signaling 1 
SD  
stable disease 
SMC  
Safety Monitoring Committee 
SR  
sustained release 
STAT 
signal transducer and activator of transcription 
SUSAR 
Suspected unexpected serious adverse reaction 
T 
temperature 
TEAE 
treatment emergent adverse event 
TME 
tumor microenvironment 
TYK  
tyrosine kinase 
ULN  
upper limit of normal 
UPENN  
University of Pennsylvania 
WBC 
white blood cell 
WT 
weight 

 
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STUDY SUMMARY 
Title 
AN OPEN-LABEL PHASE I/II SAFETY AND EFFICACY STUDY OF 
ITACITINIB IN COMBINATION WITH EVEROLIMUS IN SUBJECTS 
WITH RELAPSED/REFRACTORY CLASSICAL HODGKIN 
LYMPHOMA  
Short Title 
Itacitinib + everolimus in HL 
Trial Phase 
Phase I/II 
IRB Number 
831774 
Protocol 
Number 
UPCC #: 45418; NCT03697408 
Study 
Population 
Subjects with relapsed/refractory classical Hodgkin lymphoma (cHL) 
Rationale 
While the majority of patients with classical Hodgkin lymphoma are cured, 
it is estimated that each year about 1000 patients will die from this disease 
in the United States alone.  Therefore, new treatment strategies need to be 
developed for these patients. 
The molecular mechanisms underlying pathogenesis of malignant Hodgkin 
and Reed–Sternberg (HRS) cells are complex.  It has been demonstrated 
that Akt, a substrate of PI3‐kinase, is constitutively activated in HL‐derived 
cell lines.  Downstream effectors of Akt signaling include mTOR substrates 
which are also phosphorylated in HRS.  Inhibitors of PI3-kinases and 
mTOR are clinically active in cHL as monotherapies.  In a phase II trial for 
patients with relapsed/refractory cHL, everolimus therapy was well 
tolerated and resulted in response rates of about 40%, but low complete 
remission rate of only 5%.  Everolimus is currently part of the NCCN 
guidelines for treatment of cHL in relapsed/refractory setting. 
Another pathway which is activated in HRS includes the JAK/STAT 
pathway which promotes tumor cell proliferation and survival.  JAK 
inhibitor produced modest responses in patients with cHL as monotherapy.   
There is a rationale to combining mTOR inhibitor and JAK inhibitor in 
patients with cHL.  In pre-clinical studies, co-treatment of mTOR inhibitor 
with JAK inhibitor resulted in synergistic activity against the proliferation 
of JAK mutated cell lines.  Clinically, a study in various lymphoma 
subtypes using double inhibition of JAK and PI3-kinase pathway showed 
particular activity in cHL with ORR 60% and CR rate 20%.  However, the 
combination was associated with pulmonary and liver toxicities and the 
study is currently on hold.  These toxicities were attributed to the PI3-kinase 
inhibitor as a class.   

 
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In our clinical trial, we plan to combine two oral agents which will target 
two pathways which are activated in HRS.  We will administer concurrently 
itacinib (JAK inhibitor) with everolimus (mTOR inhibitor and a 
downstream effector of PI3-kinase) and hope to achieve synergistic effect 
without the severe toxicities observed in the PI3-kinase combination. 
Design 
This is an open-label, single-group, Phase I/II study of itacitinib in 
combination with everolimus in subjects with relapsed or refractory cHL.  
Phase I will evaluate the safety and tolerability of itacitinib when combined 
with everolimus in subjects with relapsed refractory cHL using a standard 3 
+ 3 design with dose-escalation or de-escalation scheme as described in 
Table 1; Phase II will evaluate the efficacy of the combination in subjects 
with cHL at the dose determined in Phase I using a Simon 2-stage optimal 
design.  Subjects may continue to receive study treatment for a duration of 
2 years (24 cycles, each cycle consisting of 28 days) or until evidence of 
disease progression, unacceptable toxicity, inability to commercially obtain 
everolimus or consent withdrawal.  Additional cycles of investigational 
treatment may be added if in the opinion of the investigator that the benefit 
risk ratio for the subject continues to be favorable. 
Methodology 
Single Center, Open-Label, Prospective Phase I/II Clinical Trial 
Study 
Duration 
Estimated duration of active enrollment is 3 years.  The duration of the 
entire study can be up to 7 years, which would include 2 years of follow-up 
after the last patient completes end of treatment visit. 
Objectives 
PHASE I 
Primary Objective  
To evaluate dose-limiting toxicities (DLTs) of combination treatment with 
itacitinib and everolimus occurring up to and during Day 28 of Cycle 1, and 
to establish a recommended Phase II dose (RP2D) in subjects with relapsed 
or refractory cHL. 
Secondary Objective 
To evaluate efficacy of itacitinib in combination with everolimus in terms 
of ORR, CR, PR, SD, duration of response, PFS, OS. 
Exploratory Objective 
To evaluate impact of itacitinib in combination with everolimus on QOL. 
 
PHASE II 
Primary Objective 
To evaluate the efficacy of itacitinib in combination with everolimus in 
subjects with relapsed or refractory cHL as demonstrated by CR rate.  

 
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Secondary Objectives 
To evaluate efficacy in terms of ORR, PR, SD, duration of response, PFS, 
OS.  
To evaluate the safety and tolerability of the treatment combination. 
Exploratory Objective 
To evaluate impact of itacitinib in combination with everolimus on QOL. 
Number of 
Subjects 
Up to 28 patients will be enrolled for planned 23 evaluable subjects 
Main Inclusion 
and Exclusion 
Criteria 
MAIN INCLUSION CRITERIA: 
1. Able to understand and voluntarily sign the informed consent form. 
2. Aged 18 years or older at the time of signing the informed consent form. 
3. Biopsy-proven diagnosis of relapsed classical Hodgkin lymphoma. 
4. Measurable disease on imaging defined as at least one lesion that can be 
accurately measured in at least two dimensions by imaging (PET/CT, 
CT, or MRI). 
5. Relapsed or refractory disease (after at least 2 prior systemic therapies); 
patients must have relapsed after ASCT, or have been deemed ineligible 
for ASCT based upon the below criteria:  
• Patients that have either progressed after treatment with, be 
intolerant to, or are not a candidate for brentuximab and 
pembrolizumab or nivolumab.  
• Are not ASCT candidates due to chemo-resistant disease (unable to 
achieve CR or PR to salvage chemotherapy) 
• Advanced age (> 65 years of age) 
• Any significant coexisting medical condition likely to have a 
negative impact on tolerability of ASCT 
6. Disease free of other malignancies for greater than or equal to 2 years. 
7. Performance status of ECOG 0-2 (Appendix 13.3). 
8. Laboratory test results within these ranges: 
• Absolute neutrophil count (ANC) > 1,000/μL 
• Platelet count > 75,000/μL 
• Serum creatinine < 2.0 mg/dL 
• AST and ALT ≤ 2.5 × institutional upper limit of normal (ULN) 
• Bilirubin < 2.0 × ULN unless due to Gilbert's disease 
• Fasting cholesterol ≤ 300 mg/dL AND fasting triglycerides 
≤ 300 mg/dL.   
9. Females of childbearing potential must have a negative serum or urine 
beta human chorionic gonadotropin (β-hCG) pregnancy test result 
within 72 hours prior to the first dose of itacitinib and must agree to use 
an effective contraception method during the study and for 6 months 
following the last dose of study drug. 

 
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10. Males who have female partners of childbearing potential must agree to 
use an effective contraceptive method during the study and for 6 months 
following the last dose of study drugs. 
11. Subject must have access to everolimus via insurance or self-pay. 
 
MAIN EXCLUSION CRITERIA: 
1. Unable to sign informed consent. 
2. Pregnant or breast-feeding females (lactating females must agree not to 
breast feed while taking the investigational agents). 
3. Any condition, including the presence of laboratory abnormalities, 
which places the subject at unacceptable risk if he/she were to 
participate in the study or confounds the ability to interpret data from 
the study. 
4. Bilirubin < 3 × ULN in the presence of liver metastases or presence of 
documented Gilbert's syndrome (unconjugated hyperbilirubinemia) 
5. Concurrent use of other anti-cancer agents or therapies during study 
treatment. 
6. Use of any other experimental drug or therapy within 28 days of 
initiating treatment with the investigational agents. 
7. Known seropositive for or active viral infection with human 
immunodeficiency virus (HIV), hepatitis C (HCV), or hepatitis B virus 
(HBV); patients who are seropositive because of hepatitis B virus 
vaccine are eligible. 
8. Previous use of JAK1 inhibitor (itacitinib) or history of disease 
progression on everolimus. 
9. Has a history, within the last 12 months, of (non-infectious) pneumonitis 
requiring systemic steroids, or current pneumonitis. 
Investigational 
Products 
Itacitinib is a small molecule inhibitor of the JAK family of protein which 
is manufactured in 100 mg sustained release tablets and will be provided to 
the participants by Incyte free of charge.  The starting dose of itacitinib in 
Phase I will be 300 mg QD (3 × 100 mg tablets); dose cohorts may be 
escalated to 400 mg QD or decreased to 200 mg QD depending on observed 
DLTs.  The recommended Phase II dose identified during Phase I will be 
the starting dose in Phase II.  Subjects may have dose reductions of 
itacitinib during the course of treatment based upon clinical and laboratory 
assessments.   
Everolimus will be administered at a dose of 5 mg QD (5 mg tablets) 
concurrently with itacitinib.  This is an FDA approved product and part of 
NCCN guidelines for relapsed/refractory cHL.  It will be obtained by the 
patient from commercial pharmacy. 
Reference 
Therapy 
None.  This protocol will be given to subjects with unmet medical needs for 
which there are no effective therapies known at this time.   

 
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Duration of 
administration  
Up to 2 years (24 cycles; each cycle is 28 days) of active therapy.  
Additional cycles of investigational treatment may be added if in the 
opinion of the investigator that the benefit risk ratio for the subject 
continues to be favorable.  Subjects who discontinue study treatment will be 
followed for disease status, subsequent anticancer treatments, and survival 
for up to 2 years from completing end of treatment (EOT) visit.  The study 
will end after the last subject completes 2 year follow-up or earlier once all 
subjects have discontinued study treatment, all subjects have died, have 
withdrawn consent, or are lost to follow-up. 
Statistical 
Methodology 
Sample size determination: Phase I portion of the study will utilize the 
standard 3 + 3 design with 6 to 15 patients enrolled.  At least 6 patients will 
need to be treated at recommended phase 2 dose (RP2D) before proceeding 
to Phase II.  A Simon optimal 2-stage design will be implemented to rule 
out the null CR rate of 5% against the alternative of 25% CR rate that might 
lead to larger, confirmatory studies.  For 80% power and 5% alpha level, 
the first stage will enroll up to 9 evaluable subjects.  If by week 16 there are 
no responders from the first 9 evaluable subjects with CR, the study will be 
stopped.  Otherwise, additional subjects will be enrolled for a total of 8-17 
evaluable treated at RP2D. 
The study will be considered successful if 2 or more subjects achieve CR. 
Evaluable subject is defined as any subject who received at least 21 days of 
therapy and with at least one efficacy evaluation measured. 
General data analysis plan: Descriptive statistics such as mean, standard 
deviation, median and range for continuous variable, and percentage for 
categorical variables will be computed.  For the safety objective, all AEs 
will be listed and tabulated by organ system and in CTCAE preferred terms.  
Point estimate of the true AE rate and 90% exact confidence intervals will 
be computed.  For the primary efficacy objective, a two-sided 90% 
confidence interval will be calculated for the CR rate as well as for the 
ORR.  Duration of response, PFS, and OS will be summarized using 
Kaplan-Meier curve, and median survival time will be estimated with the 
associated 90% CI.  FACT-Lym questionnaires will assess health related 
QOL.   
Safety 
Evaluations  
A DLT will be defined as the occurrence of any toxicities in Table 2 
occurring up to and during Day 28 of Cycle 1, except those with a clear 
alternative explanation (e.g., disease progression) or transient (≤ 72 hours) 
abnormal laboratory values without associated clinically significant signs or 
symptoms based on investigator and sponsor determination.  All DLTs will 
be assessed by the investigator using CTCAE v5 criteria (NCI 2018).  In 
order to be included in the tolerability review, subjects must have received 
the cohort-specific dose of itacitinib and everolimus for at least 75% of the 
days during the 28-day surveillance period of Cycle 1 or have experienced a 

 
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DLT.  Additional subjects may be enrolled to achieve a minimum cohort 
size should withdrawal or dose interruptions/reductions result in subjects 
being non-evaluable.  The maximum tolerated DLT rate is set to be 30%.  
During Phase II portion of the study, a Bayesian stopping rule will be 
employed to monitor excess DLT rate.  Under the assumption of a beta 
prior of (1,5), that is 1 DLT in 6 patients, the study will be stopped if 4 in 6, 
5 in 9, 6 in 12, or 7 in 15 DLT are observed during cycle 1 in phase II of the 
study.  The posterior probability that the true DLT rate is above 30% at each 
stopping would be around 77 to 79%. 
Subjects who experience a DLT or an unacceptable toxicity (i.e. not able to 
resume therapy within 28 days due to unresolved toxicity) beyond the DLT 
window will be also considered in the determination of the RP2D dose. 
Any grade 5 hematologic and non-hematologic event related to the study 
treatments (at any time) will be considered a DLT. 
Data and 
Safety 
Monitoring 
Plan  
This study will be monitored according to the Sponsor Data and Safety 
Monitoring Plan. 
 
1 BACKGROUND AND STUDY RATIONALE 
This document is a protocol for a human research study using itacitinib combined with 
everolimus in patients with relapsed or recurrent classical Hodgkin Lymphoma (cHL).  This 
study is to be conducted according to all applicable University of Pennsylvania Research Policies 
and Procedures and all applicable Federal and state laws and regulations. 
1.1 
Background and Relevant Literature  
Classical Hodgkin lymphoma (cHL) represents 10% of all lymphomas in the U.S. with about 
8,000 newly diagnosed patients each year [1].  While it is a curable malignancy for most 
patients, about 20% will not be cured with conventional treatments (chemotherapy, radiation).  
Second line therapy utilizing autologous stem cell transp4lant (ASCT) may rescue some patients 
with relapsed/refractory disease, but those who progress after have poor prognosis with median 
OS about 25 months [2].  Recent progress using immuno-conjugates or immune checkpoint 
inhibitors in relapsed/refractory Hodgkin lymphoma has been encouraging, but these therapies 
are not curative and about 1/3 of patients will not respond[3].  Furthermore, brentuximab may 
not be suitable for patients with neuropathy and PD-1 inhibitors may be contraindicated in those 
with autoimmune diseases, pneumonitis, or after allogeneic stem cell transplant.  In our own 
practice, we have observed a growing number of young cHL patients who are progressing after 
these novel therapies creating a need for new treatment approaches. 
The unique biology of cHL, characterized by scant Hodgkin Reed-Sternberg (HRS) cells within 
a pro-inflammatory tumor microenvironment (TME), is rich with therapeutic targets [4].  
Constitutive activation of several signaling pathways protects HRS cells from apoptotic signals 

 
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and supports the TME, contributing to HRS cell survival, metabolism and immunity.  For 
example, it has been demonstrated that Akt, a substrate of PI3‐kinase, is constitutively activated 
in HL‐derived cell lines.  Several downstream effectors of Akt signaling, including mTOR 
substrates 4E‐BP1 and p70 S6 kinase are also phosphorylated in HRS.  In fact, everolimus, 
mTOR inhibitor, has been shown to be effective as monotherapy in a phase II trial for patients 
with relapsed/refractory cHL [5].  Nineteen heavily pretreated cHL patients were treated with 10 
mg of everolimus which resulted in ORR 47% (8 PRs, 1 CR), but the CR rate was low at 5%.  
Overall, it was well tolerated; however, 4 patients experienced Grade 3 or higher pulmonary 
toxicity.  There was no reported hepatotoxicity with everolimus in this study [5].  Similar clinical 
activity, albeit lower, was observed in a multi-center, phase II study of single-agent everolimus 
in the same patient population with 38 evaluable patients.  The interim report demonstrated a 
37% ORR (13 PRs and 1 CR) with low CR rate of 2.6% [5].  Everolimus is currently a part of 
NCCN guidelines as an option for patients with relapsed/refractory cHL; however, it is not 
currently FDA approved for this indication.  
Other pathway are involved in the pathogenesis of malignant HRS cells.  JAK/STAT signaling 
pathway activation in HRS cells has been described due to genomic amplifications or 
inactivating mutations in SOCS1, a JAK inhibitor [6].  This genomic abnormality leading to 
JAK/STAT activation is present in approximately 40% of HL cases [7].  JAK inhibition as 
monotherapy has been shown to produce modest responses with ORR 19% and no CR in 33 
patients in phase II study, but the treatment was well tolerated [8].  A phase I study of SB1518 
(JAK2/FLT3 inhibitor) showed that over 50% of patients with HL had stable disease after 8 
weeks of daily administration.  Moreover, toxicities experienced were mostly Grade 1 or 2 [9].    
Concurrent inhibition of multiple activated pathways could result in enhanced activity and may 
represent a better strategy in HL.  In pre-clinical studies, co-treatment of mTOR inhibitor with 
JAK inhibitor resulted in synergistic activity against the proliferation of JAK mutated cell lines 
[10, 11].  Clinically, a study in various lymphoma subtypes showed that itacitinib (JAK1 
inhibitor) in combination with PI3Kδ inhibitor (INCB040093) was particularly active in HL [12, 
13].  Of 6 evaluable patients receiving INCB040093, ORR was 50% (1 CR); of 9 evaluable 
patients receiving INCB040093 + itacitinib, ORR was 67% (2 CRs).  However, there have been 
concerning toxicities including PCP pneumonia (in 10% of patients, but in none with cHL) and 
LFT elevations (about 50% of patients, mostly grade 2 or lower).  These were most likely 
attributed to the PI3Kδ inhibitor (INCB040093) considering similar toxicities with other drugs in 
this class.  The planned phase II trial in cHL (combining 100 mg twice daily of INCB040093 
plus 300 mg of itacitinib once daily) was put on hold.   
We propose to conduct a phase I/II trial using combination of itacitinib, an oral JAK1 inhibitor, 
with everolimus, an oral mTOR inhibitor, for patients with relapsed/refractory cHL.  While both 
agents have activity in cHL, concurrent inhibition of both pathways in the mutation-rich HRS 
cells and the tumor microenvironment is more likely to result in deeper disease control (as 
demonstrated by CR rate) compared to everolimus monotherapy alone.  We hope that combining 
itacitinib with everolimus (as a downstream effector of PI3-kinase) will result in synergistic 
effect without the toxicities seen when itacitinib was combined with PI3Kδ inhibitor 
(INCB040093).  Both agents are oral and provide patients with convenient route of 
administration. 

 
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See section 10 for additional information on risk. 
1.2 
Description of the Investigational Products 
1.2.1 
Itacitinib adipate 
Itacitinib adipate (referred to herein as itacitinib) is a small molecule inhibitor of the JAK family 
of protein TYKs with selectivity for JAK1 that is proposed for development for the treatment of 
MPNs, including MF; GVHD; solid tumors; B-cell malignancies; and inflammatory diseases, 
including RA and psoriasis.  Itacitinib drug substance is a white to off-white powder.  Itacitinib 
100 mg (free base equivalent) sustained release tablets contain the active ingredient (itacitinib 
adipate), hypromellose, microcrystalline cellulose, lactose monohydrate, and magnesium 
stearate.  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 MPNs and a number of chronic inflammatory conditions, and JAK1 has 
been shown to cooperate with other JAKs to mediate the signaling of a number of inflammatory 
cytokines.  Therefore, JAK inhibitors represent potential therapeutic agents for these disease 
states.  See the itacitinib investigator’s brochure for additional information. 
1.2.2 
Everolimus 
Everolimus is an FDA approved oral agent which is labeled for several malignancies including 
breast cancer, lung cancer, and renal cell carcinoma.  It is also part of NCCN guidelines for 
relapsed/refractory cHL.  It potently inhibits the mammalian target of rapamycin (mTOR) 
blocking a key downstream effector of growth factor signaling.  The functional consequences of 
mTOR inhibition are a rapid decline in protein translation including key glucose and amino acid 
transporters, resulting in a complete abrogation of extracellular nutrient uptake.  Inhibition of 
mTOR results in cellular starvation, and everolimus is a potent initiator of metabolic stress for 
cancer cells.  See the everolimus labeling for additional information. 
1.3 
Nonclinical Data 
1.3.1 
Itacitinib 
Itacitinib did not demonstrate off-target activity or any activity in a number of non-JAK family 
kinases.  In vitro studies indicate that itacitinib potently inhibits JAK1 with 22- to > 500-fold 
selectivity over the other JAK family members, JAK2, JAK3, and TYK2, and does not 
significantly inhibit (< 30% inhibition) a broad panel of approximately 60 other kinases.  
Itacitinib is potent in cytokine-driven cell-based assays (IC50 values of approximately 10 nM to 
350 nM).  Itacitinib also inhibits the growth of the cytokine-dependent human myeloid plasma 
cell line, INA-6.  Additional inhibition is seen for signal transducer and activator of transcription 
(STAT) protein phosphorylation and proinflammatory cytokines, such as interleukin (IL)-23 and 
IL-6 with IC50 values of approximately 30 nM to 100 nM.  This inhibition is lessened in JAK2-
dependent assays, suggesting that itacitinib is JAK2-sparing in cells (IC50 values of ~1 μM or 
greater).  In JAK-dependent malignancy in vivo models, itacitinib continuous infusion impedes 
subcutaneous INA-6 expressing wild-type JAKs, achieving plasma concentrations well below 
those necessary to inhibit JAK2.  

 
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Single oral doses of itacitinib up to 2000 mg/kg in rats and up to 1000 mg/kg in dogs produced 
no adverse effects.  In multiple-dose studies in rats, dose-related body weight decreases and 
lower food consumption were noted.  Pharmacology-related alterations in the multiple-dose rat 
studies included reversible lowering of white blood cell (WBC) count, reversible lymphoid 
depletion in lymphoid tissues, and reduction in bone marrow cellularity.  The no-observed-
adverse-effect-level (NOAEL) in the 6-month rat study was 300 mg/kg per day.  In dogs, 
gastrointestinal (GI) inflammation was the dose-limiting toxicity (DLT) in multiple-dose studies 
of up to 3 months in duration.  In the 6- and 9-month dog studies, generalized demodicosis, an 
effect secondary to the immunosuppressive effect of itacitinib, was the DLT.  The NOAEL in the 
9-month study was 10 mg/kg per day. 
Cytochrome P450 3A4 is the major isozyme responsible for the metabolism of itacitinib in 
human liver microsomes.  In a cultured human hepatocyte assay, itacitinib did not induce 
CYP1A2, CYP2B6, or CYP3A4/5 activity or mRNA levels, suggesting that the potential to 
induce P450 in clinical studies is low. 
Fetotoxicity and fetal malformations were observed at the highest dose levels tested when 
itacitinib was administered to pregnant rats and rabbits; these effects were considered secondary 
to severe maternal toxicity at the same dose levels. 
Itacitinib lacks potential for genotoxicity as evaluated through assessments, including a bacterial 
reverse mutation assay, in vitro chromosomal aberrations study in primary human peripheral 
blood lymphocytes, and in vivo micronucleus study in rats. 
Human pharmacokinetics (PK) were investigated in the Incyte trial INCB 39110-103.  This was 
a multiple-dose, double-blind, randomized, placebo-controlled, dose escalation study in which 63 
subjects were exposed orally to one of two formulation variants (SR1 or SR3) at either 200mg, 
400mg, 600mg or 800mg doses in fasting and non-fasting scenarios.  Steady-state PK was 
reached within 48 hours postdose for all the treatment groups, suggesting that the t½ values after 
the first dose were likely ≤ 14 hours.  Both formulations had similar mean t½ values; 6.6 to 13 
hours for SR1 (fasted or fed) and 6.5 to 8.1 hours for SR3 (fed only).  Systemic accumulation 
was similar among the BID dose regimens; on average, geometric mean Cmax, Cmin, and AUC0-τ 
increased by approximately 2-fold at the PK steady-state versus after the first dose.  Additional 
information about itacitinib can be found in the Investigator’s Brochure. 
1.3.2 
Everolimus 
Everolimus selectively inhibits mTOR a highly conserved serine-threonine kinase, which is 
present in all cells and is a central regulator of protein synthesis.  mTOR is the only currently 
known target of everolimus.  mTOR is downstream of PI3K/AKT pathway, a pathway known to 
be dysregulated in a wide spectrum of human cancers including cHL. 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours.  The bioavailability of the drug 
is believed to be 11% or greater.  The AUC0-τ is dose-proportional over the dose range between 5 
to 70 mg in the weekly regimen.  Steady-state levels were achieved within two weeks of once 
daily dosing.  There was no evidence of increased oncogenesis in rats and mice at 0.2 and 4.3-
times, respectively, the estimated clinical exposure for Renal Cell Carcinoma patients.  
Additionally, in rats, everolimus was found to cross the placenta and adversely affect male 

 
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fertility at 0.5mg/kg doses and above.  Accordingly, inclusion criteria require both male and 
female subjects to use contraception.  Everolimus is a substrate of CYP3A4 and a substrate and 
moderate inhibitor of Pg.  Following oral administration, everolimus is the main circulating 
component in human blood and is considered to contribute the majority of the overall 
pharmacologic activity.  
In a recently published Phase II study of everolimus monotherapy (10mg daily, oral, 28 day 
cycles) in relapsed/refractory NHL, hematologic toxicity was most frequently observed (Gr 3/4 
anemia (15%; 8/55), neutropenia 12%; (12/55), and thrombocytopenia (33%; 18/55); febrile 
neutropenia was not observed and 8/55 discontinued therapy because of adverse events.  The 
authors concluded that everolimus monotherapy was safe and effective (ORR 35% (19/55) 
overall and 61% (14/23) for FL) [15].  Age, weight and gender in the adult population do not 
affect everolimus clearance.  For more information, refer to the package insert. 
1.4 
Clinical Data to Date 
1.4.1 
Itacitinib 
1.4.1.1 
Monotherapy 
As of December 2017, there have been 4 completed phase 1 studies and 3 ongoing study in 
healthy adult subjects.  Studies INCB 39110-101, -102, and -103 explored the PK, safety, and 
preliminary pharmacology of itacitinib, and Study INCB 39110-115 evaluated the effects of 
itacitinib on renal function.  The ongoing studies are: a  Phase 1, open-label, relative 
bioavailability study comparing itacitinib sustained release (SR) formulations with immediate-
release (IR) formulations and evaluating the effect of food on the bioavailability of these 
formulations (INCB 39110-105) is being conducted in healthy subjects; a Phase 1, open-label, 
mass-balance, PK, and metabolite profile study of radiolabeled itacitinib (INCB 39110-109); and 
a Phase 1, open-label, drug-drug interaction study in healthy subjects (INCB 39110-110). 
In the completed clinical pharmacology studies, itacitinib was administered to 197 healthy adult 
subjects as a single dose, repeated single doses, or multiple doses for up to 10 days.  In the 
ongoing bioavailability and food-effect study (INCB 39110-105), 129 subjects have been 
administered itacitinib SR and IR formulations.  Sustained release is likely needed to maintain 
JAK inhibition over the dose administration interval given the relatively short half-life of IR 
formulation and to reduce peak-trough ratio.  Of the formulations studied, the SR3 formulation 
was selected for expanded study because it had the greatest relative bioavailability of the SR 
formulations in reference to the IR formulation and had less variable PK than the other SR 
formulations.  Additionally, the SR3 formulation may be administered without regard to food 
based on the least significant impact on total exposure (measured by AUC0–∞) compared with 
other formulations when administered with a medium-fat meal.  An analysis of single-dose 
administration of itacitinib 100 mg, 200 mg, and 300 mg as SR3 100 mg tablets demonstrated 
that exposure increases in a greater-than-proportional manner. 
In the ongoing and completed clinical pharmacology studies, itacitinib was generally safe and 
well-tolerated in healthy subjects, with few discontinuations.  The majority of treatment-
emergent adverse events (TEAEs) were mild in severity.  There have been no clinically 

 
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significant, unanticipated safety findings or trends observed.  The main drug effect identified was 
a rapidly reversible dose-related decrease in neutrophil counts presumably caused by neutrophil 
margination; neutrophil decreases generally resolved within 24 to 48 hours of dose 
discontinuation.  Other reversible hematologic abnormalities, including decreased reticulocyte 
count, were observed after multiple-dose administration of higher dose levels at which JAK2 
inhibition was noted.   
See Section 5 of the itacitinib investigator’s brochure for additional information. 
1.4.1.2 
Combination Therapies 
Itacitinib has been evaluated in various combination trials in both solid and hematologic 
malignancies.  These included combination with gemcitabine and nab-paclitaxel in subjects with 
advanced or metastatic solid tumors, in combination with epacadostat in solid tumors, in 
combination with INCB050465 (an investigational PI3Kδ inhibitor) in solid tumors, and with 
pembrolizumab in solid tumors. 
In hematologic malignancies, itacitinib is being evaluated in combination with INCB040093, a 
novel phosphatidylinositol 3-kinase (PI3K) inhibitor with specificity for the delta isoform 
(PI3Kδ), in 2 clinical studies.  As of the data cutoff date, 72 subjects with B-cell malignancies 
have been treated with INCB040093 in combination with itacitinib in Study INCB 40093-102.  
All subjects reported at least 1 TEAE.  Nine subjects (12.5%) died on study; the TEAEs leading 
to death were hypoxia (2 subjects) and disease progression, pneumonia, Pneumocystis jirovecii 
pneumonia (PCP), small intestinal obstruction, death (unknown cause), cardiac arrest, and 
cardiorespiratory arrest (1 subject each).  No DLTs have been reported.  TEAEs reported in 
≥ 30% of subjects included nausea, cough, fatigue, pyrexia, vomiting, chills, 
thrombocytopenia/platelet count decreased, and diarrhea.  Treatment-related SAEs were noted 
for 14 subjects (19.4%) in this study; many of the treatment-related SAEs in this study were 
classified as infections.  The most frequently reported SAE in this study was PCP (5 subjects, 
6.9%) which appears to be a drug class issue for PI3K inhibitors.  The use of a standard 
Pneumocystis prophylaxis regimen is now mandated in subjects receiving combination therapy 
with INCB040093 and itacitinib.  Since implementing this requirement, the only case of PCP 
reported occurred in a subject who had previously reported PCP. 
Study INCB 40093-201 is an ongoing, Phase 2, open-label study of the safety and efficacy of 
INCB040093, as monotherapy and in combination with itacitinib, in subjects with relapsed or 
refractory HL.  As of the data cutoff date, 6 subjects in this study have been administered 
INCB040093 in combination with itacitinib.  There have been no deaths or DLTs in the study.  
Of the 6 subjects enrolled, 4 subjects (66.7%) reported at least 1 TEAE.  The most frequently 
reported TEAEs were nausea and vomiting (3 subjects each, 50.0%).  The only SAE reported in 
this study was Grade 3 pyrexia for 1 subject; this event was considered to be treatment-related.  
Two subjects (33.3%) in this study reported TEAEs of Grade 3 or higher.  No subject 
discontinued treatment because of a TEAE. 
1.4.2 
Everolimus 
Everolimus has been in development for patients with cancer since 2002 and thousands of 
patients have been treated on various clinical trials or as part of standard of care.  It is currently 

 
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FDA approved for several solid cancers metastatic renal cell carcinoma, breast cancer, 
neuroendocrine tumors, and unresectable lung cancer. 
The clinical activity of everolimus in cHL was demonstrated in two trials as monotherapy.  A 
phase II trial with everolimus (mTOR inhibitor) for patients with various lymphomas included 
19 heavily pretreated HL patients.  Everolimus showed an ORR 47%, but the CR rate was low at 
5%.  Although most patients experienced toxicity, the incidence of most of these complications 
was low and they were manageable with dose reductions.  Ten patients (53%) had dose 
reductions or treatment delays.  Adverse events at least possibly attributable to the study therapy 
included the following: 10 patients experienced a grade 3 or higher hematologic toxicity (six 
grade 3, four grade 4) and six patients experienced a grade 3 or higher non-hematologic toxicity 
(five grade 3, one grade 4).  Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 
32%, 5%, and 32% of patients, respectively.  Thrombocytopenia was the cause of most dose 
reductions and was rapidly reversible with drug delays of typically one week.  Three patients had 
grade 3 pulmonary toxicity (two with dyspnea and one with pleural effusion) and one patient had 
grade 4 pulmonary toxicity (pneumonitis).  There was no reported hepatotoxicity with 
everolimus in this study [17].  Similar clinical activity, albeit lower, was observed in a multi-
center, phase II study of single-agent everolimus in the same patient population with 38 
evaluable patients.  The interim report demonstrated a 37% ORR (13 PRs and 1 CR) with low 
CR rate of 2.6% [9].  The most common hematologic AEs were thrombocytopenia (39%) and 
anemia (24%); the most common nonhematologic AEs were fatigue (47%), cough (29%), 
dyspnea (26%).  Based on results of these studies, everolimus is currently a part of NCCN 
guidelines as an option for patients with relapsed/refractory HL.   
1.5 
Combination of Itacitinib and Everolimus Safety 
In light of the available non-clinical and clinical information to date, the expected profile of 
adverse events of the combination are expected to be consistent with the individual 
monotherapies.  Because of the potential for myelosuppression of JAK inhibitors as a class and 
also some of the additional myelosuppressive effects of everolimus, subjects will have 
hematologic parameters closely monitored during this clinical study.  It is expected that the 
everolimus dose of 5 mg is less likely to result in prohibitive hematological toxicities.  If there 
are clinically relevant declines in hematology parameters, investigational therapy may be 
interrupted until resolution or discontinuation.  While hepatotoxicity was seen only for JAK 
inhibitor in combination with PI3Kδ, everolimus monotherapy in cHL showed no significant 
safety signals for liver toxicities.  However, liver function tests will be monitored closely. 
The 10% risk of PCP pneumonia in a study combining studies of itacitinib and PI3Kδ for various 
types of lymphoma was attributed to the PI3Kδ.  However, considering that patients treated with 
everolimus had also some pulmonary toxicities (but not PCP), we plan to administer PCP 
prophylaxis (Appendix 13.6) and exclude any patients with history (within the past 12 months) 
of steroid requiring pneumonitis or active pneumonitis.   
For additional information see Section 5.6 

 
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1.6 
Dose Rationale for the Combination of Itacitinib and Everolimus 
Both itacitinib and everolimus are metabolized by cytochrome P450 3A4 in human liver 
microsomes.  However, in cultured human hepatocyte assays, itacitinib did not induce CYP1A2, 
CYP2B6, or CYP3A4/5 activity or mRNA levels, suggesting that the potential to induce P450 in 
clinical studies is low.  The potential of itacitinib to inhibit human liver microsomal CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 activity was also investigated.  
The inhibitory IC50 values for itacitinib were > 25 μM for all isozymes, thus the potential for 
itacitinib to cause clinically meaningful drug-drug interactions is low.   
In terms of the itacitinib, we plan to use either 200 mg, 300 mg, or 400 mg daily dose depending 
on tolerability and DLTs during the first Cycle 1 in Phase I patients.  Steady-state PK was 
reached within 48 hours post-dose for all the treatment groups in healthy volunteers (i.e. 200 mg 
daily, 400 mg daily).  Other combination trials (e.g. INCB 39110-206 of itacitinib in 
combination with ibrutinib in DLBCL) use a 300 mg daily starting dose of itacitinib.  In light of 
this information, the Phase I starting dose of 300 mg was selected.  Utilizing the 3+3 design and 
close monitoring for DLTs, we will de-escalate to 200 mg daily or escalate to 400 mg daily as 
per study design (Table 1).  This will determine the itacitinib recommended Phase II dose 
(RP2D). 
Everolimus will be administered at 5 mg daily at all 3 cohorts and Phase II.  While two studies as 
monotherapy in cHL used 10 mg daily dosing, we use 5 mg daily due to the fact that 50% of 
patients required dose reductions or treatment delays with the 10 mg dosing (mostly due to 
reversible thrombocytopenia).  Considering that JAK inhibitors may have also some 
hematologist toxicities, we decided to use 5 mg of everolimus during this combination study 
with itacitinib.  In a study of everolimus with a multitarget tyrosine kinase inhibitor, lenvatinib, 
in renal cell carcinoma, the recommended phase 2 dose for everolimus was also 5 mg daily [18].  
Additionally, it appears that both 5 mg daily and 10 mg daily dosing of everolimus is effective 
by pharmacokinetic studies and in clinical experience from the trials where dose reduction did 
not affect outcome [5]. 
2 STUDY OBJECTIVES 
2.1 
Phase I 
2.1.1 
Primary Objective 
To evaluate dose-limiting toxicities (DLTs) of combination treatment with itacitinib and 
everolimus occurring up to and during Day 28 of Cycle 1, and to establish a recommended Phase 
II dose (RP2D) in subjects with relapsed or refractory cHL. 
2.1.2 
Secondary Objective 
The secondary objective of Phase I is to evaluate the efficacy of itacitinib in combination with 
everolimus in terms of CR, ORR, PR, SD, duration of response, PFS, and OS. 

 
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2.1.3 
Exploratory Objective 
To evaluate impact of itacitinib in combination with everolimus on QOL. 
2.2 
Phase II 
2.2.1 
Primary Objective 
The primary objective of Phase II is to evaluate the efficacy of itacitinib in combination with 
everolimus in subjects with relapsed or refractory cHL as demonstrated by CR rate. 
2.2.2 
Secondary Objective 
The secondary objectives of Phase II are as follows: 
• To evaluate efficacy in terms of ORR, PR, SD, duration of response, PFS, OS.  
• To evaluate the safety and tolerability of the treatment combination. 
 
2.2.3 
Exploratory Objective 
To evaluate impact of itacitinib in combination with everolimus on QOL. 
3 INVESTIGATIONAL PLAN 
3.1 
General Design 
This is an open-label, single-group, Phase I/II study of itacitinib in combination with everolimus 
in subjects with relapsed or refractory cHL.  Phase I will evaluate the safety and tolerability of 
itacitinib when combined with everolimus in subjects with relapsed refractory cHL using a 3 + 3 
design; Phase II will evaluate the efficacy of the combination in subjects with cHL at the dose 
determined in Phase I using a Simon 2-stage expansion design.  Subjects may continue to receive 
study treatment for 2 years or until evidence of disease progression, unacceptable toxicity, 
inability to obtain commercial everolimus or consent withdrawal.  The number of cycles may be 
extended if sufficient data is provided by the manufacturer demonstrating safety of the itacitinib 
monotherapy and the subject continues to receive a clinical benefit.   
3.1.1 
Screening Phase 
Subjects with relapsed/refractory cHL will be recruited from the practices at the University of 
Pennsylvania.  Subjects will not be reimbursed for participation.  After signing the ICF, 
screening assessments may be completed over a period of up to 28 days. 
3.1.2 
Study Intervention Phase I 
Utilizing 3 + 3 design, 6 to 15 subjects will be enrolled to Phase I portion of the trial (with at 
least 6 subjects treated at RP2D).  The starting dose of itacitinib will be 300 mg once daily (QD) 
in combination with everolimus 5 mg QD.  Depending on tolerability, the dose of itacitinib in 
combination with everolimus could be increased to 400 mg QD (Cohort 2) or decreased to 200 

 
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mg QD (Cohort -1).  There will be no intra-patient dose escalations in phase I.  The dose of 
everolimus will remain 5 mg QD for each cohort. 
Additional subjects may be enrolled to achieve a minimum cohort size should withdrawal or 
dose interruptions/reductions result in a subject being non-evaluable.  Dose cohorts are outlined 
in Table 1, and the design is depicted in Figure 1. 
Subjects who experience a DLT or an unacceptable toxicity (i.e. not able to resume therapy 
within 28 days due to unresolved toxicity) beyond the DLT window will be also considered in 
the determination of the RP2D dose. 
Table 1: Dose Cohort Design 
Cohort 
Subjects 
Regimen 
DLTs 
Action 
 
 
 
 
 
-1 
0-6 
Everolimus 5 mg QD 
itacitinib 200 mg QD 
0/6 
Begin Phase 2 at Cohort -1 dose 
1/3 
Enroll 3 additional subjects (6 total) at Cohort -
1 level; if no additional DLT, begin Phase 2 at 
Cohort -1 dose; if 1 or more additional DLTs, 
terminate study 
≥ 2 
Terminate study 
 
 
 
 
 
1  
(starting 
dose) 
3-6 
Everolimus 5 mg QD 
itacitinib 300 mg QD 
0/3 
Escalate to Cohort 2 dose 
1/3 
Enroll 3 additional subjects (6 total) at Cohort 1; 
if no additional DLT, begin Phase 2 at Cohort 1 
dose; if 1 or more additional DLTs, de-escalate 
to Cohort -1  
≥ 2 
De-escalate  to Cohort -1 
 
 
 
 
 
2 
0-6 
Everolimus 5 mg QD 
itacitinib 400 mg QD 
0/6 
Begin Phase 2 at Cohort 2 dose 
1/3 
Enroll 3 additional subjects at Cohort 2 (6 total); 
if no additional DLT, begin Phase 2 study at 
Cohort 2 dose; if 1 or more additional DLTs, 
treat 3 more patients on Cohort 1 dose, if 0-1 
DLTs on Cohort 1, then RP2D is Cohort 1, if  ≥ 
2 DLTs on Cohort 1, then de-escalate and treat 
6 patients at Cohort -1; if 0-1/6 have DLTs – the 
RP2D is Cohort -1, if ≥ 2 DLTs, then study is 
terminated 
≥ 2  
Treat 3 more patients on Cohort 1 dose (6 total), 
if 0-1 DLTs on Cohort 1, then RP2D is Cohort 
1, if  ≥ 2/3 DLTs on Cohort 1, then reduce to 
Cohort -1 and treat 6 patients.  If 0-1/6 of 
Cohort -1 have DLTs – then RP2D is Cohort -1, 
if ≥ 2 DLTs, then study is terminated 
 

 
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Figure 1: Dose Cohort Design 
 
3.1.3 
Study Intervention Phase II 
Subjects with cHL will receive the recommended Phase II dose (RP2D) of itacitinib in 
combination with everolimus as determined in Phase 1.  Phase II will enroll 8 to 17 subjects 
depending on Cohort expansion in the Phase I portion.  Since 6 of the Phase I subjects will be 
recruited, treated and followed in the same way as the Phase II subjects, they will be considered 
as accrued to the Phase II study as well.  At least 14 subjects will be treated at RP2D level and 
evaluable for CR rate.  Using a Simon 2-stage optimal design, if there are no responders with CR 
by the 16 week response assessment from the first 9 evaluable subjects at the RP2D, the null 
hypothesis will be considered as supported, and the study will be terminated.  If there are no CRs 
in the first several patients (week 8 or 16 assessment), we will suspend the study enrollment and 
await final response assessment on all 9 patients (until week 16).  The study will be considered 
successful if the total number of subjects with CR is ≥ 2 in Phase II. 
3.1.4 
Follow Up Phase 
Subjects who discontinue treatment for any reason will be followed for resolution of treatment-
related adverse events and survival.  At treatment discontinuation, subjects will undergo a safety 
assessment approximately 28 days post the last dose of protocol therapy.  Subjects will be 

 
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followed for additional therapy and progression/survival data every three months (+/- 1 month) 
for the first year and every 6 month (+/- 1 month) for the second year after study discontinuation.  
3.1.5 
Allocation to Interventional Group  
Patients who sign ICF will be assigned a 7 digit number.  First 5 digits will be the study UPCC 
number and the last 2 digits will be the subject's number.  This subject number will be 
maintained throughout the study and will not be reassigned.  Subjects who withdraw consent or 
discontinue from the study after being assigned a subject number will retain their initial number.  
During Phase I, subjects will be assigned to specific itacitinib dose Cohort as described in Table 
1/Figure 1. For Phase II, subjects will be treated at the RP2D determined in Phase I. 
3.2 
DLT Definition 
A DLT will be defined as the occurrence of any toxicities in Table 2 occurring up to and 
including Day 28 of Cycle 1, except those with a clear alternative explanation (e.g., disease 
progression) or transient (≤ 72 hours) abnormal laboratory values without associated clinically 
significant signs or symptoms based on investigator and sponsor determination.  All DLTs will 
be assessed by the investigator using CTCAE v5 criteria (NCI 2018).  In order to be included in 
the tolerability review, subjects must have received the cohort-specific dose of itacitinib and 
everolimus for at least 75% of the days during the 28-day surveillance period of Cycle 1 or have 
experienced a DLT.  
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug (see Section 5.6); however, for the purposes of dose cohort 
escalation/de-escalation, expanding a dose cohort, and determining the RP2D, decisions will be 
made based on events that are observed from the first day of study drug administration through 
and including Day 28.  A lower RP2D may subsequently be determined based on relevant 
toxicities that become evident after Day 28. 
Subjects who experience a DLT or an unacceptable toxicity (i.e. not able to resume therapy 
within 28 days due to unresolved toxicity) beyond the DLT window will be also considered in 
the determination of the RP2D dose. 
Any grade 5 hematologic and non-hematologic event related to the study treatments (at any time) 
will be considered a DLT.  
Table 2: DLT defining toxicities 
TOXICITY 
Non-hematologic 
• 
Any ≥ Grade 3 non-hematologic toxicity, EXCEPT the following: 
– 
Transient (≤ 72 hours) abnormal laboratory values without associated clinically significant signs or 
symptoms. 
– 
Nausea, vomiting, and diarrhea adequately controlled with medical therapy within 48 hours. 

 
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– 
Singular or non-fasting elevations in blood glucose (i.e., blood glucose excursions will be considered 
toxicities if fasting blood glucose is elevated on 2 separate sequential occasions). 
Hematologic 
• 
Grade 3 thrombocytopenia with bleeding. 
• 
Grade 4 thrombocytopenia. 
• 
Febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.5°C). 
• 
Grade 4 neutropenia that does not recover to ≤ Grade 2 in ≤ 3 days after interrupting study drug. 
• 
Grade 4 anemia unresponsive to treatment for 3 days 
Note: itacitinib is suspected to cause transient decreases in ANC as a result of margination; therefore, DLT rules 
require neutropenia to persist after holding itacitinib for 3 days.  The use of growth factors is permitted at the 
discretion of the investigator.  If the clinical status of the subject allows, investigators are encouraged to wait 24 
hours before starting growth factors, to determine if WBC margination is contributing to the degree of 
neutropenia.   
 
3.3 
Primary Study Endpoints 
AEs will be assessed using NCI CTCAE v5.0.  Efficacy endpoints will be assessed using the 
Lugano Classification (Appendix 13.4) (19).  Duration of response will be defined as the time 
from earliest date of disease response until earliest date of disease progression.  QOL assessment 
will be performed by Fact-lym questionnaires (See Appendix 13.1).  The presence or absence of 
B symptoms (fevers over 100.4°F, drenching night sweats, weight loss of 10% of baseline 
weight) and of pruritus will be assessed by the research staff and recorded during study visits.  
3.3.1 
Phase I 
3.3.1.1 
Primary Phase I Endpoints 
Safety and tolerability will be assessed by evaluating the frequency, duration, and severity of 
AEs (including SAEs and dose-limiting toxicities [DLTs]) and changes in clinical and laboratory 
assessments. 
3.3.1.2 
Secondary Phase I Endpoints 
Efficacy will be assessed by CR rate, ORR (CR and PR), clinical benefit (CR, PR and SD), and 
duration of response. 
3.3.1.3 
Exploratory Phase I Endpoints 
• QOL (Fact-lym) questionnaires. 
• B symptom and pruritus resolution. 
 

 
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3.3.2 
Phase II 
3.3.2.1 
Primary Phase II Endpoints 
• Efficacy will be assessed by CR rate, defined as the percentage of subjects achieving CR 
as their best response. 
 
3.3.2.2 
Secondary Phase II Endpoints 
• ORR (CR and PR), clinical benefit (CR, PR and SD), and duration of response (defined 
as the time from earliest date of disease response until earliest date of disease 
progression). 
• Safety and tolerability will be assessed by evaluating the frequency, duration, and 
severity of AEs (including SAEs and dose-limiting toxicities [DLTs]) and changes in 
clinical and laboratory assessments. 
 
3.3.2.3 
Exploratory Phase II Endpoints 
• QOL (Fact-lym) questionnaires. 
• B symptom and pruritus resolution. 
 
4 STUDY POPULATION AND DURATION OF PARTICIPATION 
4.1 
Inclusion Criteria 
1. Able to understand and voluntarily sign the informed consent form. 
2. Aged 18 years or older at the time of signing the informed consent form. 
3. Biopsy-proven diagnosis of relapsed classical Hodgkin lymphoma. 
4. Measurable disease on imaging defined as at least one lesion that can be accurately measured 
in at least two dimensions by imaging (PET/CT, CT or MRI).  Minimum measurement must 
be ≥ 15mm in the longest axis or ≥ 10mm in the short axis. 
5. Relapsed or refractory disease (after at least 2 prior systemic therapies); patients must have 
relapsed after high-dose therapy with ASCT, or have been deemed ineligible for high-dose 
therapy with ASCT based upon the below criteria:  
• Patients that have either progressed after treatment with, be intolerant to, or are not a 
candidate for brentuximab and pembrolizumab or nivolumab. The reason for forgoing 
such therapies must be clearly documented. 
• Are not ASCT candidates due to chemo-resistant disease (unable to achieve CR or PR to 
salvage chemotherapy), advanced age (≥ 65 years of age), or any significant coexisting 

 
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medical condition (renal, pulmonary, or hepatic dysfunction) likely to have a negative 
impact on tolerability of ASCT 
6. Disease free of other malignancies for greater than or equal to 2 years with the exception of 
basal cell, squamous cell carcinomas of the skin, fully excised melanoma in situ, carcinoma 
in situ of the cervix or breast. 
7. Performance status of ECOG 0-2 (Appendix 13.3). 
8. Laboratory test results within these ranges (of note, patients who have cytopenias due to 
documented cHL involvement of the bone marrow may be considered for enrollment after 
discussion with the PI, Medical Director and Sponsor): 
• Absolute neutrophil count (ANC) > 1,000/µL 
• Platelet count > 75,000/µL 
• Serum creatinine < 2.0 mg/dL 
• Bilirubin < 2.0 × ULN unless bilirubin increase was due to Gilbert's disease.  Further 
evaluation should be performed to confirm and document the origin of increase. 
• AST and ALT ≤ 2.5 × institutional upper limit of normal (ULN) 
• Fasting cholesterol ≤ 300 mg/dL AND fasting triglycerides ≤ 300 mg/dL.  NOTE: In case 
one or both of these thresholds are exceeded, the patient can only be included after 
initiation of appropriate lipid lowering medication prior initiating study treatment. 
9. Females of childbearing potential must have a negative serum or urine beta human chorionic 
gonadotropin (β-hCG) pregnancy test result within  72 hours prior to the first dose of 
itacitinib and must agree to use an effective contraception method during the study and for 6 
months following the last dose of study drug; females of non-childbearing potential are those 
who are post-menopausal for more than 1 year or who have had a bilateral tubal ligation or 
hysterectomy.  Female patients undergoing active fertility preservation therapy/egg 
harvesting which include hCG injections are expected to have mild elevation of hCG.  These 
patients may be allowed to participate in the trial despite elevation of hCG after providing 
documentation of negative hCG prior the hCG injection and statement from her fertility 
specialist that they are not pregnant. 
10. Males who have partners of childbearing potential must agree to use an effective 
contraceptive method during the study and for 6 months following the last dose of study 
drug. 
11. Must be able to comply with the study and follow-up requirements. 
12. Subject must have access to everolimus via insurance or self-pay. 
 

 
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4.2 
Exclusion Criteria 
1. Unable to sign informed consent form. 
2. Pregnant or breast-feeding females (lactating females must agree not to breast feed while 
taking the investigational agents). 
3. Any condition, including the presence of laboratory abnormalities, which places the subject 
at unacceptable risk if he/she were to participate in the study or confounds the ability to 
interpret data from the study.  For Example: 
• symptomatic congestive heart failure of New York Heart Association Class III or IV 
(Appendix 13.5) 
• unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction 
within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any 
other clinically significant cardiac disease  
• severely impaired lung function with O2 saturation that is 88% or less at rest on room air  
• active (acute or chronic) or uncontrolled severe infections 
• condition requiring ongoing use of medications that are considered STRONG or 
MODERATE CYP3A4 inhibitors or inducers and P-gp substrates at study screening.  
However, those who require weak inhibitors/inducers can be enroll at discretion of the PI. 
See Appendix 13.2 for a list of excluded and cautionary concomitant medications. 
• liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).  
4. Has a history (within the past 12 months) of (non-infectious) pneumonitis requiring systemic 
steroids, or active pneumonitis. 
5. Bilirubin < 3 × ULN in the presence of liver metastases or presence of documented Gilbert's 
syndrome (unconjugated hyperbilirubinemia) 
6. Concurrent use of other anti-cancer agents or therapies during study treatment. 
7. Use of any other experimental drug or therapy within 28 days of initiating treatment with the 
investigational agents. 
8. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), 
hepatitis C (HCV), or hepatitis B virus (HBV); patients who are seropositive because of 
hepatitis B virus vaccine are eligible. 
9. Previous use of JAK1 inhibitor (itacitinib), or history of progression on everolimus. 
 
4.3 
Subject Recruitment 
Subjects will be recruited from the clinical oncology practices at the Hospital of the University 
of Pennsylvania.  Subjects will not be reimbursed for participation. 

 
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4.4 
Duration of Study Participation 
From enrollment, subjects will remain on active treatment for up to two (2) years, or until 
progression, intolerance, withdrawal of the consent, or termination of the study.  Additional 
cycles of investigational treatment may be added if in the opinion of the investigator that the 
benefit risk ratio for the subject continues to be favorable.  Patients who, after starting this 
investigational combination therapy, lose the ability to obtain everolimus commercially and do 
not take it for duration of 28 days, will be taken off study.  After end of treatment (EOT) visit, 
subjects will remain in follow-up for an additional two years.   
4.5 
Total Number of Subjects and Sites  
The total planned number of evaluable subjects at UPenn will be 23 (including those in Phase I 
and II portions).  To complete Phase I portion utilizing the 3 + 3 design, it is expected that 6 to 
12 subjects will be enrolled.  For phase II, 11 to 17 subjects will be enrolled.  It is expected that 
total of 17-20 subjects will be treated at the RP2D dose since 3 to 6 patients from Phase I will be 
treated under the same regimen as Phase II patients.  In order to be included in the tolerability 
review of Phase I, subjects must have received the cohort-specific dose of itacitinib and 
everolimus for at least 75% of the days during the first 28-day surveillance period or have 
experienced a DLT.  Up to 5 additional subjects may be enrolled to achieve a minimum cohort 
size should withdrawal or dose interruptions/reductions result in subjects being non-evaluable 
during Phase I. 
4.6 
Vulnerable Populations  
No vulnerable populations will be recruited. 
4.7 
Telemedicine Visits 
To safeguard the welfare of subjects during COVID surges and/or situations that may negatively 
impact their safety, telemedicine visits may be utilized. The telemedicine option will be 
discussed with the subject prior to the scheduled visit. Visit documentation will state that the 
visit was conducted via telemedicine, and it will state which intervention(s) and/or assessment(s) 
were and were not completed. If clinically indicated, labs may be performed at an outside testing 
facility. 
5 TREATMENT 
5.1 
Itacitinib 
5.1.1 
Description of Itacitinib 
Refer to Section 1.2.1 
5.1.2 
Intervention Regimen 
In Phase I, itacitinib tablets will be administered orally (PO) at the cohort-specific dose (Refer to 
Table 1/Figure 1) QD.  In Phase II, itacitinib tablets will be administered PO at the RP2D 
identified in Phase I. 

 
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Subjects may have dose reductions of itacitinib during the course of treatment based on AEs, 
clinical evaluation, and laboratory assessments.  See Section 5.6.1 for itacitinib dose 
modification guidance. 
Subjects are permitted to remain on itacitinib until withdrawal from study treatment is 
considered necessary or until 2 years of therapy.  Additional cycles of investigational treatment 
may be added if in the opinion of the investigator that the benefit risk ratio for the subject 
continues to be favorable.     
5.1.3 
Receipt 
Itacitinib will be provided to the study team as 100 mg tablets.  All Incyte investigational product 
labels will be in the local language and will state “Caution: New Drug--Limited by Federal (or 
United States) law to investigational use.” 
5.1.4 
Storage 
All itacitinib drug product should be stored at ambient conditions (15°C to 30°C, or 59°F to 
86°F). 
5.1.5 
Preparation 
No preparation is required.   
5.1.6 
Administration and Accountability 
Itacitinib may be taken without regard to food.  Due to the potential for WBC margination, blood 
samples should be collected before study treatment administration at all applicable study visits. 
The subject must be instructed in the handling of itacitinib as follows: 
• Store the study medication at room temperature (15°C to 30°C, or 59°F to 86°F). 
• Remove only the number of tablets from the study drug bottle needed at the time of 
administration. 
• Do not remove doses in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed doses. 
• Take study medication with a glass of water. 
• Do not take another dose if vomiting occurs after taking study medication. 
• Do not take study medication on the day of clinic visits until after blood samples are 
collected. 
• Keep study drug in a safe place and out of reach of children. 
• Bring all used and unused study medication to the site at each visit. 
 

 
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5.2 
Everolimus 
5.2.1 
Description of Everolimus 
Refer to Section 1.2.2 
5.2.2 
Intervention Regimen 
In Phase I and II, everolimus tablets will be administered orally (PO) at 5 mg QD.  
5.2.3 
Receipt 
Everolimus will be acquired by the subject from a commercial pharmacy.  The subject is 
prescribed 28 - 5 mg tablets, packaged in a carton (typically 4 individual blister cards each 
containing 7 tablets for a total of 28 tablets).  However, if the pharmacy has to substitute the 
5 mg strength (e.g., due to a shortage), the only substitution permitted is a 2.5 mg everolimus 
tablet.  The subject should contact the clinic at the time the pharmacy informs them of the issue. 
5.2.4 
Storage 
Everolimus tablets must be stored in accordance with storage conditions and shelf life as 
indicated in the manufacturer's approved label.  Tablets are blister-packed under aluminum foil, 
which should be opened only at the time of administration as drug is both hygroscopic and light-
sensitive. 
5.2.5 
Preparation 
No preparation is required.   
5.2.6 
Administration and Accountability 
Subjects will be instructed on how to handle their medication.  Everolimus should be 
administered orally once daily, preferably in the morning, at the same time as the itacitinib every 
day with or without food.  Everolimus tablets should be swallowed whole with a glass of water.  
The tablets must not be chewed or crushed.   
The subject must be instructed in the handling of everolimus as follows: 
• Store the study medication at room temperature. 
• Remove only the number of tablets from the study drug blister pack as needed at the time 
of administration. 
• Do not remove doses in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed doses. 
• Take study medication with a glass of water. 
• Do not take another dose if vomiting occurs after taking study medication. 

 
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• Do not take study medication on the day of clinic visits until after blood samples are 
collected. 
• Keep study drug in a safe place and out of reach of children. 
• Bring all used and unused study medication to the site at each visit. 
 
5.3 
Overdose 
Any dose of itacitinib or everolimus in excess of that specified in this Protocol is considered to 
be an overdose.  Signs and symptoms of an overdose that meet any SAE criterion must be 
reported as a SAE in the appropriate timeframe and documented as clinical sequelae to an 
overdose.  Subjects who ingested more than the recommended dosage are instructed to 
immediately contact the study team and should be closely monitored and given appropriate 
supportive treatment.  
5.4 
Subject Compliance Monitoring 
The subject compliance with the investigational regimen will be assessed during the scheduled 
visits via discussions with the subject and a count of the returned study drugs.  Subjects will also 
be instructed to bring all study drugs with them to the study visits in order for site personnel to 
conduct tablet counts to assess study drug accountability.  If subjects are determined to be non-
compliant with the regimen, they may be removed from the trial at investigator discretion. 
5.5 
Return or Destruction of Investigational Product 
Subjects will be asked to return all empty containers/blister packs and any unused study 
medication to each visit (see Sections 5.1.6 and 5.2.6).  Unused itacitinib will be destroyed by 
the IDS pharmacy, when so authorized by the Sponsor.  The everolimus is being dispensed 
through a specialty pharmacy contracted with the subject’s insurance company. Study staff will 
adequately document pill counts and start/stop dates in the subject’s EMR, but study staff will 
not collect or store unused everolimus that was supplied to a subject through their insurance 
company. 
5.6 
Modifications after DLT period 
For subjects who are unable to tolerate the protocol-specified dosing schedule after DLT period 
(Cycle 1), dose adjustments are permitted in order to keep the subject on study drug for both 
itacitinib and everolimus.  Treatment should also be delayed for major events (major events are 
non-treatment-related grade 3 and 4 hematologic and non-hematologic toxicities) if drug 
administration may further complicate the non-treatment related event.  If a major event requires 
a delay of treatment, treatment must be delayed until toxicity is resolved (≤ Grade 1 or ≤ 
baseline).  For treatment-related toxicities and major events after the DLT period (for both 
phase I and II), if toxicity is not resolved in 4 weeks, subject will be permanently taken off study. 
In a study using concurrent oral medications, it may be challenging to determine attribution 
especially since there may be some overlapping toxicities (e.g. cytopenias).  Therefore, unless 

 
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there is a clear attribution to one of the drugs, both drugs (itacitinib and everolimus) will be held 
or adjusted at the same time due to adverse events according to the guidelines below in Table 3. 
5.6.1 
Dose Modification for Hematologic and Non-Hematologic Toxicities  
Treatment with itacitinib and everolimus may be delayed up to 4 weeks (28 days) to allow for 
resolution of toxicity.  Subjects may resume treatment if no medical condition or other 
circumstance exists that, in the opinion of the investigator, would make the subject unsuitable for 
further participation in the study.  The treating investigator should contact the Sponsor Medical 
Director to discuss the case of any subject whose treatment has been delayed for more than 28 
days before restarting treatment with itacitinib and everolimus. 
Because subjects may enter the study with extensive pretreatment and/or severe bone marrow 
infiltration by the primary disease, dose interruption and reduction rules are provided as 
guidelines (see Table 3, Table 4, Table 5 and Table 6).  Individual decisions regarding dose 
reduction following the DLT period should be made using clinical judgment, taking into account 
relatedness of the AE to the study drug and the subject's underlying condition.  Adverse events 
that have a clear alternative explanation or transient (≤ 72 hours) abnormal laboratory values 
without associated clinically significant signs or symptoms may be exempt from dose-reduction 
rules. 
Table 3: Guidelines for Interruption and Restarting Study Drugs due to AEs 
suspected to result from itacitinib or everolimus 
ADVERSE EVENT 
ACTION TAKEN 
CHEMISTRY 
• 
AST and/or ALT > 3.0 × ULN or 
> 3.0 of the baseline if baseline 
was abnormal 
Step 1: Interrupt itacitinib and everolimus up to 28 days until the 
toxicity has resolved to ≤ Grade 1 (unless approved otherwise by the 
medical director). 
Step 2: Restart itacitinib and everolimus at same dose, if unrelated.  If 
assessed as related to itacitinib, restart at next lower dose.  If assessed as 
related to everolimus, restart at next lower dose.  Monitor as clinically 
indicated. 
HEMATOLOGY 
• 
ANC ≤ 1.0 × 109/L unless due to 
underlying disease  
• 
Platelet count is < 60 × 109/L 
unless due to underlying disease 
Step 1: Interrupt itacitinib and everolimus up to 28 days until the 
toxicity has resolved to ≤ Grade 1 or pre-therapy baseline.  
Step 2: Restart itacitinib and everolimus at same dose; monitor as 
clinically indicated. 
• 
Grade 4 ANC (< 0.5 × 109/L)  
• 
≥ Grade 3 ANC with an oral 
temperature of at least 38.5°C 
OR with ≥ Grade 3 infection.  
• 
Platelet count is < 35 × 109/L  
Step 1: Interrupt itacitinib and everolimus up to 28 days until the 
toxicity has resolved to ≤ Grade 1.  
Step 2: Restart itacitinib and everolimus at same dose, if unrelated.  If 
assessed as related to itacitinib, restart at next lower dose.  If assessed as 
related to everolimus, restart at the next lower dose.  Monitor as 
clinically indicated. 

 
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ADVERSE EVENT 
ACTION TAKEN 
OTHER 
• 
Any Grade 1 or Grade 2 toxicity  
Continue study treatment and treat the toxicity; monitor as clinically 
indicated. 
• 
Any Grade 3 toxicity, if 
clinically significant and not 
manageable by supportive care 
Step 1: Interrupt itacitinib and/or everolimus up to 28 days until the 
toxicity has resolved to ≤ Grade 1. 
Step 2: Restart itacitinib and/or everolimus at same dose if unrelated.  
If assessed as related to itacitinib, restart at next lower dose.  If assessed 
as related to everolimus, restart at the next lower dose.  Monitor as 
clinically indicated.   
• 
Any recurrent Grade 3 toxicity 
after dose reductions  
Discontinue study itacitinib and/or everolimus administration.  
Exceptions require approval of sponsor. 
• 
Any other Grade 4 toxicity  
Discontinue itacitinib and/or everolimus administration.  Exceptions 
require approval of sponsor.   
 
Table 4: Guidelines for Interruption and Restarting Study Drugs due to AEs 
suspected to result from everolimus 
ADVERSE EVENT 
ACTION TAKEN 
Non-infectious Pneumonitis 1 
Grade 1 
No specific therapy is required  
Administer 100% of everolimus dose.  However, depending on the clinical scenario, 
investigator may hold everolimus during the work-up. 
Grade 2 
Symptomatic only.  Prescribe corticosteroids if cough is troublesome.   
Hold until recovery to ≤ Grade 1.  Subjects will be withdrawn from the study if they 
fail to recover to ≤ Grade 1 within 28 days.   
Grade 3 
Prescribe corticosteroids if infective origin is ruled out.  Taper as medically indicated.   
Hold treatment until recovery to ≤ Grade 1.  May restart protocol treatment within 28 
days at a reduced dose (by one level) if evidence of clinical benefit.  
Subjects will be withdrawn from the study if they fail to recover to ≤ Grade 1 within 
28 days.   
Grade 4 
Prescribe corticosteroids if infective origin is ruled out.  Taper as medically indicated.   
Discontinue treatment.   
Stomatitis 1 
Grade 1 
Use conservative measures such as non-alcoholic mouth wash or salt water (0.9%) 
mouth wash several times a day until resolution 
Grade 2  
Withhold everolimus until improvement to Grade 0 or 1. Resume at same dose.  
If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of 
previous dose; change to every other day dosing if the reduced dose is lower than the 
lowest available strength. 
Grade 3 
Withhold everolimus until improvement to Grade 0 or 1. Resume at 50% of previous 
dose; change to every other day dosing if the reduced dose is lower than the lowest 
available strength. 

 
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ADVERSE EVENT 
ACTION TAKEN 
Grade 4 
Discontinue treatment. 
Hyperlipidemia 
Grade 2 
Treat with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g., 
atorvastatin, pravastatin) or appropriate lipid-lowering medication, in addition to diet.  
Subjects should be monitored clinically and through serum biochemistry for the 
development of rhabdomyolysis and other adverse events as required in the product 
label/data sheets for HMG-CoA reductase inhibitors. 
Grade 3  
Withhold everolimus until improvement to Grade 0, 1, or 2. Resume at 50% of 
previous dose 
Grade 4 
Discontinue treatment.   
For additional details, refer to section 5.6.2 
 
Table 5: Guidelines for Dose Reductions for Itacitinib 
Current Dose 
First Dose Reduction 
Second Dose Reduction 
300 mg QD 
200 mg QD 
Discontinue 
400 mg QD 
300 mg QD 
200 mg QD 
200 mg QD 
Discontinue 
Discontinue 
 
Table 6: Guidelines for Dose Reductions for Everolimus 
Current Dose 
First Dose Reduction 
Second Dose Reduction 
5 mg QD 
2.5 mg QD 
Discontinue 
2.5 mg QD 
Discontinue 
Discontinue 
 
5.6.2 
Adverse Events Described with Everolimus and Management 
5.6.2.1 
Non-infectious Pneumonitis 
Non-infectious pneumonitis is a class effect of rapamycin derivatives.  Cases of non-infectious 
pneumonitis (including interstitial lung disease) have also been described in subjects taking 
everolimus.  Some of these have been severe and on rare occasions, a fatal outcome was 
observed. 
A diagnosis of non-infectious pneumonitis should be considered in subjects presenting with non-
specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and 
in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of 
appropriate investigations.  Subjects should be advised to report promptly any new or worsening 
respiratory symptoms. 
Subjects who develop radiological changes suggestive of non-infectious pneumonitis and have 
few or no symptoms may continue everolimus therapy without dose alteration.  If symptoms are 

 
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moderate (Grade 2), consideration should be given to interruption of therapy until symptoms 
improve.  The use of corticosteroids may be indicated.  Everolimus may be reintroduced at a 
reduced dose until recovery to Grade 1 or better. 
For cases where symptoms of non-infectious pneumonitis are severe (Grade 3), everolimus 
therapy should be discontinued and the use of corticosteroids may be indicated until clinical 
symptoms resolve.  Therapy with everolimus may be re-initiated at a reduced dose depending on 
the individual clinical circumstances. 
5.6.2.2 
Hyperlipidemia and Management 
Everolimus has been described to cause hyperlipidemia in some subjects.  Treatment of 
hyperlipidemia should take into account the pre-treatment status and dietary habits.  Blood tests 
to monitor hyperlipidemia must be taken in the fasting state.  Grade 2 hypercholesterolemia 
(> 300 mg/dL) or Grade 2 hypertriglyceridemia (> 300 mg/dL) should be treated with a 3-
hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g., atorvastatin, pravastatin) or 
appropriate lipid-lowering medication, in addition to diet.  Subjects should be monitored 
clinically and through serum biochemistry for the development of rhabdomyolysis and other 
adverse events as required in the product label/data sheets for HMG-CoA reductase inhibitors. 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with 
an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, 
markedly elevated creatine kinase (CPK) levels and myoglobinuria, acute renal failure and 
sometimes death.  The risk versus benefit of using this therapy should be determined for 
individual subjects based on their risk of cardiovascular complications of hyperlipidemia.  See 
section 10 for additional information on risk. 
5.6.2.3 
Stomatitis and Management 
Everolimus has been described to cause stomatitis/oral mucositis/mouth ulcers in some subjects.  
It should be treated using local supportive care. 
Follow the paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers: 
• For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth 
wash or salt water (0.9%) mouth wash several times a day until resolution. 
• For more severe toxicity (Grade 2 in which case subjects have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case subjects cannot maintain 
adequate oral alimentation), the suggested treatments are topical analgesic mouth 
treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as 
triamcinolone oral paste 0.1% (Kenalog in Orabase®). 
• Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen 
mouth ulcers.  It is preferable to avoid these agents. 
• Antifungal agents must be avoided unless a fungal infection is diagnosed.  In particular, 
systemic imidazole antifungal agents (ketoconazole, fluconazole, itraconazole, etc.) 
should be avoided in all subjects due to their strong inhibition of everolimus metabolism, 

 
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thereby leading to higher exposures.  Therefore, topical antifungal agents are preferred if 
an infection is diagnosed.   
 
6 STUDY EVALUATIONS AND PROCEDURES 
6.1 
Screening  
The screening period is the interval between the signing of the ICF and the day that the subject is 
enrolled in the study (Day 1).  Informed consent must be obtained before performing any study-
specific procedures, but imaging from standard of care prior to screening will be acceptable for 
baseline tumor measurement.  A subject who fails screening may repeat the screening process 1 
time if the investigator believes there has been a change in eligibility status (e.g., following 
recovery from an infection).  Any screening studies done outside of this site’s standard of care to 
obtain everolimus (ie any additional imaging or blood work) will be delayed until after 
everolimus was secured from insurance.  Assessments that are required to demonstrate eligibility 
may be performed over the course of 1 or more days during this phase: 
• Review and signing of the Informed Consent Form 
• Complete medical history, including prior and current medications, treatments, and anti-
cancer therapies. 
• Physical Exam and evaluation of ECOG PS (Appendix 13.3) 
• Vital signs, including blood pressure, heart rate, oral temperature and weight 
• Imaging with PET/CT scan or CT scan or MRI scan to obtain baseline tumor 
measurements (within 8 weeks prior to initiating study treatment) 
• Complete blood count with WBC differential, serum chemistry panel including sodium, 
potassium, chloride, CO2, calcium, serum creatinine, BUN, total bilirubin, alkaline 
phosphatase, AST, ALT, albumin, uric acid, LDH, and erythrocyte sedimentation rate 
• Viral screening tests to include testing for Hepatitis B (hepatitis B core antibody, hepatitis 
B surface antigen, hepatitis B surface antibody), Hepatitis C (hepatitis C antibody), HIV 
(HIV 1 and 2 antibody or viral load) 
• Fasting lipid profile (triglycerides, total cholesterol, HDL and LDL) 
• For women of childbearing potential, a serum pregnancy test must be performed within 
72 hours prior to initiating treatment with itacitinib and everolimus unless the subject was 
undergoing egg harvesting (including hCG injections which may cause in elevated hCG 
levels) within 3 weeks prior to starting therapy; for those subjects, written statement from 
the treating fertility specialist is required to document that subject is not pregnant. 
 

 
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6.2 
Concomitant Medications 
Prior and concomitant medications and procedures will be reviewed to determine study 
eligibility. 
Both itacitinib and everolimus are metabolized by CYP 3A4.  Subjects will be instructed not to 
take any additional excluded medications (including over-the-counter products; see 
Appendix 13.2) during the course of the study without prior consultation with the investigator.  
At each visit, the investigator will ask the subject about any new medications he/she is or has 
taken after the start of the study drug. 
All Concomitant medications/Significant non-drug therapies taken ≤ 30 days prior to start and 
after start of study drug, including physical therapy and blood transfusions, should be recorded. 
The following conditions apply during the entire duration of the study:  
• No other investigational therapy should be given to subjects. 
• No anticancer agents other than the study medication should be given to subjects.  If such 
agents are required for a subject then the subject must be withdrawn from the study. 
• Oral contraceptives in preclinical and clinical data have shown everolimus to have 
CYP3A4 inhibitory activity rather than induction activity, induction of metabolism of 
contraceptive hormones by everolimus is unlikely.  Consequently, administration of 
everolimus should not reduce the efficacy of oral contraceptives. 
• No chronic treatment with systemic steroids (at a dose equivalent of greater than 20 mg 
prednisone per day) or other immunosuppressive agents.  Topical or inhaled 
corticosteroids are allowed. 
• The use of live vaccines and close contact with those who have received live vaccines 
should be avoided during the study treatment.  Examples of live vaccines include 
intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, some 
varicella and TY21a typhoid vaccines. 
• Oral anticoagulants such as warfarin are CYP2C9 substrates and, as such, no interaction 
with everolimus/itacitinib is expected.  However, drug-drug interaction studies between 
macrolide antibiotics and warfarin have produced mixed outcomes and the disparity in 
these findings has led to the conclusion that multiple factors may alter the clearance of 
warfarin.  The co-administration of everolimus/itacitinib and oral anticoagulants is 
possible but should be subject to verification of coagulation (INR) once steady state is 
reached. 
• All subjects will be treated prophylactically with an antiviral agent (e.g., acyclovir) to 
prevent varicella re-activation or other viral infections 
Inhibitors of CYP3A4 and/or P-gp 
Co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) 
or P-glycoprotein (P-gp) should be avoided.  See Appendix 13.2 for detailed list of medications. 

 
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Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole) or P-gp 
inhibitors should be used with caution.  If subject requires co-administration of moderate 
CYP3A4 inhibitors or P-gp inhibitors, reduce the dose of everolimus to half the currently used 
dose.  If the inhibitor is discontinued the everolimus dose should be returned to the dose used 
prior to initiation of the moderate CYP3A4/P-gp inhibitor. 
Seville orange, star fruit, grapefruit and their juices affect P450 and P-gp activity.  Concomitant 
use should be avoided. 
See Table 7 for a summary of actions to be taken when the use of a CYP3A4/P-gp inhibitor is 
required. 
Table 7: Recommended Dosage Modifications for Concurrent Use of a P-gp 
substrate or CYP3A4 Inhibitor 
Type of CYP3A4 
inhibitor or P-gp 
substrate 
ACTION TAKEN 
Strong Inhibitor 
For temporary use – discontinue both agents (everolimus and itacitinib) until 
completion of inhibitor therapy. 
For extended use (> 28 days) – discontinue from study.  
Moderate Inhibitors 
Reduce treatment of both agents (everolimus and itacitinib) to 50% during 
treatment with moderate inhibitors. 
Weak Inhibitors 
Use caution.  No treatment adjustments required. 
Note: See appendix 13.2 for a list of CYP3A4 inhibitors and P-gp substrates  
 
Inducers of CYP3A4 and/or P-gp  
Avoid the use of strong CYP3A4 inducers.  If subject requires co-administration of strong 
CYP3A4 inducers (i.e., phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital, St. John’s 
wort), he or she should be removed from study.  See Appendix 13.2 for detailed list of 
medications. 
See Table 8 for a summary of actions to be taken when the use of a CYP3A4 inducer or P-gp 
substrate is required. 
Table 8: Recommended Dosage Modifications for Concurrent Use of a P-gp 
substrate or CYP3A4 Inducer 
Type of P-gp substrate or 
CYP3A4 Inducer 
ACTION TAKEN 
Strong Inducer 
For temporary use - Use caution.  No treatment adjustments required.  
For extended use (> 28 days) – discontinue from study.  
Moderate Inducer 
Use caution.  No treatment adjustments required. 
Weak Inducer 
Use caution.  No treatment adjustments required. 
Note: See appendix 13.2 for a list of P-gp substrate or CYP3A4 Inducer 
 

 
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6.3 
Diet/Activity/Other Considerations 
6.3.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.  They will be instructed to avoid Seville orange, star fruit, 
grapefruit and their juices. 
6.3.2 
Contraception 
Everolimus and/or itacitinib may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if everolimus and/or itacitinib have transient adverse effects on the composition of sperm.  
Therefore while enrolled, all subjects must agree not to participate in a conception process (i.e. 
active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization, etc.). 
Female subjects of reproductive potential (women who have reached menarche or women who 
have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses 
within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy 
or bilateral oophorectomy]) must have a negative serum or urine pregnancy test performed 
within 72 hours of Cycle 1/Day 1 per Table 9 Schedule of Study Procedures. 
All participants participating in sexual activity that could lead to pregnancy must agree to use 
two methods of birth control.  The two birth control methods can be either two barrier methods 
or a barrier method plus a hormonal method to prevent pregnancy.  Subjects should start using 
birth control from screening throughout the study period up to 120 days after the last dose of 
study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm with 
spermicide (cannot be used in combination with cervical cap), cervical cap with spermicide (only 
if you have not given birth), male condom or female condom, contraceptive sponge (only if you 
have not given birth).  Hormonal contraceptives (estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection.  
Intrauterine Device (IUD), surgical sterility (tubal ligation or a partner that has undergone a 
vasectomy), or contraceptive rod implanted into the skin is also considered an acceptable method 
of birth control as long as a barrier method is also utilized.   
Subjects may also agree to agree to completely abstain from intercourse during participation in 
this study and for 120 days after your last dose of study drug.  Abstinence at certain times of the 
cycle only, such as during the days of ovulation, after ovulation and withdrawal are not 
acceptable methods of birth control. 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement above.  If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study. 

 
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6.3.3 
Use in Nursing Women 
It is unknown whether the study drugs are excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment. 
6.4 
Study Intervention Phase 
 
6.4.1 
Cycle 1 Day 1 
• Physical Examination and evaluation of ECOG PS (Appendix 13.3)   
• Vital signs: blood pressure, heart rate, temperature, weight, oxygen saturation 
• Baseline QOL FACT-lym questionnaire (Appendix 13.1; does not need to be repeated if 
done within 14 days prior to starting therapy) 
• CBC with WBC differential and platelets (does not need to be repeated if previously 
performed within 3 days of starting treatment with itacitinib and everolimus) 
• Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT, uric acid, LDH, and 
erythrocyte sedimentation rate (does not need to be repeated if previously performed 
within 3 days of starting treatment with itacitinib and everolimus) 
• For women of childbearing potential, a serum pregnancy test must be performed within 
72 hours prior to initiating treatment with itacitinib and everolimus unless the subject is 
actively undergoing egg harvesting (including HCG injections) 
 
6.4.2 
Cycle 1 Day 8 (+/- 3 Days)  
• Physical Examination and evaluation of ECOG PS (Appendix 13.3)   
• Vital signs: blood pressure, heart rate, temperature, weight, oxygen saturation   
• CBC with differential and platelets (does not need to be repeated if previously performed 
within 24 hours before Day 8 Visit) 
• Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT, uric acid, and LDH 
(does not need to be repeated if previously performed within 24 hours before Day 8 Visit)   
• Review of interim adverse events and concomitant medications 
 
Note:  Only CBC and CMP results must be received before the subject can proceed with 
mediation treatment.   Other test results may be received after the subject has received 
mediation treatment. 

 
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6.4.3 
Cycle 1 Day 15 (+/- 3 Days) 
• Physical Examination and evaluation of ECOG PS (Appendix 13.3)   
• Vital signs: blood pressure, heart rate, temperature, weight, oxygen saturation   
• CBC with differential and platelets (does not need to be repeated if previously performed 
within 24 hours before Day 15 Visit) 
• Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT (does not need to be 
repeated if previously performed 24 hours before Day 15 Visit) 
• Review of interim adverse events and concomitant medications 
• QOL FACT-lym questionnaire (Appendix 13.1) 
 
Note:  Only CBC and CMP results must be received before the subject can proceed with 
mediation treatment.  Other test results may be received after the subject has received 
mediation treatment. 
6.4.4 
Cycle 1 Day 22 (+/- 3 days) 
• CBC with differential and platelets (does not need to be repeated if previously performed 
within 24 hours before Day 22 Visit) 
• Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT (does not need to be 
repeated if previously performed 24 hours before Day 22 Visit) 
 
6.4.5 
Cycles 2-24 Day 1 (+/- 7 days) 
• Physical Examination and evaluation of ECOG PS (Appendix 13.3)   
• Vital signs: blood pressure, heart rate, temperature, weight, and oxygen saturation   
• CBC with differential and platelets (does not need to be repeated if previously performed 
within 24 hours before Day 1 Visit) 
• Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT, uric acid, LDH, and 
erythrocyte sedimentation rate (does not need to be repeated if previously performed 24 
hours before Day 1 Visit)  
• Review of interim adverse events and concomitant medications 
• Fasting lipid profile every 2 months during active therapy (triglycerides, total cholesterol, 
HDL and LDL) – starting with Day 1 of Cycle 2. 
• QOL FACT-lym questionnaire (Appendix 13.1) 

 
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Note:  Only CBC and CMP results must be received before the subject can proceed with 
mediation treatment.  Other test results may be received after the subject has received mediation 
treatment. 
Additional cycles of investigational treatment may be added if in the opinion of the investigator 
that the benefit risk ratio for the subject continues to be favorable.  During these additional 
cycles, the same assessments will be captured as cycles 4-24. 
In the event that a telemedicine visit is conducted, the following tests will be postponed until the 
next in-person visit: 
• Physical examination 
• Vital Signs 
• Return of IP 
• Fact-lym QOL questionnaire 
 
6.4.6 
End of Treatment Visit (EOT) 
The following will be performed at the time of study discontinuation, whether due to study 
completion or early withdrawal from study participation.  This visit should occur within 28 days 
from the last dosing: 
• Physical Exam and evaluation of ECOG PS (Appendix 13.3) 
• Vital signs (Blood pressure, heart rate, temperature, weight, oxygen saturation) 
• CBC with differential and platelets 
• Serum chemistry panel including sodium, potassium, chloride, CO2, calcium, serum 
creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT, uric acid, LDH, and 
erythrocyte sedimentation rate 
• Fasting lipid profile 
• Serum pregnancy test (women of child-bearing potential) 
• Assessment of adverse events and concomitant medications 
• QOL FACT-lym questionnaire (Appendix 13.1) 
 
6.4.7 
Safety Assessments 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 28 days (+/- 7 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 as 

 
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described in section 8.3.  Reasonable effort should be made to have the subject return for the 
follow-up visit and report any AEs that may occur during this phase.  
If a subject is scheduled to begin a new anticancer therapy before the end of the safety follow-up 
period, the safety follow-up visit should be performed before new anticancer therapy is started.  
Once new anticancer therapy has been initiated, the subject will move into the survival follow-up 
period.  
6.4.8 
Follow-up Phase 
6.4.8.1 
Follow-up Period for Disease Status 
Subjects who discontinue study treatment for a reason other than disease progression will move 
into the disease status follow-up period for 2 years from the EOT visit.  They should be assessed 
at least every 3 months (+/- 30 Days) using physical exam and standard of care blood work 
(CBC with diff, Serum Chemistry panel including sodium, potassium, chloride, CO2, calcium, 
serum creatinine, BUN, total bilirubin, alkaline phosphatase, AST, ALT,) during the first year 
and every 6 months (+/- 30 Days) for the second year.  The follow-up portion of the study will 
end at 2 years from the EOT of the last subject or earlier once all subjects have discontinued 
study treatment, and all subjects have died, have withdrawn consent, or are lost to follow-up. 
The imaging frequency will be at the discretion of the treating physician, but at least every 6 
months (+/- 1 month) to monitor disease status during the first 2 years after EOT.  Every effort 
should be made to collect information regarding disease status until:  
• The start of new antineoplastic therapy 
• Disease progression  
• Death 
• The end of the study 
Patients who undergo HDT/allogeneic SCT within one year of completing study treatment will 
be followed for one year after the transplant, in order to collect data from the following events:  
GVHD, pulmonary complications, hepatic veno-occlusive disease, immune-mediated AEs, 
critical illness, and transplant-related mortality. 
6.4.8.2 
Follow-up for Survival Status 
Once a subject has confirmed disease progression, or starts a new anticancer therapy, the subject 
moves into the survival follow-up period.  The subject should then be contacted by telephone, 
email, visit, or by review of the subject’s EMR at least every 12 weeks, according to the tables 
below, to assess for survival status. Subject will remain enrolled until completion of follow-up, 
death, withdrawal of consent, or the end of the study, whichever occurs first.   

 
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Disease Follow-Up Phase (for subjects with non-disease progression) 
 
EOT + 28 
days 
EOT + 3 
mo. 
EOT + 6 
mo. 
EOT + 9 
mo. 
EOT +12 
mo. 
EOT + 18 
mo. 
EOT + 24 
mo. 
Physical 
 
X 
X 
X 
X 
X 
X 
Labs* 
 
X 
X 
X 
X 
X 
X 
All AEs** 
X 
 
 
 
 
 
 
Imaging 
 
 
X 
 
X 
X 
X 
* CBC with diff, serum chemistry panel including sodium, potassium, chloride, CO2, calcium serum creatinine, 
BUN, total bilirubin, alkaline phosphatase, AST, ALT 
** Related AEs should be followed until resolution, lost to follow up, or judged to be permanent 
 
Survival Follow-Up Phase (for subjects with disease progression or those who have started a 
new anticancer therapy) 
 
EOT* + 28 
days 
EOT + 12 
wks. 
EOT + 24 wks. 
EOT + 36 wks. 
EOT + 48 
wks.** 
All AEs*** 
X 
 
 
 
 
Check survival**** 
 
X 
X 
X 
X 
* Survival Follow-Up starts at EOT if PD, or if not PD, then when a new anticancer therapy starts 
** Every 12 weeks until death, withdrawal of consent, or the end of the study, whichever occurs first. 
*** Related AEs should be followed until resolution, lost to follow up, or judged to be permanent 
**** By telephone, email, visit, or review of EMR 
 
6.5 
Physical Examination 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician's assistant, or a certified registered nurse practitioner.  
The physical examination will include the following organ or body system assessments: skin; 
head, eyes, ears, nose, and throat; lungs; cardiovascular system; abdomen; extremities; lymph 
nodes. 
6.6 
Laboratory Assessment 
Specific laboratory assessments are listed in Table 9.  The total amount of blood to be 
drawn/collected over the course of the trial (from pre-trial to post-trial visits), including 
approximate blood volumes drawn/collected by visit and by sample type per subject may vary 
depending upon clinical course of the subject and length of time on trial.  Blood draws will be 
completed before the subject receives the morning dose of itacitinib. Subjects will be allowed to 
have lab work performed at external labs in the event that a study visit is conducted remotely, if 
clinically indicated. 

 
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6.7 
Radiographic Evaluations 
Subjects will undergo radiographic evaluations to assess disease status at the time points listed 
below.  Timing of radiographic evaluations may be altered based on clinical indication or the 
discretion of the treating physician.   
• Baseline imaging (preferably with FDG-PET/CT, but CT C/A/P or MRI C/A/P are also 
acceptable) within 8 weeks of starting therapy. 
• If imaging was performed as standard of care before signing of the ICF but within 8 
weeks of Day 1, then the results from that assessment may be recorded in the eCRF in 
lieu of a study-specific assessment. 
• Response assessment with imaging (investigator choice depending on clinical situation) 
at week 8 and 16 during the first 4 months of active therapy and every 16 weeks for the 
remaining active treatment period. 
• Imaging will be performed at least every 6 months during the 2 year follow-up period 
after EOT for patients who came off study for reasons other than progression and who 
did not start another therapy. 
 
6.8 
Unscheduled Visits 
An unscheduled visit can occur at any time during the study.  The date for the visit and any data 
(i.e. recording of new AEs) generated must be recorded in subject’s chart. 
6.9 
Subject Withdrawal  
6.9.1 
Treatment Discontinuation 
A subject may be discontinued from treatment regimen using itacitinib and everolimus prior to 
the expected completion for disease progression, failure to adhere to protocol requirements, 
failure to obtain everolimus or if the investigator or subject deems it in the subject’s best interest 
to discontinue.  The reason justifying study treatment discontinuation should be documented in 
the study records.  Subjects who discontinue the study regimen prior to completion will remain 
on study for follow-up, unless they withdraw consent.  All subjects who receive at least 1 dose of 
study drug will be followed for toxicity, response and survival unless they withdraw consent.   
A subject may be withdrawn from the study (during treatment or follow-up) for reasons 
including death, subject withdrawal of consent for further follow-up, if the subject is lost to 
follow-up, or at study termination by study sponsor or by Incyte (drug manufacturer/funding 
sponsor).  If the Sponsor and/or the Investigator should discover conditions arising during the 
study that indicate the subject should be terminated, an appropriate schedule for termination will 
be instituted.  All subjects who are terminated will complete EOT visit (see section 6.4.6). 
The investigator retains the right to terminate his participation in the study at any time.  Should 
this occur, the investigator is to notify the Sponsor in writing. 

 
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The sponsor may terminate the study electively or if required by regulatory decision (e.g., FDA 
request).  If the study is terminated prematurely, the sponsor will notify the investigators, the 
IRB and regulatory bodies of the decision and reason for termination of the study. 
 

 
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Table 9: Schedule of Study Procedures  
Study Phase 
Screening 
Cycle 1 
Cycles  
2-24d, p 
EOTl 
Disease 
Follow-up 
Survival 
Follow-up 
Study Days  
Day -28 to -1 
Day 1 
Day 8 ±3 
Day 15 ±3 
Day 22 ±3 
Day 1 ±7 
 
 
 
Visit Number  
1 
2 
3 
4 
5 
6 - 30 
31 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
X 
 
X 
X 
 
 
FACT-lym questionnaire 
 
Xj 
 
X 
 
Xq 
X 
 
 
Physical Examination 
X 
X 
X 
X 
 
Xq 
X 
Xf 
 
Vital Signs: BP, HR, T, WT, O2 
Saturation 
X 
X 
X 
X 
 
Xq 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
 
 
 
 
 
X 
 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
 
 
X 
 
 
Confirm that PCP prophylaxis was 
startedk 
 
X 
 
 
 
 
 
 
 
Clinical Laboratory  
Evaluationa,b, i, m, 
X 
Xn 
Xg 
Xg 
Xg 
Xh, n, q 
X 
Xf 
 
Antiviral Medicationo 
X 
 
 
 
 
 
 
 
 
Cohort Assignment (Phase I) 
 
X 
 
 
 
 
 
 
 
Dispense Investigational Product 
 
X 
 
 
 
Xr 
 
 
 
Everolimus Availability by Subject 
X 
 
 
 
 
 
 
 
 
Adverse Event Assessment   
 
 
X 
X 
 
X 
X 
 
 
Assess drug compliance/subject’s 
study calendar 
 
 
X 
X 
 
X 
X 
 
 
Imagingd 
X 
 
 
 
 
Xq 
X 
Xe 
 
Follow-up anti-cancer treatments 
 
 
 
 
 
 
 
 
X 
a  
Hematology parameters will include a complete blood count: white blood cells, red blood cells, hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils and bands (if reported). 

 
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b  
Serum chemistry parameters will include sodium, potassium, chloride, blood urea nitrogen (BUN), creatinine, glucose, calcium, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin, uric acid, LDH, erythrocyte sedimentation rate, and fasting lipid panel.  Uric acid and LDH shall be performed 
during Screening, Cycle 1 Day 1, Cycle 1 Day 8, Day 1 of Cycle 2 through Cycle 24, and EOT.  Erythrocyte sedimentation rate shall be performed during 
Screening, Day 1 of Cycle 1, Day 1 of Cycle 2 through Cycle 24, and EOT.  The fasting lipid panel will be drawn only on screening and Day 1 of every 2 
cycles (starting with Day 1 Cycle 2).  
c  
A serum pregnancy test will be performed at screening and EOT.  Urine pregnancy test will be performed only if pregnancy is suspected during treatment; 
positive results must be confirmed with a serum pregnancy test.  Pregnancy testing will only be required for women of childbearing potential. 
d  
Baseline imaging (preferably with FDG-PET/CT, but CT C/A/P or MRI C/A/P are also acceptable) within 8 weeks of starting therapy.  If imaging was 
performed as standard of care before signing of the ICF but within 8 weeks of Day 1 Cycle 1, then the results from that assessment may be recorded in the 
eCRF in lieu of a study-specific assessment.  Response assessment with imaging (investigator choice depending on clinical situation) at week 8 and 16 
during the first 4 months of active therapy and every 16 weeks for the remaining active treatment period.  Timing of each imaging is acceptable within +/- 1 
week of the protocol specified during first 4 months of therapy and +/- 2 weeks during the remaining active treatment period. 
e  
Imaging will be performed at least every 6 months during the 2 year follow-up period after EOT and then at the discretion of the treating physician. 
f  
In disease follow-up phase – subjects who discontinue study treatment for a reason other than disease progression will be followed-up for 2 years from EOT.  
They should be assessed at least every 3 months (+/- 1 month) using physical exam and standard of care blood work during the first year and every 6 months 
(+/- 1 month) for the second year.  Imaging will be done every 6 months (+/- 1 month) during the 2 years of follow-up. 
g  
Plus/minus 3 days 
h  
Plus/minus 7 days 
i  
Viral screening tests to include testing for Hepatitis B (hepatitis B core antibody, hepatitis B surface antigen, hepatitis B surface antibody).  Hepatitis C 
(hepatitis C antibody), HIV (HIV 1 and 2 antibody or viral load) 
j  
Does not need to be repeated if done within 14 days prior starting study treatment 
k  
PCP prophylaxis (see appendix 13.6 for options) will start before or at Day 1 Cycle 1 and continue until EOT visit. 
l  
EOT visit should occur within 28 days of last dosing. 
m  Results may be obtained up to 3 days prior to treatment. 
n  
CBC and CMP results must be received before the subject can proceed with mediation treatment.   
o  
Antiviral medication to be taken for the duration of the active trial treatment  
p  
Additional cycles of investigational treatment may be added if in the opinion of the investigator that the benefit risk ratio for the subject continues to be 
favorable.  
q 
Not performed when visit is via telemedicine. If clinically indicated, labs may be performed at an outside testing facility. 
r 
Study medicine will be shipped directly to subject when a telemedicine visit occurs. 
 
 

 
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7 STATISTICAL PLAN 
7.1 
Sample size 
Sample size determination: Utilizing 3 + 3 design, 6 to 15 subjects will be enrolled to Phase I 
portion of the trial (with at least 6 subjects treated at RP2D).  Phase II will enroll 8 to 17 subjects 
depending on expansion needs in the Phase I portion.  At least 14 subjects will be treated at 
RP2D level and evaluable for CR rate.  The sample size for phase II was based on a decision 
between 2 pre-specified hypotheses about the probability of CR rate (p).  The null hypothesis H0: 
p = 5% reflects a response rate that would be of no clinical benefit compared to everolimus 
alone, and the alternative hypothesis Ha: p = 25% is a CR rate that might lead to larger, 
confirmatory studies.  Using a Simon 2-stage optimal design, a total of 17 subjects at RP2D will 
be needed for 80% power at 1-sided alpha = 0.05 level.  If by the 16 week visit there are no 
responders with CR from the first 9 evaluable subjects (at any itacitinib dose level), the null 
hypothesis will be considered as supported, and the study will be terminated. 
7.2 
Statistical Methods 
Time to event data including OS, PFS, DOR will be analyzed using Kaplan-Meier method, 
treating subjects with no observed death as censored at their last date known to be alive for OS or 
last documented tumor measurement for PFS and DOR.  Median survival and 90% CI will be 
estimated.  Overall survival data will continue to be collected until 75% of subjects have died, 
have withdrawn consent, or are lost to follow-up. 
7.2.1 
Interim Efficacy Analysis  
The efficacy analysis is based on Simon 2 stage optimal design and will be performed after the 
enrollment of the first 9 evaluable subjects.  If there are no responders with CR from the first 9 
evaluable subjects (at the 8 week or 16 week response assessment, at any itacitinib dose level), 
the null hypothesis (CR rate of 5% or lower with the new combination) will be considered as 
supported, and the study will be terminated.  If there are no CRs in the first three (3) patients 
(week 8 or 16), we will suspend the study enrollment and await final response assessment on all 
9 patients (6 in Phase I and 3 in Phase II).  The study will be considered successful if the total 
number of subjects with CR is ≥ 2 in Phase II (at the 8 week or 16 week response assessment). 
7.2.2 
Interim Safety Analyses  
The safety analysis is based on Bayesian probability calculations and will be performed after the 
first 6 subjects treated at the RP2D and then after enrollment of 9, 12, and 15 subjects at RP2D 
dose.  The max tolerated DLT (see section 3.2) rate is 30% and a beta prior of (1,5) is assumed 
(that is 1 DLT in 6 subjects).  The study will be terminated if 4 DLTs in 6 subjects, 5 in 9, 6 in 
12, or 7 in 15 are observed.  The posterior probability that the true DLT rate is above 30% at 
each stopping would be around 77 to 79% (79%, 78%, 78%, and 77% respectively). 
If there are two (2) study related deaths in the phase I portion, the study will be terminated. 

 
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7.3 
Subject Population for Analysis – Phase I 
In order to be included in the tolerability review, a subject must have received the cohort-specific 
dose of itacitinib and everolimus for at least 75% of the days during the 28-day DLT surveillance 
period or have experienced a DLT.  Additional subjects may be enrolled to achieve a minimum 
cohort size of 3-6 (see Figure 1) should withdrawal or dose interruptions/reductions result in a 
subject being non-evaluable.  Subjects who receive at least one dose of the combined treatment 
(itacitinib and everolimus) will be assessed for adverse events, response, survival and 
exploratory analyses (FACT-lym, resolution of B symptoms or pruritus).   
7.4 
Primary Analyses 
The primary endpoint of Phase I is safety and tolerability by evaluating the frequency, duration, 
and severity of AEs as assessed by the investigators using CTCAE v5.0 criteria.  The primary 
endpoint of Phase II is CR rate; a subject will be considered as a complete responder if his or her 
best overall response is CR on the Lugano Classification (Appendix 13.4) (Cheson et al 2014).  
The rate of responders will be estimated together with 90% confidence interval (CI).  The study 
will be considered successful if the total number of complete responders is ≥ 2 in Phase II. 
7.5 
Secondary Analyses  
Lugano Classification (Appendix 13.4) (19) will be used to evaluate efficacy in terms of ORR, 
CR, PR, SD.  Progression-free survival (PFS) will be determined from the enrollment date until 
the earliest date of disease progression, as measured by investigator assessment of objective 
radiographic disease assessments per Lugano Classification, or death due to any cause if earlier.  
Progression-free survival data will be analyzed using Kaplan-Meier method, treating subjects 
with no observed death or progression as censored at the last valid radiologic assessment visit.  
Median PFS and 90% CI will be estimated. 
Overall survival (OS) will be determined from the enrollment date until death.  Survival data will 
be analyzed using Kaplan-Meier method, treating subjects with no observed death as censored at 
their last date known to be alive.  Median survival and 90% CI will be estimated.  Overall 
survival data will continue to be collected until 75% of subjects have died, have withdrawn 
consent, or are lost to follow-up. 
The DOR is defined as the difference of the end of response and the start of response for subjects 
who have achieved a response.  The start of a response will be the first visit where the subject 
achieves PR or better based on the Lugano Classification.  The end of response will be the first 
visit where PD is assessed based on the Lugano Classification.  Duration of response will be 
assessed using Kaplan-Meier method for subjects who achieve a response.  Median duration and 
90% CI will be estimated.  Subjects who are still responding at the time of database freeze or 
discontinuation will be censored at the last valid radiologic assessment visit. 
7.6 
Other Analyses 
Exploratory end points include exploration of health-related quality of life during therapy 
(HRQOL) using The FACT-lym questionnaire.  This has been validated in subjects with various 
forms of lymphoma.  It contains 42 items (questions) covering HRQOL and common lymphoma 

 
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symptoms and treatment side-effects.  The questionnaire begins with the Functional Assessment 
of Cancer Therapy - General (FACT-G), which contains 27 items covering four core HRQOL 
subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), 
and Functional Wellbeing (7).  The FACT-Lym also includes an Additional Concerns subscale 
(15 items), addressing issues typically experienced by lymphoma subjects.  Some of the issues 
covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating.  
The FACT-Lym also asks subjects about their concerns about lumps and swelling, fevers, 
infections, weight, appetite, emotional stability and treatment.  Other exploratory endpoints 
include resolution of B symptoms (fevers over 100.4, drenching night sweats, weight loss of over 
10%) and pruritus.  We will also record the time it took between enrollment to resolution of these 
symptoms and the duration of the disease-related symptoms. 
7.7 
Subject Population for Analysis – Phase II 
In order to be included in the tolerability review, a subject must have received the cohort-specific 
dose of itacitinib and everolimus for at least 75% of the days during the 28-day DLT surveillance 
period or have experienced a DLT.  Additional subjects may be enrolled to achieve a minimum 
cohort size of 3, should withdrawal or dose interruptions/reductions result in a subject being non-
evaluable.  In order to be included in the efficacy evaluation, a subject must have received at 
least 21 days of study-specified therapy.  Subjects who receive at least one dose of the combined 
treatment (itacitinib and everolimus) will be assessed for adverse events, survival and 
exploratory analyses (FACT-lym, resolution of B symptoms or pruritus).   
8 SAFETY AND ADVERSE EVENTS 
8.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Intercurrent illnesses or injuries should be 
regarded as adverse events.   
A pre-existing condition should be recorded as an adverse event if the frequency, intensity or the 
character of the condition changes.  
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any of the 
following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality.  
• The abnormality suggests organ toxicity. 
• The abnormality is of a degree that requires active management. 

 
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Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that, 
in the view of either the investigator or the sponsor, is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.  They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-subject hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
Dose Limiting Toxicity 
See section 3.2 for a description of the Dose Limiting Toxicities (DLT). 
8.2 
Expected Adverse Events 
Refer to the itacitinib Investigator’s Brochure and the everolimus package insert for the expected 
adverse events. 
8.3 
Recording of Adverse Events 
Safety will be assessed by monitoring and recording potential adverse effects using the Common 
Toxicity Criteria version 5 at each study visit.  Participants will be monitored by medical 
histories, physical examinations, and other studies.  If CTCAE grading does not exist for an 
adverse event, the severity of mild, moderate, severe, life-threatening, and death, corresponding 
to Grades 1-5, will be used whenever possible. 
At each contact with the subject during the treatment phase of the study (before EOT), the 
investigator will seek information on adverse events by non-directive questioning and, as 
appropriate, by examination.  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.  Information on all adverse events will be recorded in the 
source documentation.  To the extent possible, adverse events will be recorded as a diagnosis and 
symptoms used to make the diagnosis recorded within the diagnosis event.   
As much as possible, each adverse event or follow-up information will be evaluated to 
determine: 
1. Severity grade (CTCAE Grade 1-5) 
2. Duration (start and end dates) 

 
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3. Relationship to the study treatment or process – [Reasonable possibility that AE is 
related: No (unrelated/ not suspected) or Yes (a suspected adverse reaction)].  If yes 
(suspected) - is the event possibly, probably or definitely related to the investigational 
treatment?  
4. Expectedness to study treatment or process – [Unexpected – if the event severity and/or 
frequency is not described in the investigator brochure (if applicable) or protocol]. 
5. Action taken with respect to study or investigational treatment or process (none, dose 
adjusted, temporarily interrupted, permanently discontinued, unknown, not applicable) 
6. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
7. Whether the event is serious 
 
Once an adverse event is detected, it should be followed until its resolution, the end of study 
visit, or until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the study 
treatment, the interventions required to treat it, and the outcome.  Related AEs should be 
followed until resolution, lost to follow up, or judged to be permanent. 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated 
Problems 
Reporting period 
Adverse events will be reported from the time of informed consent until EOT visit.  Once a 
subject enters into the safety follow up period as described in section 6.4.8, subjects will only be 
followed for unresolved adverse events. 
Investigator reporting: notifying the study sponsor 
Every SAE, regardless of suspected causality (e.g., relationship to study drug(s) or study 
procedure or disease progression) must be reported to the sponsor within 24 hours of learning of 
its occurrence.   
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 considered completely unrelated to a previously reported one should be 
reported separately as a new event.  
Send the notification (MedWatch or CIOMS form) to the Sponsor.   
New information regarding the SAE will be reported as it becomes available and in the same 
manner as the initial SAE (i.e. MedWatch or CIOMS).  The investigator must follow the event to 
resolution or until the event is deemed and documented irreversible, whichever is longer, up to 6 
months from the last treatment.  

 
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Investigator Reporting: Local Reporting Requirements  
The investigator will report AEs and SAEs to his/her IRB/EC of record and other local 
regulatory groups per the local requirements.  
8.5 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug or 
process may have interfered with the effectiveness of a contraceptive medication or method.  
When a pregnancy has been confirmed in a subject during maternal or paternal exposure to study 
drug and/or process, the following procedures should be followed to ensure subject safety: 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  Follow-
up should be conducted for each pregnancy to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
8.6 
Protocol Exceptions and Deviations 
Exception (Prospective action) 
An exception is defined as a one-time, intentional action or process that departs from the 
approved study protocol, intended for one occurrence.  If the action disrupts the study progress, 
such that the study design or outcomes may be compromised, or the action compromises the 
safety and/or welfare of study subjects, advance documented approval from the Regulatory 
Sponsor and local regulatory review committees, per institutional guidelines, is required.  
Approval from the Regulatory Sponsor must be received prior to submission to the local 
regulatory review committees. 
Deviation (Retrospective action) 
A deviation is defined as a one-time, unintentional action or process that departs from the 
approved study protocol, involving one incident and identified retrospectively.  If the deviation 
disrupts study progress, such that the study design or outcomes may be compromised, or the 
deviation compromises the safety and/or welfare of study subjects, the deviation must be 
reported to the Regulatory Sponsor within 5 days of PI knowledge and to local regulatory review 
committees per institutional guidelines.  
Report the following information on the Sponsor’s exception/deviation form:  
• Protocol number 
• Subject number 
• Description of the exception or deviation 
• Rationale 
• Impact on subject safety 
• Impact on data integrity 
 

 
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Deviations that are assessed by the PI to not disrupt the study progress, such as not affecting the 
study design or outcome, or compromising the safety and/or welfare of study subjects, should be 
documented in site records and contain documentation of the PI’s assessment. 
8.7 
Stopping Rules (safety and efficacy) 
The safety analysis is based on Bayesian probability calculations and will be performed after the 
first 6 subjects treated at the RP2D and then after enrollment of 9, 12, and 15 subjects at RP2D 
dose.  The maximum rate of unacceptable toxicity (AEs that would fit the definition of DLT 
from phase 1 at any point or AEs that do not allow the subject to restart treatment within 28 
days) is 30% and a beta prior of (1,5) is assumed (that is 1 unacceptable toxicity in 6 subjects).  
The study will be terminated if 4 unacceptable toxicities in 6 subjects, 5 in 9, 6 in 12, or 7 in 15 
are observed.  The posterior probability that the true rate of unacceptable toxicities is above 30% 
at each stopping would be around 77 to 79% (79%, 78%, 78%, and 77%, respectively). 
The efficacy analysis is based on Simon 2 stage optimal design and will be performed after the 
enrollment of the first 9 evaluable subjects treated at the RP2D.  If there are no responders with 
CR from the first 9 evaluable subjects (at the 8 week or 16 week response assessment, at any 
itacitinib dose level), the null hypothesis (CR rate of 5% or lower with the new combination) will 
be considered as supported, and the study will be terminated.  The study will be considered 
successful if the total number of subjects with CR is ≥ 2 in Phase II (at the 8 week or 16 week 
response assessment). 
If there are two (2) study related deaths during the phase I portion of the trial, the study will be 
terminated. 
Any death in the Phase II portion will result in pausing enrollment of the study until investigation 
is completed.  If there are two (2) study related deaths in the Phase II portion of the study will be 
terminated.  
8.8 
Monitoring 
This study will be monitored according to the Sponsor Data and Safety Monitoring Plan. 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the above noted study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), has adequate space to conduct the monitoring visit, and that site 
staff, including the PI, can meet with the monitor to discuss findings. 
8.9 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).  

 
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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
Notify the Sponsor in real-time if an audit/inspection notification is received. 
9 STUDY ADMINISTRATION, DATA HANDLING AND RECORD 
KEEPING 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period.  
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All entries will be entered into an electronic data 
capture system (EDC) via PennCTMS/VELOS.  The Principal Investigator is responsible for 
assuring that the data entered into eCRF is complete, accurate, and that entry and updates are 
performed in a timely manner. 

 
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9.4 
Data Collection and Management  
For subjects having entered the survival follow-up period of the study, the site will use 
continuing subject records to supply data on subsequent treatment regimens, tumor assessments 
(if discontinued treatment for a reason other than progression), and OS in the eCRF.  For subjects 
who do not intend to return to the study investigator for their ongoing care, follow-up should be 
maintained by phone contact, subject records, and public records/databases at intervals of about 
12 weeks. 
If the subject discontinues study treatment and actively withdraws consent for collection of 
follow-up data (e.g., subsequent anticancer treatments and survival), then no additional data 
collection should occur; however, subjects will have the option of withdrawing consent for study 
treatment but continuing in the follow-up period of the study for safety/efficacy assessments. 
9.5 
Records Retention 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the protocol therapy, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; SAE reports, pharmacy 
dispensing records; recorded data from automated instruments; copies or transcriptions certified 
after verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and drug accountability; original signed informed consents, etc.]) be retained by the 
Investigator for as long as needed to comply with applicable regulations (at least 2 years after 
discontinuing clinical development or after the last marketing approval). The Investigator agrees 
to adhere to the document/records retention procedures by signing the protocol.  
10 ETHICAL CONSIDERATIONS 
This study is to be conducted in accordance with applicable US government regulations and 
international standards of Good Clinical Practice (FDA Title 21 part 312 and International 
Conference on Harmonization guidelines), and applicable institutional research policies and 
procedures. 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB concerning the conduct of the study will 
be made in writing to the investigator and a copy of this decision will be provided to the sponsor 
before commencement of this study. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject and the investigator-designated research professional obtaining the consent. 

 
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The protocol is listed on clinicaltrials.gov. 
10.1 Risks 
Refer the itacitinib investigator’s brochure for the risks associated with itacitinib.  Refer to 
section 5.6.2 and the everolimus package insert for the risks associated with everolimus. 
10.2 Benefits 
The combination of oral therapies has potential to be active in subjects with relapsed/refractory 
HL.  Also, both agents are oral which makes this therapy convenient for subjects.   
10.3 Risk Benefit Assessment 
The potential benefits (effective oral therapy for subjects with limited options) outweigh the risks 
of this combination. 
10.4 Informed Consent Process / HIPAA Authorization  
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedures.  Documentation that informed consent occurred prior to the subject’s entry 
into the study and the informed consent process should be recorded in the subject’s source 
documents.  The original consent form signed and dated by the subject and by the person 
consenting the subject prior to the subject’s entry into the study, must be maintained in the 
Investigator’s study files.  A copy of the signed ICF must be provided to the study subject.   
10.5 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy 
on Conflicts of Interest Related to Research.  
11 PUBLICATION PLAN 
Publication of the results of this trial will be governed by University of Pennsylvania policies. 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 

 
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12 REFERENCES 
1. 
Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2013. CA Cancer J Clin, 
2013. 63(1): p. 11-30. 
2. 
Moskowitz, A.J., et al., Outcomes for Patients Who Fail High Dose Chemoradiotherapy 
and Autologous Stem Cell Rescue for Relapsed and Primary Refractory Hodgkin 
Lymphoma. British Journal of Haematology, 2009. 146(2): p. 158-163. 
3. 
Younes, A., et al., Checkmate 205: Nivolumab (nivo) in classical Hodgkin lymphoma 
(cHL) after autologous stem cell transplant (ASCT) and brentuximab vedotin (BV)—A 
phase 2 study. Journal of Clinical Oncology, 2016. 34(15_suppl): p. 7535-7535. 
4. 
Steidl, C., J.M. Connors, and R.D. Gascoyne, Molecular pathogenesis of Hodgkin's 
lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol, 
2011. 29(14): p. 1812-26. 
5. 
Johnston, P.B., et al., A Phase II trial of the oral mTOR inhibitor everolimus in relapsed 
Hodgkin lymphoma. Am J Hematol, 2010. 85(5): p. 320-4. 
6. 
Weniger, M.A., et al., Mutations of the tumor suppressor gene SOCS-1 in classical 
Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 
accumulation. Oncogene, 2006. 25(18): p. 2679-84. 
7. 
Kuppers, R., New insights in the biology of Hodgkin lymphoma. Hematology Am Soc 
Hematol Educ Program, 2012. 2012: p. 328-34. 
8. 
Van den Neste, E., et al., Phase II study of oral JAK1/JAK2 inhibitor ruxolitinib in 
advanced relapsed/refractory Hodgkin lymphoma. Haematologica, 2018. 
9. 
Younes, A., 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(33): p. 4161-7. 
10. 
Bartalucci, N., et al., Co-targeting the PI3K/mTOR and JAK2 signalling pathways 
produces synergistic activity against myeloproliferative neoplasms. J Cell Mol Med, 
2013. 17(11): p. 1385-96. 
11. 
Bogani, C., et al., mTOR inhibitors alone and in combination with JAK2 inhibitors 
effectively inhibit cells of myeloproliferative neoplasms. PLoS One, 2013. 8(1): p. 
e54826. 
12. 
Forero-Torres, A., et al., A phase 1 study of INCB040093, a PI3Kδ inhibitor, alone or in 
combination with INCB039110, a selective JAK1 inhibitor: Interim results from patients 
(pts) with relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). Journal of 
Clinical Oncology, 2015. 33(15_suppl): p. 8558-8558. 
13. 
Phillips, T.J., et al., Interim analysis of a phase I study of INCB040093, a PI3Kδ 
inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor, in 
patients (pts) with relapsed or refractory (r/r) B-cell malignancies. Journal of Clinical 
Oncology, 2015. 33(15_suppl): p. 8520-8520. 
14. 
Lemoine, M., et al., The pan-deacetylase inhibitor panobinostat induces cell death and 
synergizes with everolimus in Hodgkin lymphoma cell lines. Blood, 2012. 119(17): p. 
4017-4025. 
15. 
Oki, Y., et al., Phase I study of panobinostat plus everolimus in patients with relapsed or 
refractory lymphoma. Clinical cancer research : an official journal of the American 
Association for Cancer Research, 2013. 19(24): p. 6882-6890. 

 
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16. 
Younes, A., et al., Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma 
after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol, 
2012. 30(18): p. 2197-203. 
17. 
Dutton, A., et al., Constitutive activation of phosphatidyl-inositide 3 kinase contributes to 
the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and 
mTOR. J Pathol, 2005. 205(4): p. 498-506. 
18. 
Motzer, R.J., et al., Lenvatinib, everolimus, and the combination in patients with 
metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. 
Lancet Oncol, 2015. 16(15): p. 1473-1482. 
19. 
Cheson BD, F.R., Barrington SF, et al., Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol., 2014: p. 3059-3068. 
 

 
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13.3 ECOG Performance Status Scores 
Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status** 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982 Available 
at: http://www.ecog.org/general/perf_stat.html. Accessed April 26, 2018. 
 
 
 

 
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13.4 Revised Criteria for Response Assessment of Malignant Lymphoma[19] 
The following table provides a summary of response criteria for malignant lymphoma according 
to Cheson (2014).  Please refer to published international guidelines for the most recent and 
complete details. 
Site  
PET-Based Response  
CT-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.  
• At interim, these findings suggest 
responding disease.  
• At EOT, these findings suggest residual 
disease.   
• ≥ 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.  
• When no longer visible, 0 × 0 mm.  
For a node > 5 mm × 5 mm but smaller than 
normal, use actual measurement.   
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, 
consider further evaluation with MRI or 
biopsy.   
Not applicable.   
Lymph nodes and 
extralymphatic sites  
• Score 4 or 5a with reduced uptake 
compared with baseline and residual 
mass(es) of any size.  
• At interim, these findings suggest 
responding disease.  
• At EOT, these findings suggest residual 
disease.   
• ≥ 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.  
• When no longer visible, 0 × 0 mm.  
For a node > 5 mm × 5 mm but smaller than 
normal, use actual measurement.   

 
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Site  
PET-Based Response  
CT-Based Response  
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.   
 
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 1 of the following)  
Individual target 
nodes/nodal lesions  
Individual target nodes/nodal lesions:  
• Score 4 or 5a with an increase in intensity 
of uptake from baseline and/or  
• New FDG-avid foci consistent with 
lymphoma at interim or EOT assessment.  
Extranodal lesions:  
• New FDG-avid foci consistent with 
lymphoma at interim or EOT 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:  
– 
LDi > 1.5 cm.  
– 
Increase by ≥ 50% from PPD nadir. 
– 
Increase in LDi or SDi from nadir:  
 0.5 cm for lesions ≤ 2 cm.  
 1.0 cm for lesions > 2 cm.  
• In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent of 
its prior increase beyond baseline (e.g., 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  
LDi = longest transverse diameter of lesion; 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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13.5 New York Heart Association (NYHA) Functional Classification 
Class 
Functional Capacity: How a patient with cardiac disease feels during physical activity 
I 
Patients with cardiac disease but resulting in no limitation of physical activity.  Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of physical activity.  They are comfortable 
at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea or anginal pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort increases. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of 
the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 
13.6 Regimens for Pneumocystis Pneumonia Prophylaxis 
DRUG 
DOSE 
Preferred regimen 
Trimethoprim-sulfamethoxazole 
1 DS tablet Monday-Wednesday-Friday 
Alternative regimens 
Dapsone 
100 mg daily 
Atovaquone suspension 
1500 mg orally once daily given with food 
Aerosolized pentamidine 
300 mg monthly (via Respigard II nebulizer)