Conditions: Advanced Cutaneous Squamous Cell Carcinoma
Keywords: Ruxolitinib Solid Organ Transplant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
In this open-label, multicenter, Phase II study, the investigators propose to evaluate the efficacy of ruxolitinib, an orally administered inhibitor of JAK1/2, in solid organ transplant recipients with advanced cSCC. In a safety lead-in of 6 patients, subjects will receive ruxolitinib 15mg twice daily (BID). After 4 weeks, if dose-limiting toxicities (DLT) are observed in 1 or fewer patients, the study will enter stage 1 of the Simon two-stage design where all subsequent patients will receive a starting dose of ruxolitinib 15mg BID. If more than 1 DLTs are observed, another cohort of 6 patients will be treated at a dose of 10mg BID. If less than 2 DLTs are observed at the new dose of 10mg, then the study will proceed to stage I using this dose; otherwise the study will stop.

Detailed description:
Approximately 5.4 million individuals in the United States are diagnosed with non-melanoma skin cancers (NMSC) annually, with the incidence increasing over time. Twenty-five percent are cutaneous squamous cell carcinomas (cSCC), which affect up to 1,350,000 individuals and result in up to 12,000 deaths annually in the US alone. Immunosuppressed patients are particularly vulnerable to the development of highly aggressive or catastrophic cSCC. Patients receiving immunosuppressive therapy, such as solid organ transplant recipients (SOTRs), and HIV/AIDS patients have an estimated 60 to 250-fold increased risk of cSCC development. In renal SOTRs, cSCC represents over 70% of all malignancies that develop, with an incidence up to 200 times that of the general population. Post-transplant cSCC occurs at a younger age and is more aggressive than in non-transplant cohorts, with 30% of cSCC recurring within 1 year and up to 8% of disease associated with metastasis. The median survival from diagnosis of metastasis is 3 years.5 Cemiplimab, an anti-PD1 antibody, recently became the first agent to achieve regulatory approval for the treatment of advanced cSCC; however, due to the risk of graft rejection, the role of immunological checkpoint blockade in the SOTR population is extremely limited. Thus, although surgical excision is effective for sporadic cSCC, there remains a large unmet medical need for novel strategies for treatment and/or prevention of multiply recurrent, locally advanced, and metastatic cSCC, particularly in immunosuppressed patients.

Arms:
arm 1: In a safety lead-in of 6 patients, subjects will receive 15mg of ruxolitinib twice daily (BID). After 4 weeks, if dose-limiting toxicities (DLT) are observed in 1 or fewer patients, the study will enter stage 1 of the Simon two-stage design where all subsequent patients will receive a starting dose of ruxolitinib 15mg BID.

Subjects will have regularly scheduled study visits at the clinical site on Day 1 and Day 15 (± 3 days) of the first 2 cycles, then on Day 1 (± 3 days) of every subsequent cycle (starting cycle 3), where safety assessments, including laboratory assessments, vital signs, and physical examinations will be performed.

Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: Ruxolitinib will be administered orally twice daily during the entirety of each 28-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 27 Jul 2023 
0 
Protocol Version: 27 Jul 2023 
 
 
 
NCT04807777 
 
 
 
 
 
 
 
 
 
 
Herbert Irving Comprehensive Cancer Center 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 27 Jul 2023 
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Protocol Version: 27 Jul 2023 
 
 
 
CUMC IRB#: AAAT5353 
Version Date:  27 Jul 2023 
TITLE: A Multi-Center Phase II study of Ruxolitinib in Solid Organ Transplant Recipients with 
Advanced Cutaneous Squamous Cell Carcinoma 
 
Coordinating Center: 
Columbia University Irving Medical Center 
 
 
Principal Investigator: 
Alexander Wei, MD 
177 Fort Washington Avenue 
Suite 6-435 Garden North 
212-305-7115 
212-305-3035 
aw3056@cumc.columbia.edu 
 
 
Ragini Kudchadkar, MD 
Winship Cancer Institute of Emory University 
1365 Clifton Road Northeast 
Atlanta, GA 30322 
 
 
Sunandana Chandra, MD 
Robert H. Lurie Cancer Center 
Northwestern University 
675 N St. Clair Street 
Chicago, IL 60611 
 
 
 
Statistician: 
 
Codruta Chiuzan, PhD 
722 W. 168th St, 6th Fl 
New York, NY 10032 
212-305-9107 
cc3780@cumc.columbia.edu 


2 
Protocol Version: 27 Jul 2023 
 
 
Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 27 Jul 2023 
 
Regulatory Sponsor: 
Alexander Wei, MD 
Columbia University Medical Center 
Depaitment of Medicine 
177 F01t Wash ingto n Avenue 
Suite 6-435 Gai·den No1t h 
212-305 -7115 
Funding Source: 
Incyte Inc. 
Study Agent: 
Ruxolitinib (Jakafi) 
Other Agent: 
NIA 
IND Status: 
 
 
Affiliate Institutions: 
Site Principal Investigator and Contact Information: 
Other Investigators at Site 
Principal Investigator: 
Ragini Kudchadkar, MD 
Winship Cancer Institute of Em01y University 
1365 Clifton Road No1theast 
Atlanta, GA 30322 
Name 
Principal Investigator: 
Sunandana Chandra, MD 
Robe1t H. Lurie Cancer Center 
No1thwestem University 
675 N St. Clair Street 
Chicago, IL 60611 
Name 
 
Initial version:24 DEC 2020 
Amended: 
1 MAY 2021 
Amended: 
21 FEB 2023 
Amended 
27 Jul 2023 


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Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder. 
 
1. 
Protocol Signature Page 
 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol. I have read and understand 
the information in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks 
and potential benefits. I will promptly submit the protocol to the applicable IRB for review and 
approval. Once the protocol has been approved by the IRB, I understand that any modification 
made during the course of the study must first be approved by the IRB, prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. I certify 
that I, and the study staff, have received the requisite training to conduct this research protocol. I 
agree to maintain adequate and accurate records in accordance with Columbia University and 
Herbert Irving Comprehensive Cancer Center policies, Federal, state and local laws and 
regulations. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
 
Principal Investigator Name (Print) 
 
 
 
 
 
Name of Institution 


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Protocol Synopsis 
 
Title 
Multi-Center Phase II Study of the JAK1/2 inhibitor, Ruxolitinib, in 
Solid Organ Transplant Recipients with Advanced Cutaneous Squamous 
Cell Carcinoma 
Short Title 
Ruxolitinib for Advanced Cutaneous Squamous Cell Carcinoma 
Protocol Number 
AAAT5353 
Phase 
Phase II 
Methodology 
This is an open-label, multi-center, phase II clinical trial with a primary 
endpoint of overall response rate by RECIST v 1.1. 
Study Duration 
36 months 
Study Center(s) 
1. Columbia University Irving Medical Center 
2. Winship Cancer Institute of Emory University 
3. Robert H. Lurie Cancer Center of Northwestern University 
Objectives 
Primary Objectives: 
• To determine the efficacy of ruxolitinib in post-transplant 
patients with advanced cutaneous squamous cell carcinoma as 
determined by overall response rate. 
Secondary Objectives: 
• To evaluate the clinical benefit of ruxolitinib as determined by 
progression free survival and overall survival. 
• To determine the safety and tolerability of ruxolitinib in post- 
transplant patients with advanced cutaneous squamous cell 
carcinoma 
• To assess the pharmacodynamics of ruxolitinib in post-transplant 
patients with advanced cutaneous squamous cell carcinoma. 
Exploratory Objectives: 
• To explore the association between clinical benefit/response and 
changes in expression of phosphorylated STAT3 and Cyclin D1 
using pre- and post-treatment tumor biopsies. 
• To explore the effect of ruxolitinib on the tumor immune 
microenvironment. 
• To explore the effect of ruxolitinib on circulating immune cell 
populations 
• To explore mechanisms of sensitivity and resistance using RNA- 
Seq analysis of tumor biopsies from responding and non- 
responding patients. 


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Number of Subjects 
Thirty-five patients will be enrolled across all 3 sites 
Each site will plan to accrue 1 patient every 2 months and we anticipate 
that the last patient will be enrolled approximately 24 months after the 
anticipated start date. 
Diagnosis and Main 
Inclusion Criteria 
Main Inclusion Criteria: 
• 
Histopathologically confirmed diagnosis of metastatic 
advanced cutaneous squamous cell carcinoma. 
• 
History of solid-organ transplant requiring immunosuppression 
• 
Age ≥ 18 yrs 
• 
Measurable disease by RECIST v1.1 
• 
KPS ≥60%, ECOG ≤2 
• 
No prior JAK Inhibitor therapy 
• 
Adequate organ function 
• 
All clinically significant toxicities from prior systemic therapy 
must be ≤ Grade 1 (with the exception of alopecia, and 
peripheral neuropathy, which may be ≤ grade 2). 
• 
Subjects must agree to undergo tumor biopsies until biopsies 
have been obtained from 10 subjects (i.e., biopsies are required 
in at least the first 10 enrolled subjects, or until a goal of 10 
study biopsies are obtained). Subjects in whom a biopsy is 
technically not feasible or in whom would result in 
unacceptable risk in the opinion of the investigator, may be 
exempted from the biopsy requirement with discussion with the 
principal investigator. 
• 
Negative pregnancy test for women of child bearing potential 
• 
Ability to take oral medications 
• 
Adequate marrow function: 
- ANC ≥1000 /mm3 
- Platelet count ≥50,000/mm3 
- Hemoglobin ≥8.0g/dL (not requiring transfusion in the past 2 
weeks) 
Study Product, 
Dose, Route, 
Regimen 
Ruxolitinib will be administered orally twice daily during the entirety of 
each 28-day cycle. There will be a safety lead-in cohort of 6 patients 
who receive the starting dose of 15mg twice daily (BID). If dose limiting 
toxicities (DLT) are seen in 1 or fewer patients, the starting dose for all 
remaining patients will be 15mg BID. If DLT’s are seen in >1 patient, 
another 6 patients will be enrolled at 10mg BID. If DLT’s are seen in 1 
or fewer patients, the starting dose for the remaining patients will be 
10mg BID. Otherwise the study will be terminated. Individual subjects 
may have dose reductions of ruxolitinib during the course of treatment, 
based upon safety laboratory assessments. 


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Duration of 
administration 
Treatment with ruxolitinib will commence following enrollment and 
continue until objective disease progression as confirmed by RECIST 
v1.1, intolerable toxicity or the occurrence of another discontinuation 
criterion. 
Reference therapy 
Historical response rates to chemotherapy in advanced cutaneous 
squamous cell carcinoma in transplant recipients (reference respone rate 
5-10%) 
Statistical 
Methodology 
Definition of primary outcome/endpoint: 
The primary endpoint is the overall response rate as defined as the best 
response, confirmed at ≥4 weeks, within the first 24 weeks of the start 
of study therapy, using RECIST v1.1 criteria. 
Definition of secondary outcomes/endpoints: 
PFS is defined as time from registration to time of clinical or 
radiographic disease progression as defined by RECIST v1.1 criteria, or 
death. OS is defined as time from registration to time of death from any 
cause. 
Analytic plan for primary objective: 
We will estimate the response rate to ruxolitinib using the exact 95% 
confidence interval based on the binomial distribution. 
Analytic plan for secondary and exploratory objectives: 
• We will estimate the survival distribution for both PFS and 
OS endpoints using the Kaplan Meier method. The log rank 
test will be used to examine differences between survival 
curves. 
• For correlative studies we will apply either the Fisher’s exact 
test or Wilcoxon rank sum test to examine the correlation 
between response status and markers for categorical and 
continuous variables, respectively. 
Sample size justification: 
We will utilize a Simon mini-max two-stage design in which a 5% RR 
is considered not promising, a 20% RR is considered promising, and the 
probabilities of a type I error (falsely accepting a non-promising therapy) 
and type II error (falsely rejecting a promising therapy) are set at 0.10 
and 0.10, respectively. Eighteen patients with advanced cSCC will be 
accrued in the first stage. If 1 or more patients achieve a response, then 
an additional 14 will be accrued. If 4 or fewer responses are seen, the 
study will be declared negative. 


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Protocol Schema: 
 
 
 


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Table of Contents 
1. 
Protocol Signature Page ...................................................................................................... 3 
1. 
Introduction ....................................................................................................................... 12 
2. 
Study Objectives ............................................................................................................... 12 
2.1 
Primary Objective ................................................................................................. 12 
2.2 
Secondary Objectives ............................................................................................ 12 
2.3 
Exploratory Objectives ......................................................................................... 13 
3. 
Background ....................................................................................................................... 13 
3.1 
Cutaneous Squamous Cell Carcinoma .................................................................. 13 
3.2 
Rationale  for  JAK  inhibition  in  advanced  cutaneous  squamous  cell 
carcinoma ...............................................................................................................13 
3.3 
Preliminary data supporting JAK inhibition in cutaneous squamous cell 
carcinoma ........................................................................................................ 14 
3.4 
Study Rationale and Hypothesis ........................................................................... 16 
4. 
Investigational Agent ........................................................................................................ 16 
4.1 
Mechanism of Action ............................................................................................ 17 
4.2 
Non-Clinical Pharmacology .................................................................................. 17 
4.3 
Animal Toxicity .................................................................................................... 18 
4.4 
Absorption, bioavailability, and pharmacokinetics ............................................... 18 
4.5 
Clinical Trials .........................................................................................................19 
4.6 
Other Agent(s)....................................................................................................... 23 
5. 
Study Design ..................................................................................................................... 23 
5.1 
General Design ...................................................................................................... 23 
5.2 
Number of Patients ................................................................................................ 24 
5.3 
Correlative Studies ................................................................................................ 24 
6. 
Subject Selection and Withdrawal .................................................................................... 26 
6.1 
Inclusion Criteria .................................................................................................. 26 
6.2 
Exclusion Criteria ..................................................................................................27 
6.3 
Inclusion of Women and Minorities ..................................................................... 28 
6.4 
Subject Recruitment .............................................................................................. 28 
6.5 
Early Withdrawal of Subjects ................................................................................29 
7. 
REGISTRATION PROCEDURES .................................................................................. 31 
7.1 
CUMC Research Participant Registration ............................................................ 31 
7.2 
Informed Consent Procedures ............................................................................... 33 
8. 
TREATMENT PLAN ........................................................................................................33 
8.1 
Agent Administration ............................................................................................ 33 
8.2 
General Concomitant Medication and Supportive Care Guidelines ..................... 34 


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8.3 
Treatment Compliance ...........................................................................................34 
8.4 
Randomization and Blinding ................................................................................ 35 
8.5 
Duration of Therapy .............................................................................................. 35 
8.6 
Duration of Follow Up .......................................................................................... 35 
8.7 
Criteria for Removal from Study .......................................................................... 35 
9. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 35 
9.1 
Required Laboratory Parameters for Initiation of a Treatment Cycle .................. 35 
9.2 
Dosing Delays/Dose Modifications for Ruxolitinib ............................................. 36 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................40 
10.1 
Adverse events ..................................................................................................... 40 
10.2 
Definitions ............................................................................................................. 43 
10.3 
Recording of Adverse Events ............................................................................... 46 
10.4 
Reporting Process ................................................................................................. 49 
11. 
PHARMACEUTICAL INFORMATION ......................................................................... 49 
11.1 
Description ............................................................................................................ 49 
11.2 
Treatment Regimen ................................................................................................49 
11.3 
Method for Assigning Subjects to Treatment Groups .......................................... 49 
11.4 
Preparation and Administration of Study Drug .................................................... 49 
11.5 
Subject Compliance Monitoring ........................................................................... 50 
11.6 
Packaging .............................................................................................................. 50 
11.7 
Blinding of Study Drug ......................................................................................... 50 
11.8 
Receiving, Storage, Dispensing and Return ......................................................... 50 
11.9 
Other Agent(s) ...................................................................................................... 51 
12. 
STUDY EVALUATIONS .................................................................................................51 
12.1 
Screening Phase .................................................................................................... 51 
12.2 
Treatment Phase .................................................................................................... 51 
12.3 
End of Treatment ...................................................................................................53 
12.4 
Follow-up Phase .................................................................................................... 53 
12.5 
Unscheduled Visits ............................................................................................... 54 
13. 
STUDY CALENDAR ...................................................................................................... 54 
14. 
BIOMARKER, CORRELATIVE, and special studies ..................................................... 56 
14.1 
Collection of samples for correlative studies ........................................................ 56 
15. 
MEASUREMENT OF EFFECT ....................................................................................... 59 
15.1 
Antitumor Effect – Solid Tumors ......................................................................... 59 
15.2 
Definitions ............................................................................................................. 59 
15.3 
Disease Parameters ............................................................................................... 59 
15.4 
Methods for Evaluation of Measurable Disease ................................................... 60 
15.5 
Response Criteria .................................................................................................. 63 
15.6 
Duration of Response ............................................................................................ 64 


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15.7 
Progression-Free Survival ..................................................................................... 65 
15.8 
Response Review .................................................................................................. 65 
15.9 
Unblinding Procedures .......................................................................................... 65 
15.10 Stopping Rules ...................................................................................................... 65 
16. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................65 
16.1 
Data Collection ..................................................................................................... 65 
16.2 
Data Reporting ...................................................................................................... 66 
16.3 
Data and Safety Monitoring Committee ............................................................... 66 
16.4 
Quality Control and Quality Assurance ................................................................ 66 
16.5 
Confidentiality ...................................................................................................... 67 
16.6 
Source Documents ................................................................................................ 68 
16.7 
Case Report Forms ................................................................................................ 68 
16.8 
Records Retention ................................................................................................. 68 
17. 
STATISTICAL CONSIDERATIONS. ............................................................................. 68 
17.1 
Study Design and Sample Size ............................................................................. 68 
17.2 
Study Endpoints and Analytic Plan....................................................................... 69 
All subjects who receive at least one dose of study drug will be considered 
evaluable and included in the efficacy and safety analysis. ................................... 69 
17.3 
Size/Accrual Rate .................................................................................................. 70 
17.4 
Stratification Factors ............................................................................................. 70 
17.5 
Reporting and Exclusions ......................................................................................70 
18. 
Protection of Human Subjects ........................................................................................... 70 
19. 
Study Finances .................................................................................................................. 71 
19.1 
Conflict of Interest ................................................................................................ 71 
20. 
Publication Plan ................................................................................................................ 71 
21. 
Guidelines for Affiliate Institutions in Multicenter Studies .............................................. 71 
21.1 
Multi-site Communication .................................................................................... 71 
21.2 
New Protocol Distribution, IRB Submission, Modifications, and Annual 
Renewals ............................................................................................................... 71 
21.3 
Regulatory Documents .......................................................................................... 72 
21.4 
Site activation ........................................................................................................ 73 
21.5 
Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process .............................................................................................. 73 
21.6 
Protocol Deviation/Subject Waiver request for Affiliate Sites: ............................ 74 
21.7 
Guidelines for Affiliate Site Monitoring ............................................................... 76 
21.8 
Adverse event reporting ........................................................................................ 77 
21.9 
Efficacy analysis/ correlative analysis ................................................................... 79 
21.10 Confidentiality ...................................................................................................... 79 
21.11 Data Reporting Plan .............................................................................................. 80 
21.12 Data Acquisition and Submission ......................................................................... 80 


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21.13 Record Keeping and Record Retention ................................................................. 80 
22. 
References ......................................................................................................................... 82 
23. 
APPENDIX ....................................................................................................................... 84 
23.1 
Appendix A: ECOG Performance Status Criteria. ................................................ 84 
23.2 
Appendix B: Appropriate contraceptive methods for study subjects. ................... 85 
23.3 
Appendix C: Strong CYP3A4 and 2C8 Inhibitors and Inducers .......................... 85 
23.4 
Appendix D: Pill Diary ......................................................................................... 87 


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1. 
INTRODUCTION 
Cutaneous squamous cell carcinoma (cSCC) is a common malignancy in patients receiving 
immunosuppressive therapy, including solid organ transplant recipients (SOTRs). These patients 
have an estimated 60- to 250-fold increased risk of cSCC development and are particularly 
vulnerable to the development of highly aggressive or catastrophic cSCC [1-4]. Post-transplant 
cSCC occurs at a younger age and is more aggressive than in non-transplant cohorts, with 30% 
recurring within 1 year and up to 8% of disease associated with metastasis [5]. The median 
survival after diagnosis of metastasis is 3 years [6]. Cemiplimab, an anti-PD1 antibody, recently 
became the first agent to achieve FDA approval for the treatment of advanced cSCC [7, 12]. 
However, due to the risk of graft rejection, the role of checkpoint blockade in the SOTR 
population is extremely limited. In retrospective series, the rate of graft rejection has ranged 
between 37-41% with a significant percentage of these patients dying as a result [8]. There is a 
dearth of data to guide decision making in patients who cannot receive cemiplimab. Two small 
phase II studies investigating epidermal growth factor receptor (EGFR) antagonists have 
demonstrated response rates of 28 and 31%, however it is unclear if these agents have any 
survival benefit and it is unknown if these response rates are seen in SOTR [13, 14]. Thus, there 
remains a large unmet medical need for novel strategies in these patients. 
 
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a 
critical role in tumorigenesis and has been implicated in cSCC. STAT proteins regulate the 
transcription of genes involved in cytokine signaling, cell proliferation, and tumorigenesis [9]. 
Elevated levels of STAT3 have been observed in a number of human epithelial cancers [10, 11]. 
Pre-clinical data from our group supports the role of JAK1/2 co-inhibition as a potential 
therapeutic strategy in cSCC. We propose to evaluate the efficacy of ruxolitinib, an orally 
administered inhibitor of JAK1/2, in solid organ transplant recipients with advanced cSCC. 
Paired pre-treatment and on-treatment biopsies will also be obtained to further define the 
mechanism of response and resistance to JAK1/2 inhibition in this population. 
 
 
2. 
STUDY OBJECTIVES 
2.1 Primary Objective 
• To determine the efficacy of ruxolitinib in post-transplant patients with advanced 
cutaneous squamous cell carcinoma as determined by overall response rate. 
2.2 Secondary Objectives 
• To evaluate the clinical benefit of ruxolitinib as determined by upon progression free 
survival and overall survival. 
• To determine the safety and tolerability of ruxolitinib in post-transplant patients with 
advanced cutaneous squamous cell carcinoma 
• To assess the pharmacodynamics of ruxolitinib in post-transplant patients with advanced 
cutaneous squamous cell carcinoma. 


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2.3 Exploratory Objectives 
• To explore the association between clinical benefit/response and changes in expression of 
phosphorylated STAT3 and Cyclin D1 using pre- and post-treatment tumor biopsies. 
• To explore the effect of ruxolitinib on the tumor immune microenvironment 
• To explore the effect of ruxolitinib on circulating immune cell populations 
• To explore mechanisms of sensitivity and resistance using RNA-Seq analysis of tumor 
biopsies from responding and non-responding patients. 
 
3. 
BACKGROUND 
3.1 
Cutaneous Squamous Cell Carcinoma 
Approximately 5.4 million individuals in the United States are diagnosed with non-melanoma 
skin cancers (NMSC) annually, with the incidence increasing over time. Twenty-five percent are 
cutaneous squamous cell carcinomas (cSCC), which affect up to 1,350,000 individuals and result 
in up to 12,000 deaths annually in the US alone.1, 2 Immunosuppressed patients are particularly 
vulnerable to the development of highly aggressive or catastrophic cSCC.3, 4 Patients receiving 
immunosuppressive therapy, such as solid organ transplant recipients (SOTRs), and HIV/AIDS 
patients have an estimated 60 to 250-fold increased risk of cSCC development. In renal SOTRs, 
cSCC represents over 70% of all malignancies that develop, with an incidence up to 200 times 
that of the general population. Post-transplant cSCC occurs at a younger age and is more 
aggressive than in non-transplant cohorts, with 30% of cSCC recurring within 1 year and up to 
8% of disease associated with metastasis. The median survival from diagnosis of metastasis is 3 
years.5 Cemiplimab, an anti-PD1 antibody, recently became the first agent to achieve regulatory 
approval for the treatment of advanced cSCC;6, 7 however, due to the risk of graft rejection, the 
role of immunological checkpoint blockade in the SOTR population is extremely limited. Thus, 
although surgical excision is effective for sporadic cSCC, there remains a large unmet medical 
need for novel strategies for treatment and/or prevention of multiply recurrent, locally advanced 
and metastatic cSCC, particularly in immunosuppressed patients 
 
3.2 
Rationale for JAK inhibition in advanced cutaneous squamous cell carcinoma 
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a 
critical role in the downstream signaling of inflammatory cytokines and various growth factors, 
and has emerged as an important therapeutic target in inflammatory and immunologic diseases.8 
Upon nuclear translocation, STAT proteins regulate the transcription of genes involved in 
cytokine signaling, cell proliferation, and tumorigenesis. Elevated levels of STAT3 have been 
observed in a number of human epithelial cancers ranging from head and neck SCC to breast 
cancer.9, 10 In murine models of cSCC, genetic disruption of STAT3 confers resistance to cSCC, 
while forced expression of constitutively active STAT3 sensitizes to cSCC formation.11 Previous 
analysis of human cSCC specimens positively correlated levels of phosphorylated (activated) 
STAT3 with increased depth of tumor invasion and metastasis.10, 12 


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3.3 
Preliminary data supporting JAK inhibition in cutaneous squamous cell 
carcinoma 
 
To es tab lish releva nce for the JAK­ 
STAT pathway in cSCC 
pathogenesis, we first examined 
protein levels for all four JAK family 
members, JAK.l , JAK.2, JAK.3, and 
TYK2, in n01mal human epide1mal 
keratinocytes (NHEK) and cSCC. We 
examined primaiy cultures ofNHEKs 
(NHEKI, 2, and 3) and cSCC 
(SCC13, SCC35, and SCC39) 
previously established in our 
laborato1y 13 from patients seen at 
CUIMC. Whole cell protein lysates were generated from primaiy NHEK (n=3) or cSCC (n=3) 
and analyzed by irmnunoblot analysis using commercially available antibodies (Cell Signaling). 
We observed expression of JAK I, JAK2, and TYK2 protein in all NHEK and cSCC cultures; 
JAK.3 was undetectable (Figure 1). Interestingly , variable levels for each JAK family protein 
were observed between NHEK and cSCC - JAKI and TYK2 were down-regulated 
approximately two-fold in cSCC compai·ed to NHEK, while JAK.2 prote in levels were 
significantly upregulated in cSCC (Figure 1). Thus, multiple JAK proteins ai·e prese n t in cSCC 
and JAK2 upregulation is present in cSCC. 
 
Cutaneous SCC cells show upregulated JAK-STAT signaling and ai·e respons ive to 
phannacological JAK inhibitors: 
To assess the role of JAK signaling 
in the tumorigenic properties of 
cSCC, NHEK and cSCC cultures 
were senun-starved for 4hr 
followed by treatment with  lmM 
of either selective JAK inhibitors 
rnxolitinib (JAK.1/2) or tofac itinib 
(JAK.1/3) for 1hr. Ce lls were then 
treated with 1Ong/ml EGF for 
30min to stimulate entiy into the 
cell cycle and harvested to 
generate protein lysates. Lysates 
were exainined by immunoblot analysis for total and activated levels of STAT3, a major 
downstream tai·get of JAK activity. While total levels of STAT3 were similar between nonnal 
and cSCC keratinocytes, constitutive levels of pSTAT3T yro7   5  we  r e  dramat 
i ca ll y  h ighe  r  in  two   of 
thr ee  cSCC cultures compared to NHEKs (Figure 2). Levels of pSTAT3Tyro7   5  were dramatically 
decreased in NHEK and cSCC cultures ti·eated with either JAK inhibitor. However, levels of 
cyclin Dl, a mai·ker of cell proliferation that is associated with increased JAK-STAT signaling in 
a number of tumor types,14 were decreased only with rnxolitinib (JAK 1/2) treatment (Figure 2). 
Fi g ur e 2 . J A K/STAT signaling in cSCC cells. lmmunoblot analysis 
of protein lysates from vehicle (Ctrl) and drug-treated NHEK and 
cSCC cultures using antibodies against active (pSTAT3Tyr705 ) , total 
STAT3 and cyclin D1. Similar results were observed in SCC35 (not 
shown). Ruxo, ruxolitinib; Tofa, tofacitinib. 
I Cyc lin 01 
 
 
II 
II 
I 
 
-I 
- 
- 
I 
 
-- 
I  E 
- 
- 
I STA T3 
I pSTAT3 '1)-17.. 
II- 
II- 
I 
 
NHEK 
SCC39 
SCC13  
    Ctrl 
Ruxo   Tola 
Ctrl 
Ruxo 
Tota 
Ctrl 
Ruxo Tota 
-
I 
NHEK  =
s
I
ec 
1::
JAK  1
t 
123 
i"3'3s39" 
JAK2 
1YK2 
o::t.IJ'":'::' , = 0: 003 
- 
1Y K2 
:04 
0 15 
04 
0 
0 
0 
jl-ACTI N 
NHEK sec 
NHEK sec 
NHEK sec 
Fi gure 1. JAK family protei n levels in NHEK and cSCC. Left: 
micrographs show immunodetection of JAK1, JAK2, JAK3, TYK2 
and p-ACTIN (loading control) in 3 independent NHEK and cSCC 
samples (SCC13, SCC35, SCC39). Right: bar graphs show 
relative densitometric units of blots normalized to P-ACTIN using 
lmageJ software. (*)- Student's t-test; Error bars- Std. Dev. 


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Figure 3. JAK inhibition blocks cSCC 
growth. Growthinhibition of cSCC13, cSCC35 
or cSCC39 cells plated each of four different 
JAK inhibitors (baricitinib (JAK1/2), ruxolitinib 
(JAK1/2), tofacitinib ( JAK1/3), fedratinib 
(JAK2). Data are averaged across all three 
cultures; n = 3 replicates per time point. The 
maximum inhibition value was selected for 
each inhibitor at the 500 nM dose. Error bars 
represent standard deviation. P value­ 
Student's t-test. 
Bar Rux Tof Fed 
e
j   40 
g, 
<( 0 
(9 
C: 
,:: 
60 
  
P  = 0.04 
 
I P = 0.02 
c: 80 
0 
 
The differential effects of rnxolitinib versus tofacitinib (JAK 1/3) on cyclin Dl protein levels 
provide insight into which JAK family members may be critical for cSCC growth. First, these 
findings largely exclude a role for JAK3, which is not detectable in NHEK or cSCC lysates 
(Figure1). Second, the reductions in pSTAT3Tyro7   5  and cyclin Dl  levels following rnxolitinib, 
which targets JAK2, but not tofacitinib treatment suggests that JAKl and JAK2 co-inhibition 
may be 11ec e ss a1y to block cyclin Dl induction and, therefore, cSCC proliferation. We further 
tested this idea with larger panels of JAK/STAT inhibitors, siRNAs and cSCC cultures shown 
below. 
 
Phaim acological JAK inhibition blocks cSCC growth: 
Since rnxolitinib (JAKl/ 2 inhibitor), but not tofacitinib (JAKl/ 3 inhibitor), treatment decreased 
cyclin D1 levels in cSCC primaiy cultures, we hypothesized that i) JAK inhibition could 
attenuate cSCC growth, and ii) co-inhibition of JAK l and JAK2 may be necessaiy to effectively 
block cSCC growth. To test our hypothesis, three independent cSCC cultures were plated at 
equal numbers in the presence of a panel of JAK inhibitors: baricitinib (JAKl/ 2), rnxolitinib 
(JAKl /2), tofacitinib (JAKl/ 3), fedratinib (JAK2), or vehicle (DMSO). Total cell numbers were 
counted at 3, 6 and 8 days. While little to no difference in cSCC numbers was observed between 
vehicle-, tofacitinib-, or fedratinib-treated cultures, 35-45% growth inhibition was observed in 
baricitinib- and 
rnxolitinib-treated 
cultures (Figure 3). 
Collectively, these 
results suggest that 
JAK l and JAK2 co­ 
inhibition may be a 
relevant therapeutic 
strategy for cSCC. 
 
JAK l /2 RNA silencing blocks cSCC growth: 
To exclude potential off-target effects of the JAK inhibitors above, we perfo1med mRNA silencing 
of JAK members using pooled siRNAs (Origene). cSCC39 cells were transfected with pooled 
siRNAs (three per pool) targeting JAKl , JAK2, TYK.2 or sc ram bled (Se r) con trol. Kn ockdown of 
each JAK family protein compai·edto SCR-transfected cells was confnm ed by immunoblot (data 
not shown). JAK3 was excluded as a target due to lack of irmmmodetectab le protein in cSCC 
cultures (Figure 1). As outlined above, cell numbers were counted at 3, 6 and 8 days later (n=3 
replicates per group and time point). Approximately 30% growth inhibition was observed in 
cSCC39 cells transfected with JAKl or JAK2 siRNAs compared to SCR siRNA control cells 
(Figure4A). TYK2 siRN A-transfected cells also demonstrated abrogated growth albeit to a lesser 


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extent 
compared 
to 
JAKl or JAK2 siRNA 
cells (Figure 4A). In a 
repeat 
experiment, 
cells 
co-transfected 
with pooled JAKl and 
JAK2 
siRNAs 
(equivalent 
  total 
siRNA 
levels 
were 
used 
compared 
to 
individual 
 pooled 
siRNA cells) showed 
dramatically reduced growth (two- to three-fold) compared to cells transfected with JAK l or JAK2 
siRNA alone (Figure 4B). Collectively, these findings indicate that the JAK-STAT pathway is 
effectively blocked by inhibitors such as baricitinib and ruxolitinib that target both JAKl  and 
JAK2 and indicate therapeutic relevance for co-targeting JAKl and JAK2 in human cSCC. 
3.4 
Study Rationale and Hypothesis 
 
We propose a multicenter, open-label, phase II clinical trial to evaluate the efficacy of 
ruxolitinib, an orally active kinase inhibitor of  JAKl  and JAK2,  in  post-transplant patients 
with advanced cutaneous squamous cell carcinoma. The analysis of pre- and post-treatment 
tumor biopsies collected from patients treated on this study  will  be  used  for 
phannacodynamic analysis to assess the biological activity of ruxolitinib in human tumor 
samples. We hypothesize that JAKl/2 co-inhibition will achieve clinical efficacy as 
deten nined by increased radiographic responses compared to historical response rates  seen 
with chemotherapy and other agents in patients with advanced cutaneous squamous cell 
carcinoma. We anticipate that inhibition of STAT3 and cyclin D1 will con elate with response to 
therapy 
 
4. 
INVESTIGATIONAL AGENT 
 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib  phosphate)  represents a  well 
established, potent and selective inhibitor of Janus kinase (JAK)1 (inhibition concentration 50% 
[IC50]=3.3 ± 1.2 nanomolar (nM)) and JAK2 (IC50=2.8 ± 1.2 nM), with modest to marked 
selectivity against tyrosine kinase (TYK)2 (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 
nM), respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth 
factors that are impo1tant for hematopoiesis and immune function. 
 
JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) 
to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading 
to modulation of gene expression. Dysregulationof the JAK./ST AT pathway has been 
associated with several types of cancers and increased proliferation as well as smvival of 
malignant cells. In pait icular, this pathway may be dysregulated in majority of patients with 
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including 
myelofibrosis (MF) and polycytheinia vera (PV), demonstrating that JAK inhibition may be 
.  ■
•
 
JAK1 
Figure 4. JAK1/2 co-silencing blocks 
cSCC growth. Line plots showing average 
cell numbers of cSCC39 cultures transfected 
with (A) Sa- (ctrl), JAK1, JAK2, JAK3 or 
TYK2 pooled siRNAs or co-transfected with 
JAK1+JAK2 pooled siRNAs (B). For each 
JAK family member, three independent 
siRNAs were used for each pool (Origene). 
(*)- P values compared to SCR-transfected 
cells in A: JAK1, P < 0.05; JAK2, P < 0.04; 
JAK2 and in B: JAK1+JAK2, P < 0.001. P values 
calculated by Student's t-test, n = 3 
replicates per group. Error bars represent 
standard deviation. 
8 
6 
Days 
3 
0 
• 
SCR 
■ 
JAK 1 
:. 
100000 
50000 
150000 
B 
z
:, 
a
200000 
E 
0 
A TYK2 
i 
■ JAK2 
250000 
125000 
SCR 
SCC39 
375000 A 


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efficacious in these diseases. 
 
Ruxolitinib (JAKAVI®) is currently approved in the European Union (EU) for the treatment of 
disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (PMF) 
(also known as chronic idiopathic MF), post-polycythemia vera myelofibrosis (PPV-MF) or 
post-essential thrombocythemia myelofibrosis (PET-MF) and for the treatment of adult patients 
with PV who are resistant to or intolerant of hydroxyurea (HU). In the USA ruxolitinib 
(JAKAFI®) is approved for the treatment of intermediate or high-risk MF, including PMF, PPV- 
MF and PET-MF and for treatment of patients with PV who have had an inadequate response to 
or are intolerant of HU. Ruxolitinib is currently under further development for the treatment of 
MF, PV, essential thrombocytopenia (ET), Graft versus Host Disease (GvHD) and other 
hematologic malignancies. 
 
4.1 Mechanism of Action 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a potent, and 
selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% [IC50]=3.3 ± 1.2 nM) 
and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 (tyrosine kinase 
2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. Ruxolitinib interferes 
with the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers 
and activators of transcription (STATs) to cytokine receptors, activation, and subsequent 
localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of 
the JAK-STAT pathway has been associated with several types of cancer and increased 
proliferation and survival of malignant cells. 
 
4.2 Non-Clinical Pharmacology 
Ruxolitinib has high aqueous solubility and high permeability in vitro based on Caco-2 cell 
culture study. In single oral dose PK studies, ruxolitinib was absorbed rapidly with mean Tmax 
values ranging from 0.5 to 2 h. In mice, dogs, minipigs and humans, there were minimal gender 
differences in the exposure of ruxolitinib and its metabolites. In rats, the Cmax and AUC (area 
under the concentration-time curve) values were several-fold higher in females compared to 
males, due to metabolism by male rat specific isozymes 2C11, 2C13 and CYP3A2. The terminal 
half-life, routes and rate of excretion for ruxolitinib-derived radioactivity and metabolites 
observed between male and female rats were similar. The oral bioavailability was variable across 
species, ranging from 22% in male monkeys to virtually complete in female rats consistent with 
the species dependent clearance observed following IV dosing. 
Following IV administration of ruxolitinib, the plasma clearance was species-dependent and 
ranged from moderate in male dogs (0.48 L/h/kg) to very high in male rats (9.4 L/h/kg). Based 
on the apparent steady-state volume of distribution, ruxolitinib was not distributed extensively 
beyond body water in dogs (1.1 L/kg) and monkeys (0.81 L/kg), but may be distributed to a 
greater degree in rats (1.6-3.8 L/kg) and minipigs (6.4 L/kg). The terminal elimination half-life 
ranged from 0.4 h (rat) to 2.5 h (dog). In monkeys, the PK parameters of ruxolitinib were 
comparable with and without the pretreatment of agents that increase gastric pH, indicating that 
elevated gastric pH is not likely to affect the oral exposure of ruxolitinib. 


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4.3 Animal Toxicity 
Ruxolitinib was evaluated in several in animal based toxicology studies and did not exhibit 
significant toxicities at target concentrations. Cardiovascular evaluation in dogs demonstrated 
lowered blood pressure and increased heart rate at the highest dose of ruxolitinib (30 mg/kg). 
Effects noted in multiple-dose toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and 
dogs (up to 12 months) were primarily those associated with the mechanism of action of 
ruxolitinib, a potent and reversible inhibitor of JAK-STAT signaling. Decreases in red blood 
cells, reticulocytes, eosinophils and lymphocytes have been observed along with lymphoid 
depletion in bone marrow and lymphoid organs. In addition, in dogs, demodectic mange, 
bacterial pneumonia and viral-induced papillomas, expected consequences of the pharmacology 
of JAK inhibition, were noted. 
Embyro-fetal assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal toxicity 
were noted at the highest doses. No teratogenicity was noted in rat or rabbit animal models. 
There were no reported effects on fertility or early embryonic development. In an evaluation of 
fertility and early embryonic development, no effects were noted on reproductive performance or 
fertility in male or female rats. Increases in post-implantation loss were noted at the higher doses. 
In a pre- and post-natal development and maternal function study in rats there were no adverse 
findings for fertility indices or for maternal and embryo-fetal survival, growth, and 
developmental parameters. Ruxolitinib passed into the milk of lactating rats with an exposure 
that was 13-fold higher than maternal plasma exposure. 
 
4.4 Absorption, bioavailability, and pharmacokinetics 
Ruxolitinib is a potent and selective inhibitor of the JAKs with selectivity for JAK1 and JAK2 
(Quintás-Cardama et al, 2010). Ruxolitinib potently inhibits JAK1 and JAK2 (IC50<5nM), yet it 
does not significantly inhibit a broad panel of 28 kinases (<30% inhibition) when tested at 200 nM 
(approximately 100 × the average IC50 value for JAK1 and JAK2 enzyme inhibition). In cell-based 
assays relevant to the pathogenesis of MPNs (myeloproliferative neoplasms), such as JAK/STAT 
signaling and the growth of cytokine-dependent tumor cell lines, ruxolitinib demonstrates IC50 
values of 80-300 nM. This effect is not due to general cytotoxicity, because ruxolitinib (up to 25 μM) 
had no significant effect on the growth of a cytokine-independent, BCR-ABL-driven cell line. In 
addition, ruxolitinib inhibited JAK/STAT signaling and growth of a cell line expressing the 
constitutively active JAK2 mutant (JAK2V617F) that has been implicated in the pathogenesis of the 
majority of Philadelphia chromosome negative MPNs. Ruxolitinib was also tested in cell-based 
assays relevant to the increased inflammatory cytokine levels observed in MPNs that contribute to 
MPN-related systemic symptoms. Ruxolitinib potently inhibited IL-23 stimulated IL-22 production 
in human T cells (IC50=50 nM), as well as IL-6, GM-CSF and TPO induced STAT3 
phosphorylation in human peripheral blood mononuclear cells with IC50 values < 100 nM. 
Ruxolitinib also inhibited GCSF stimulated STAT3 phosphorylation in human neutrophils (IC50=28 
± 9 nM), as well as TPO induced STAT3 phosphorylation in human whole blood (IC50=281 ± 62 
nM). Finally, ruxolitinib inhibited the production of IL-17 in response to IL-23 in T cells, and the 
production of monocyte chemotactic protein-1 in response to IL-6 in peripheral blood mononuclear 
cells with IC50 values of ≤120 nM (Fridman et al, 2011). 
Ruxolitinib inhibited splenomegaly in mice resulting from intravenous (IV) inoculation of cells 
expressing the clinically relevant JAK2V617F mutation (Quintás-Cardama et al, 2010). After 3 
weeks of treatment, more than 90% of vehicle-treated mice had succumbed to disease while more 
than 90% of ruxolitinib -treated mice survived. Treatment with ruxolitinib also reduced inflammatory 


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cytokine levels in these mice. The effects of ruxolitinib were also tested in a mouse disease model of 
polycythemia vera-like disease, based on transplantation of a 1:1 ratio of JAK2 wild type green 
fluorescent protein (GFP)-expressing murine bone marrow cells with JAK2V617F-positive murine 
bone marrow cells, which have a repopulation advantage. In this model, oral ruxolitinib treatment at 
doses of 30 or 90 mg/kg twice a day for 21 consecutive days reduced levels of phosphorylated 
STAT5 (pSTAT5) in the spleen, as well as the spleen size. Ruxolitinib also effectively reduced the 
red cell parameters (RBC count, Hgb, Hct and reticulocyte count) and neutrophil count. The 
treatment was well tolerated as assessed by monitoring body weight, and histological assessments of 
spleen and bone marrow samples post-therapy revealed a decrease of hypercellularity (erythroid and 
myeloid lineages) in ruxolitinib treated groups as compared to vehicle treated animals. However, no 
significant decrease in the mutant allele burden surrogate readout (percentage of GFP-negative cells, 
i.e. cells expressing JAK2V617F) was observed, as assessed by flow cytometry. Treatment of mice 
with ruxolitinib in a cytokine-dependent multiple myeloma (MM) xenograft model resulted in a 
dose-dependent suppression of phosphorylated STAT3 (pSTAT3) and tumor growth. Efficacy was 
also observed in additional preclinical tumor models representing both hematologic and solid tumors. 
Taken together, these data indicate that ruxolitinib will be able to inhibit wild-type and mutant JAKs 
in the clinical setting and are consistent with its observed efficacy in patients with MPNs. 
 
4.5 Clinical Trials 
To date, more than 9,400 patients have received ruxolitinib in Novartis and Incyte sponsored 
interventional clinical trials. The clinical experience of ruxolitinib in humans is mainly based on 
data obtained in patients with myelofibrosis (MF), polycythemia vera (PV), and graft versus host 
disease (GVHD). Limited data are available in healthy volunteers, essential thrombocytosis, 
multiple myeloma, prostate cancer, pancreatic cancer, thalassemia and rheumatoid arthritis. 
 
The clinical database (safety set) in solid tumor and hematologic malignancies consists of 787 
patients treated in 6 studies evaluating patients with myelofibrosis (MF) (n=679), prostate cancer 
(n=22), MM (n=13), essential thrombocythemia (ET), and polycythemia vera (PV) (n=73), of 
whom 617 patients received ruxolitinib. Hematologic events are the most frequently reported 
adverse events (AEs) and include thrombocytopenia and anemia. The majority of these AEs are 
of Grades 1-2, seldom led to study drug discontinuation (<1% of patients), and can be usually 
managed through dose reduction or interruption. Increased rates of anemia resulted in an increase 
in packed red blood cell (PRBC) transfusion requirements for some ruxolitinib-treated patients. 
Platelet transfusions while on ruxolitinib were rare. Biochemistry laboratory abnormalities of 
alanine aminotransferase (ALT), aspartate aminotransferase (AST) and cholesterol were 
reported. The majority of these increases were Grade 1 or 2. No Grade 4 events were reported. 
 
Safety in clinical pharmacology studies 
The safety profile for ruxolitinib in the Phase I development program was assessed in over 145 
healthy subjects for single doses from 5 mg to 200 mg, and in 53 healthy subjects for repeat 
doses from 15 mg to 50 mg b.i.d. and 50 to 100 mg q.d. Ruxolitinib has also been administered 
to 32 subjects with various degrees of renal impairment, 24 subjects with various degrees of 
hepatic impairment, and 50 subjects with RA (rheumatoid arthritis). AEs were, in general, mild 
and resolved without interventions. In the first in human study one subject had hyponatremia 
after receiving 5 mg ruxolitinib. The hyponatremia was assessed as severe in intensity, unrelated 


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to study medication, reversed within 5 days, and was reported as a serious adverse event (SAE). 
A Phase I dose escalation study and a study to evaluate food effect in Japanese healthy 
volunteers showed that administration of ruxolitinib with a high-fat meal led to results that were 
in line with results from the North American study. A Phase I dose escalation study in Chinese 
healthy volunteers showed similar overall results over a dose range of 10-50 mg. The 
pharmacokinetics of ruxolitinib was linear in the dose range studied, with a short half-life of 2-4 
hours resulting in no notable drug accumulation following multiple doses. 
In the repeat-dose study in healthy subjects, the intensity of an adverse event was graded 
according to the protocol-defined toxicity criteria based on Rheumatology Common Toxicity 
Criteria V 1.0. The dose-limiting AE was neutropenia, which occurred at a dose of 50 mg b.i.d. 
Neutropenia as an AE was noted in three subjects, all receiving the highest dose of ruxolitinib, 
50 mg b.i.d. Neutropenia at the Grade 4 level, assessed as severe, led to study drug 
discontinuation on Day 5 in one subject, and was reported as a SAE. Neutrophil count returned 
to a normal level 12 days after the final dose of study medication. In two other subjects, 
neutropenia was Grade 1 or 2, and resolved with dose interruption or during continued dosing. 
The AE profile was similar for single- and multiple-dose studies, and no differences were 
observed between males and females. The most frequent (≥2 subjects) treatment-emergent AEs 
(TEAEs) occurring in the Phase I multiple-dose study were: neutropenia (4.2%), dizziness 
(2.8%), headache (2.8%) and nausea (2.8%). Overall, in healthy volunteer studies where frequent 
sampling of the neutrophil count was performed, a transient, reversible decrease in neutrophil 
count was frequently seen following dosing, which reversed after 12-24 hours off drug. 
Two clinical pharmacology studies are ongoing to evaluate the effect of ruxolitinib on the 
pharmacokinetics of orally administered midazolam in healthy males subjects and of monophasic 
oral contraceptives in health female subjects. 
 
The first Periodic Safety Update Report (PSUR) for ruxolitinib covered the reporting period 
from 16 Nov 2011 to 22 Feb 2013. A critical analysis of the efficacy and safety data revealed 
that the overall benefit-risk assessment of ruxolitinib remains favorable. Based on a single 
confirmed case of PML in an MF patient treated with ruxolitinib, this condition has been 
identified as an important potential risk. Reports of tuberculosis continue to be received in 
ruxolitinib-treated subjects in clinical trials. While the cumulative incidence of these tuberculosis 
reports appears to decline since the original Phase III trials, given the potential impact of 
JAK1/JAK2 inhibition upon immune defense, the risk tuberculosis will be monitored closely in 
subsequent PSURs. 
 
Phase III studies in patients with myelofibrosis 
The Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I, (COMFORT-I) was a 
randomized, double-blind, placebo-controlled, multicenter study comparing the efficacy and 
safety of ruxolitinib tablets to a matched placebo in 309 patients with MF. The primary objective 
was to evaluate the efficacy, safety and tolerability of ruxolitinib given b.i.d. compared to 
placebo in patients with MF. Patients were randomized in a 1:1 ratio of ruxolitinib: placebo with 
no stratification. Ruxolitinib starting dose was based on baseline platelet count as follows: 
patients with baseline platelet count >200 x109/L started at 20 mg b.i.d. and patients with 
baseline platelet count >100 x 109/L to ≤200 x 109/L started at 15 mg b.i.d. The primary 
endpoint for this study was the percentage of patients with ≥35% reduction in spleen volume 


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assessed by imaging (MRI or CT) from baseline, at Week 24. The Controlled Myelofibrosis 
Study with Oral JAK Inhibitor Treatment II (COMFORT II) was an open-label, randomized, 
active-comparator, multicenter study comparing the efficacy and safety of ruxolitinib tablets 
versus best available therapy as selected by the investigators in 219 adults patients with 
myelofibrosis. Key eligibility criteria were as follows: adult MF patients, not candidates for stem 
cell transplantation, with two or more risk factors identified by IPSS, palpable spleen length ≥5 
cm below the left costal margin, peripheral blast count <10%. The primary endpoint for this 
study was the percentage of patients with ≥35% reduction in spleen volume assessed by imaging 
(MRI or CT) from baseline, at Week 48. These trials identified statistically significantly larger 
proportion of patients randomized to ruxolitinib achieved a ≥35% reduction from baseline in 
spleen volume compared to patients randomized to control. This effect was seen at both Week 24 
(primary endpoint in COMFORT-I) and Week 48 (primary endpoint in COMFORT-II). For 
patients who remained on study, the median percent reduction from baseline in spleen volume in 
both ruxolitinib arms was approximately 30%, was reached as early as Week 12 and was 
maintained throughout the study. The control arms had a median percent increase from baseline 
in spleen volume throughout the study. 
 
Phase III studies in patients with polycythemia vera 
The RESPONSE Trial was a global, randomized, open label phase III pivotal study comparing 
ruxolitinib (starting dose of 10 mg b.i.d.) with best available therapy (HU, pipobroman, 
immunomodulatory drugs, pegylated interferon or interferon, anagrelide, observation only) in 
PV patients. The protocol was designed for patients with evidence of need for phlebotomy and 
splenomegaly, either resistant or intolerant to HU. The primary endpoint was a composite one 
with phlebotomy control (absence of phlebotomy from Week 8 to 32) and reduction in spleen 
volume by MRI (or CT if MRI is clinically contraindicated) of at least 35% measured at 32 
weeks. Two key secondary endpoints included durability of the primary endpoint and complete 
hematologic remission. The primary efficacy objective was based on a composite endpoint 
consisting of Hct control (absence of phlebotomy eligibility) and of at least 35% spleen volume 
reduction as assessed by central radiologic evaluation. Significantly more patients randomized to 
ruxolitinib met the primary endpoint at Week 32 when compared to patients randomized to BAT, 
22.7% vs. 0.9%, respectively (p<0.0001). Significantly more patients randomized to ruxolitinib 
maintained primary response (Hct control and spleen volume reduction) at Week 48 when 
compared to patients randomized to BAT, 20.0% vs. 0.9%, respectively, (p<0.0001). Among the 
25 patients randomized to ruxolitinib who had achieved primary response (Hct control and ≥35% 
reduction in spleen volume), 23 maintained the response through data cutoff (15-Jan-2014). The 
probability of maintaining primary response for 48 weeks and longer after the start of response 
was 0.90. Longer follow-up to Week 80 showed that no further patients had lost the primary 
response. 
 
Ruxolitinib for the treatment of inadequately controlled PV without splenomegaly (RESPONSE- 
2) followed the pivotal RESPONSE study which demonstrated that ruxolitinib was superior to 
BAT at controlling Hct and improving splenomegaly and symptoms in PV patients with 
splenomegaly who were inadequately controlled with HU. In the RESPONSE-2 study, the efficacy 
and safety of ruxolitinib was assessed in controlling disease in patients with PV without 
splenomegaly who need second-line therapy. The primary endpoint was the proportion of patients 


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achieving Hct control at week 28. Analyses were done according to an intention-to-treat principle, 
including data from all patients randomly assigned to treatment. Hct control was durable for a 
higher proportion of patients in the ruxolitinib arm compared to the BAT arm at Week 52 (59.5% 
vs 6.7%, respectively) and at Week 80 (47.3% vs 2.7%, respectively). The median duration of Hct 
control was not achieved in the ruxolitinib and the BAT arm. The estimated proportion of patients 
without an event at 72 weeks was 80.7% in the ruxolitinib arm. The proportion of patients without 
event at 72 weeks in the BAT arm was not reported due to very small number of patients 
responding to BAT. CHR was durable for a higher proportion of patients in the ruxolitinib arm 
compared to the BAT arm at Week 52 (23.0% vs 4.0%, respectively) and at Week 80 (24.3% vs 
2.7%, respectively). In the ruxolitinib arm, the median duration of CHR was 34.0 weeks. The 
median duration of CHR in the BAT arm was not reported due to very small number of patients 
responding to BAT. 
 
Phase I/II study in patients with prostate cancer 
A Phase II, open label study of ruxolitinib administered orally to patients with androgen 
independent metastatic prostate cancer (AIPC) was performed. The primary endpoint was PSA50 
(prostate-specific antigen) response rate, a clinically validated endpoint associated with clinical 
benefit in patients with metastatic prostate cancer. This endpoint is defined as a PSA decline 
from baseline of 50% or greater, confirmed by measurement on two occasions at least 4 weeks 
apart. The study used a Simon 2-stage optimal design. The first stage of the trial (Part 1) was 
designed to enroll 21 patients. If fewer than two PSA50 responses were observed in the first 
21 patients (no later than 10 weeks after the last patient in the first stage is enrolled), the trial 
would be closed and the agent will be declared inactive as a monotherapy. If two or more PSA50 
responses are seen in the first stage, an additional 20 patients would be enrolled in the second 
stage (Part 2) for a total of 41 patients. The study in patients with advanced prostate cancer 
completed enrollment of 22 subjects in the first stage of the study. The study endpoint permitting 
advancement to a second stage of the study was not reached. Seventeen of 22 subjects enrolled 
experienced death or protocol-defined progressive disease while on study. 
 
Given that all patients discontinued the study due to protocol-specified lack of efficacy, the 
primary efficacy endpoint of PSA50 response rate was not assessed. Similarly, the secondary 
endpoints of median time to progression and tumor response rates were not assessed. All patients 
provided samples for the secondary endpoints of evaluating population PK and plasma PD 
markers; however, the samples were not assessed as part of this analysis. 
 
The primary endpoint of safety and tolerability was assessed in this analysis. All patients 
experienced at least one TEAE, and the majority of patients (16 patients; 72.7%) experienced 
treatment-related TEAEs. The events associated with ruxolitinib treatment included anemia, 
fatigue, diarrhea, nausea, leukopenia and peripheral edema, all of which were not unexpected 
events in this patient population of metastatic androgen AIPC, as were the most frequently 
reported severe or life-threatening TEAEs (anemia, thrombocytopenia, peripheral edema, 
increased blood alkaline phosphatase, bone pain). 
 
Treatment with ruxolitinib was generally well-tolerated. Among the 11 SAEs reported by nine 
patients, the only SAE that was reported by more than one patient was anemia (two patients), and 


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only two SAEs were considered to be possibly or definitely related to study medication by the 
investigator (cardiac arrest and anemia, respectively). Further, only one patient discontinued 
treatment as a result of an AE (anemia). Among the four deaths, cardiac arrest was deemed by 
the investigator as possibly related to study medication in one patient, but the patient had other 
risk factors that may have also contributed to the event; the other three deaths were likely 
associated with medical history and metastatic AIPC. 
 
Eight patients had laboratory abnormalities that resulted in serious, severe, or life-threatening 
AEs, which included the following events: anemia, increased blood alkaline phosphatase, 
increased γGT, thrombocytopenia, hyperuricemia, and leukopenia. There was no specific trend 
among patients with regards to laboratory abnormalities or ECG values out of the normal range. 
Overall, there were no specific safety concerns associated with ruxolitinib. 
 
 
4.6 Other Agent(s) 
Not applicable 
 
5. 
STUDY DESIGN 
5.1 
General Design 
This is an open-label, multi-center,  Phase  II  study  to  evaluate  the  efficacy  of  ruxolitinib 
in post-transplant patients with advanced cutaneous squamous cell carcinoma. 
 
Study Intervention: In a safety lead-in of 6 patients, subjects will receive ruxolitinib 15mg 
BID. After 4 weeks, if dose-limiting toxicities (DLT) are observed in 1 or fewer patients, the 
study will enter stage 1 of the Simon two-stage design where all subsequent patients will receive 
a starting dose of ruxolitinib 15mg BID. If more than 1 DLTs are observed, another cohort of 6 
patients will be treated at a dose of 10mg BID. If less than 2 DLTs are observed at the new dose 
of 10mg, then the study will proceed to stage I using this dose; otherwise the study will stop. 
 
Individual subjects may have dose reductions of ruxolitinib during the course of treatment, based 
upon safety laboratory assessments. 
 
Schedule of Evaluations: Subjects will have regularly scheduled study visits at the clinical site 
on Day 1 and Day 15 (± 3 days) of the first cycle, then on Day 1 (± 3  days)  of  every 
subsequent cycle (starting cycle 2), where safety assessments, including laboratory assessments, 
vital signs, and physical examinations will be performed (see Section 12 for study calendar). 
 
Response to treatment will be determined by CT scans of the chest, abdomen, and pelvis with 
contrast. The overall response rate for the primary endpoint evaluation will be determined by 
RECIST v1.1 criteria. In patients who are unable to get a CT scan w/ contrast due to renal 
function (or any other reason), an MRI with and without contrast may be used instead. Imaging 
will be performed at the following time points: 


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Baseline scan 
Baseline scan within 4 weeks prior to first treatment 
Weeks 1 – 32 
Every 8 weeks +/- 1 week (at weeks 8, 16, 24, 32) 
Weeks 33 – until disease 
progression 
Every 12 weeks +/- 1 week (at weeks 44, 56, 68, 80, 92, 104) 
2 years 
If subjects achieve ongoing disease control at 2 years, patients 
will be continued on study treatment and observed with imaging 
every 12 weeks +/- 2 weeks. 
 
Duration of treatment: Subjects will continue treatment until confirmed radiographic disease 
progression, intolerable toxicity or side effects (Section 6.5.1). 
 
Correlative studies: A minimum of 10 enrolled subjects must undergo paired biopsies for 
correlative studies. CT-guided biopsies will be collected at baseline and between C2D1 and 
C2D8 of therapy for correlative studies. A biopsy at the time of disease progression is optional 
in all subjects. Subjects in whom a biopsy is technically not feasible or in whom would result in 
unacceptable risk, in the opinion of the investigator, may be exempted from the biopsy 
requirement with discussion with the principal investigator. 
 
Whole blood will be requested as outlined in section 13.2 for peripheral blood mononuclear cell 
(PBMC) and circulating tumor DNA (ctDNA) collection to evaluate the effect of ruxolitinib on 
circulating immune cell populations before and during treatment and to further evaluate ctDNA 
as a potential biomarker of disease response. 
 
Duration of follow-up: Adverse events and laboratory tests will be graded using the NCI 
CTCAE v5.0 scoring system. Adverse events will be assessed continuously during the study and 
for 90 days after the last dose of treatment. Subjects will be followed for at least 90 days post- 
study, or until all treatment related adverse events have recovered to baseline or are deemed 
irreversible by the investigator. Subjects who are removed from study for reasons other than 
progression of disease will be followed every 3 months with imaging to evaluate disease status 
and survival analysis while the study remains open. 
 
5.2 
Number of Patients 
Utilizing a Simon Two-Stage Mini-Max design, 18 patients with advanced cSCC will be accrued 
in the first stage. If 1 or more patients achieve a response, then an additional 14 will be accrued. 
If 3 or fewer responses are seen, the study will be declared negative. If the initial safety lead-in 
does not result in advancement to stage I, an additional 6 patients will need to be accrued for a 
second safety lead-in. Assuming a 10% drop-out rate, we anticipate a total accrual of 35 patients 
with a maximum potential accrual of 41 patients (see Statistical Considerations). 
 
5.3 
Correlative Studies 
5.3.1 Tumor biopsies for pharmacodynamic assessment 
 
The biological activity of ruxolitinib will be assessed by performing paired tumor biopsies 


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at baseline, and between Cycle 2 Day 1 and Cycle 2, Day 8 of study therapy. These biopsies will 
be mandatory in the first 10 patients enrolled on Stage I of the study (first 18 enrolled subjects), 
and optional in subsequent  patients.  A  biopsy  at  the  time  of  disease  progression  is 
optional in all patients. (Note: If sufficient flash frozen tumor material is available from a prior 
tumor biopsy performed within 3 months of registration with no intervening therapy, then a 
repeat baseline biopsy will not be necessary.) 
 
A goal of at least 3 cores and up to 8 cores from the patient’s tumor biopsy specimen, if safe to 
obtain, will be obtained for research purposes. The first core will be placed in buffered formalin 
and paraffin-embedded as standard of care. Subsequent cores will be flash frozen. 
 
5.3.2 Blood Collection 
 
Whole blood will be requested as outlined in section 13.2 for peripheral blood mononuclear cell 
(PBMC) and circulating tumor DNA (ctDNA) collection to evaluate the effect of ruxolitinib on 
circulating immune cell populations before and during treatment and to further evaluate ctDNA 
as a potential biomarker of disease response. 
 
 
Detailed specimen processing and shipping information can be found in the laboratory 
manual. 
Correlative analysis may include some or all of the following studies: 
 
• 
IHC and/or Western blot and qRT-PCR to evaluate changes in STAT3, Cyclin D1, and 
other proteins 
• 
Multiplex immunohistochemistry to assess changes in the immune microenvironment 
• 
Bulk and single cell RNA-Seq analysis may be performed on paired tumor biopsies to 
assess mechanisms of disease response and resistance 
• 
Additional studies may be performed in the future. 
 
Samples will be stored on-site and shipments will be sent to the Owens laboratory by batch 
shipments when requested to the address listed below: 
 
Owens Laboratory 
Columbia University Medical Center 
1130 St. Nicholas Avenue 
ICRC Room 207 
New York, NY 10032 
 
The analyzing laboratories will be notified by email (AAAT5353@columbia.edu) the day the 
samples are sent. The email will contain the following information: 
• Subject ID 


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• Subject Initials 
• Date of collection 
• Time point (e.g. baseline, cycle 2 day 1, end of treatment, etc) 
• Name of study center 
• Shipment date 
• Contents of shipment 
 
Samples should be shipped via courier so that the package is tracked appropriately (specifically 
Federal Express or UPS). The samples should be shipped for morning delivery, Monday through 
Thursday for optimal processing. 
 
Samples will be tracked through a Microsoft Excel tracker. 
 
 
6. 
SUBJECT SELECTION AND WITHDRAWAL 
6.1 
Inclusion Criteria 
1. Histologically confirmed diagnosis of cSCC. 
2. Unresectable or metastatic cSCC. 
3. History of solid-organ transplant requiring immunosuppression 
4. Allowable prior therapies: 
a. A maximum of 4 prior therapies for metastatic disease are allowed. 
5. Male or female subjects, age 18 years or older. 
6. ECOG performance status ≤ 2 (Appendix A) 
7. Life expectance of ≥ 3 months. 
8. Laboratory parameters within the following Protocol-defined range. All screening 
laboratory tests should be performed within 28 days of treatment initiation and must be 
independent of hematopoietic growth factor support. 
• Absolute neutrophil count ≥ 1.5 x 109/L. 
• Platelets ≥ 100 x 109/L. 
• Hemoglobin ≥ 9 g/dL (transfusion is acceptable to meet this criteria) 
• Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN) OR calculated 
creatinine clearance ≥ 50 mL/min for subjects with creatinine levels > 1.5 x 
institutional ULN. 
• Aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase ≤ 2.5 x 
ULN, or ≤ 5 x ULN in subjects with liver metastases. 
• Total bilirubin ≤ 1.5 x ULN 
o Note: patients with hyperbilirubinemia clinically consistent with an inherited 


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disorder of bilirubin metabolism (eg, Gilbert syndrome) will be eligible at the 
discretion of the principal investigator. 
• International normalized ratio (INR) or prothrombin time (PT) < 1.5x ULN unless 
subject is receiving anticoagulation therapy as long as PT or INR is within therapeutic 
range of intended use of anticoagulant. 
• Activated partial thromboplastin time (aPTT) < 1.5 x ULN unless subject is receiving 
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of 
anticoagulants. 
 
9. Presence of baseline measureable disease by RECIST v1.1 for solid tumors, defined as at 
least one lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 
mm with conventional techniques or as ≥ 10 mm with spiral CT scan, MRI, or calipers by 
clinical exam. (See Section 15.4 for the evaluation of measurable disease). 
 
10. The effects of ruxolitinib on the developing human fetus are unknown, and thus female 
subjects of childbearing potential (defined as women who have not undergone surgical 
sterilization with a hysterectomy and/or bilateral oophorectomy, and are not 
postmenopausal (defined as ≥ 12 months of amenorrhea)) must have a negative 
pregnancy test at screening and must agree to use adequate contraception (complete 
abstinence, or two methods of birth control (Appendix B)) prior to study entry and until 
at least 4 months after the last dose of study treatment. Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. 
 
11.  Fertile men must also agree to use adequate contraception (2 barrier methods or 
abstinence) during the study and for up to 4 months after the last dose of study drug. 
 
12. Subjects must agree to pre- and on-treatment tumor biopsies. Subjects in whom biopsy is 
technically not feasible or in whom would result in unacceptable risk, in the opinion of 
the investigator, may be exempted from the biopsy requirement with discussion with the 
principal investigator. Use of outside archived tumor tissue for a baseline biopsy is not 
permitted. 
 
13. Willingness and ability to provide written informed consent prior to any study-related 
procedures and to comply with all study requirements. 
 
6.2 
Exclusion Criteria 
1. At least 21 days must have elapsed since the last dose of systemic chemotherapy or 
immunotherapy and the first dose of study drug. 
2. At least 14 days must have elapsed since the last dose of radiation therapy and the first 
dose of study drug. 
3. Patients who have previously been treated with a JAK inhibitor. 


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4. Patients who are receiving any other investigational agents concurently. 
5. Patients who have had recent major surgery within a minimum 4 weeks prior to 
6. starting study treatment, with the exception of surgical placement for vascular access. 
7. Patients with a history of allergic reactions attributed to compounds of similar chemical 
or biologic composition to ruxolitinib. 
8. Patients with symptomatic or growing brain metastases. Patients with brain metastases 
that have been treated and have remained stable for at least one month prior to initiation 
of study therapy are eligible. 
9. Concurrent use of strong CYP3A4 or CYP3A4 substrate drugs with a narrow therapeutic 
range within 14 days or 5 drug half-lives, whichever is longer, before start of study drug. 
A list of strong CYP3A4 and 2C8 inhibitors and inducers can be found in Appendix C. 
10. HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with ruxolitinib. In addition, these patients are 
at increased risk of lethal infections when treated with marrow- suppressive therapy. 
11. Subjects with known active hepatitis B or C, or chronic hepatitis B or C requiring 
treatment with antiviral therapy. 
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
13. Patients being actively treated for a second malignancy. 
 
6.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
6.4 
Subject Recruitment 
A member of the  patient’s  treatment  team,  the  protocol  investigator,  or  research  team  at 
the multi-center sites will identify potential research participants. If the investigator is a part of 
the treatment team, s/he will screen the patient as to eligibility, and will discuss the study and the 
possibility of enrollment in the research study with the patient. The preliminary screen of 
eligibility will be confirmation for the diagnosis of advanced cutaneous squamous cell 
carcinoma. 
 
Potential subjects that meet these basic criteria will be referred by their treatment physician to 
the investigator, co-investigators, or research staff of the study. Minority and women are well 
represented in cutaneous oncology  clinics,  and  we  expect  that  they  will  be  well 
represented in the trial accrual. The principal investigator, Richard Carvajal, MD, will be 
available to all patients for further questions and information through  a  contact  number  will 
be provided on the consent form. 
 
During the initial conversation between the investigator/research staff and the patient, the patient 


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may be asked to provide  certain  health  information  that  is  necessary  to  the  recruitment 
and enrollment process. The investigator/research staff may also review portions of their 
medical records in order to further  assess  eligibility.  They  will  use  the  information 
provided by the patient  and/or  medical  record  to  confirm  that  the  patient  is  eligible  and 
to contact the patient regarding study enrollment.  If  the  patient  turns  out  to  be  ineligible 
for the research study, the research staff will destroy all information collected on the patients 
during the initial conversation and medical records review, except for any information that must 
be maintained for screening log purposes. 
 
6.5 
Early Withdrawal of Subjects 
When and How to Withdraw Subjects 
 
Patients may withdraw from study at any time. Patients who  discontinue  early should 
return within 30 days of the last dose of the study drugs for a follow up evaluation. Any 
assessments listed for the final visit should be performed at that time. 
 
In addition, any of the following conditions require withdrawal of the subject from study 
treatment: 
• 
Disease progression defined by RECIST 1.1 
• 
Severe, unexpected toxicities/side effects 
• 
Lost to follow up or non-compliance with the protocol schedule 
• 
An AE or current illness that in the opinion of the investigator or sponsor warrants the 
subject’s withdrawal from treatment 
• 
Necessary treatment with other investigational drug or other anticancer medications 
prohibited by protocol 
• 
Participation in another clinical study using anti-cancer agents 
• 
Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under this protocol 
• 
Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception during the course of the study and for 3 months  following 
discontinuation of study treatment 
• 
Women who are pregnant or are breast feeding 
• 
If the patient withdraws consent for continued participation, he/she will be removed from 
study. 
The reason for study treatment discontinuation will be documented. For subjects who 
discontinue or are withdrawn from study treatment, every effort must be made to undertake 
protocol specified follow up procedures and end of treatment assessments, if possible unless 
consent to participate in the study is also withdrawn. 
 
If a subject is discontinued from study treatment because of an AE considered to be related to 
study treatment and the event is ongoing 30 days after the last dose of study treatment, the event 


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must be followed until resolution or determination by the investigator that the event has become 
stable or irreversible. 
 
If a subject withdraws consent  to  participate  in  the  study  the  reason  for  withdrawal will 
be documented, no further study procedures or assessments will be performed, and no further 
study data will be collected for this subject other than the determination of survival status from 
public records such as governmental vital statistics or obituaries. 


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Data Collection and Follow-up for Withdrawn Subjects 
 
Even though subjects may be withdrawn prematurely from the study, it is imperative to collect at 
least survival data on such subjects throughout the protocol defined follow-up period for that 
subject (though careful thought should be given to the full data set that should to be collected on 
such subjects to fully support the analysis). Such data is important to the integrity of the final 
study analysis since early withdrawal could be related to the safety profile of the study drug. If a 
subject withdraws consent to participate in the study, attempts will be made to obtain consent 
from the subject to record at least survival data up to the protocol-described end of subject 
follow-up period. It must be a high priority to try to obtain at least survival data on all subjects 
lost to follow-up and to note what methods should be used before one can state the subject is 
truly lost to follow-up (e.g. number of phone calls to subject, phone calls to next-of-kin if 
possible, certified letters, etc.). Subjects withdrawn because of unacceptable adverse events will 
be followed-until resolution or stabilization of the adverse event. 
7. REGISTRATION PROCEDURES 
7.1 
CUMC Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office. 
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or fax to 
212.305.5292, with the subject line “AAAT5353 Pending Subject Registration Request (PHI)”. 
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database. This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 


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pending registration submissions are as follows: 
 
• Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
• The completed/signed IRB approved HIPAA Authorization form 
• Completed/signed CPDM ICF checklist 
• Completed/signed HICCC personal census form 
• Completed/signed CPDM Demographics Note to File 
 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
• The completed/signed study specific Eligibility Checklist (signed by an Physician level 
Investigator) 
• Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent 
process information, along with providing source documentation of any other 
items needed for screening/eligibility that are not captured in other source 
document forms (e.g., positive investigator statements of unique eligibility items 
not captured via other direct source documentation, concomitant medication lists, 
etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 
• Please note: subject line of email or fax should include the following: “AAAT5353 
Complete Subject Registration Request (PHI)”. 
 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. .All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar. Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information. Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 


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7.2 
Informed Consent Procedures 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
8. 
TREATMENT PLAN 
8.1 Agent Administration 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks for ruxolitinib are described in Section 10. Appropriate dose modifications for ruxolitinib 
are described in Section 9. No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient's malignancy. 
 
If all eligibility criteria are met, study participants will initiate ruxolitinib twice daily. One cycle 
will consist of 4 weeks of therapy. 
 
• 
Patients will be provided with a Medication Diary for ruxolitinib (Appendix D), 
instructed in its use, and asked to bring the diary with them to each appointment. 
• 
Doses of ruxolitinib will be taken  orally  with  approximately  8  oz.  of  water. 
Subjects should fast at least 1 hour before administration and 1 hour after administration 


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of the drug. Study drug should be taken at approximately the same time each day. Study 
drug should be swallowed whole and not crushed, chewed, or dissolved in water. 
• 
Missed  doses  (outside  of   a   2   hour   dosing   window)   should   be   skipped   and 
not administered as a  double  dose  at  the  next  administration.  Missed  doses  should 
be recorded on the Medication Diary but will not be considered violations of the protocol. 
• 
Subjects who vomit their dose should be instructed NOT to make up that dose. Doses that 
are vomited should not be replaced. 
• 
Patients will be instructed that ruxolitinib can be stored at room temperature. 
• 
No premedication or other supportive medications are required. 
 
8.1.1 Investigational Agent(s) 
 
Ruxolitinib will be administered twice daily, in the morning and evening, approximately 12 
hours apart, without regard to food. If a dose is late but within 4 hours of its scheduled 
administration time it should be taken; if more than 4 hours have passed, the dose should be 
omitted and the patient should continue treatment with the next scheduled dose. If vomiting 
occurs while taking dose, no redosing is allowed before the next rescheduled dose. 
 
Patients will not require any premedications, however supportive medications to control 
symptoms such as nausea, emesis, diarrhea, and pain will be provided for symptom control. 
 
Doses will be self-administered. Subjects will be required to keep a pill diary (Appendix D). 
Each cycle of treatment will last 28 days. 
 
8.1.2 Other Agent(s) 
 
Not applicable 
 
8.1.3 Other Modality(ies) or Procedures 
 
Not applicable 
 
8.2 General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of IND Agent with other concomitantly administered 
drugs through the CYP3A4 pathway, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential to affect 
CYP3A4 pathways. 
 
8.3 Treatment Compliance 
Treatment compliance with all study-related medications should be emphasized to the subject by 
the site personnel. Subjects will bring all bottles of unopened, empty, and unused study drug with 


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them to each study visit. The appropriate study personnel will maintain records of study drug 
receipt and dispensing. Any discrepancy regarding the dose administered and the reason for the 
discrepancy will be recorded in the electronic case report form (eCRF). At each clinic visit, patients 
will be questioned about their compliance with study drug administration, and their dosing diary 
should be reviewed. Bottles of study drug, including all bottles of unopened, partially opened, or 
empty bottles cannot be destroyed or returned to the depot until a monitor reviews and verifies all 
tablet counts for compliance. 
 
8.4 Randomization and Blinding 
Not applicable. 
 
8.5 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for until one of 
the following criteria applies: 
• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse events(s) 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
8.6 Duration of Follow Up 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. Patients who are taken off therapy for any reason other than 
death or disease  progression  will  continue  to  undergo  reimaging  studies  every  8  weeks 
(+/- 1 week) until disease progression, start of a new anticancer therapy,  or  death.  After 
disease progression or  start  of  a  new  anticancer  therapy,  patients  will  be  followed  in 
clinic or by telephone on an approximately every 12  weeks  schedule  (+/-  2  weeks)  until 
death for the purposes of survival follow-up. 
 
8.7 Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 6.5 applies. The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 
 
 
9. 
DOSING DELAYS/DOSE MODIFICATIONS 
9.1 
Required Laboratory Parameters for Initiation of a Treatment Cycle 
A cycle of therapy may be initiated provided that the patient meets the following criteria on Day 


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1 of each cycle: 
• 
ANC ≥ 1,000/mcL 
• 
Platelets ≥ 50,000/mcL 
• 
Hemoglobin ≥ 8 g/dL 
• 
Non-hematologic toxicity recovered to ≤ tolerable grade 2 (or baseline) 
• 
No evidence of progressive disease 
 
9.2 
Dosing Delays/Dose Modifications for Ruxolitinib 
Patients  may  continue  ruxolitinib  for  Grade  1  or  tolerable  Grade  2  toxicity  without  a 
dose reduction (graded according to NCI CTCAE v5.0). For intolerable Grade 2, Grade 3 or 
Grade 4 toxicity, ruxolitinib must be withheld until the toxicity has resolve to Grade 1 or 
tolerable Grade 2. At the discretion of the treating physician, ruxolitinib may then  be  resumed 
as per following guidelines (Table 1-6). If  an adverse event is not covered in the table, doses 
may be reduced or held at the discretion of the investigator for the subject’s safety. The tables are 
intended to serve as guidance and cases in which the management is unclear  should  be 
discussed with the principal investigator or study medical monitor as appropriate. 
 
Subjects with adverse events that are manageable with supportive therapy may not require dose 
reductions (e.g., nausea/vomiting may be treated with antiemetics, diarrhea may be treated with 
loperamide, and electrolyte abnormalities may be corrected with supplements rather than by dose 
reduction). 
 
Subjects will be withdrawn from the study treatment if they fail to recover to Grade 0, Grade 1 or 
tolerable grade 2 (or within 1 grade of starting values for pre-existing laboratory abnormalities) 
from a treatment-related adverse event  within  21  days  unless  the  principal  investigator 
agrees that the subject should remain on he study because of evidence that the patient is/may 
continue deriving benefit from continuing study treatment. 


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Table 1. Dose Modifications 
 
Dose Level 
Dose 
1 
15mg twice daily 
0 
10mg twice daily 
-1 
5mg twice daily 
-2 
5mg once daily 
Table 2. Management recommendations for decreased neutrophil count: 
 
Neutropenia 
Management/Next Dose for 
Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold* until < Grade 2. Resume at one 
dose level lower, if indicated.** 
Grade 4 
Hold* until < Grade 2. Resume at one 
dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off protocol 
therapy. 
**Patients requiring > two dose reductions should go off 
protocol therapy. 
 
Table 3. Management recommendations for decreased platelet count: 
 
Thrombocytopenia 
Management/Next Dose for 
Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold* until < Grade 2. Resume at 
one dose level lower, if indicated.** 
Grade 4 
Hold* until < Grade 2. Resume at 
one dose level lower, if indicated.** 
*Patients requiring a delay of >2 weeks should go off 
protocol therapy. 
**Patients requiring > two dose reductions should go off 
protocol therapy. 


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Table 4. Management recommendations for anemia: 
 
Anemia 
Management/Next Dose for 
Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Transfuse PRBC as clinically 
indicated. Hold* until ≤ Grade 2. 
Resume at one dose level lower, 
per investigator discretion** 
Grade 4 
Transfuse PRBC as clinically 
indicated. Hold* until ≤ Grade 2. 
Work up for alternative causes of 
blood loss. First occurrence: 
Resume at one dose level lower. 
Second occurrence: off therapy. 
*Patients requiring a delay of >2 weeks should go off 
protocol therapy. 
**Patients requiring > two dose reductions should go off 
protocol therapy. 
Table 5. Management recommendations for febrile neutropenia: 
 
Febrile Neutropenia 
Management/Next Dose for 
Ruxolitinib 
≤ Grade 1 
N/A 
Grade 2 
N/A 
Grade 3 
Hold* until ≤ Grade 2. Resume at 
one dose level lower ** 
Grade 4 
Hold* until ≤ Grade 2. First 
occurrence: Resume at one dose 
level lower. Second occurrence: off 
therapy. 
*Patients requiring a delay of >2 weeks should go off 
protocol therapy. 
**Patients requiring > two dose reductions should go off 
protocol therapy. 
Grade 3: ANC <1.0 X 109/L with a single temperature of 
>38.3 ° C (101° F) or a sustained temperature of ≥ 38 ° C 
(100.4 ° F) for more than 1h 
Grade 4: Life-threatening consequences; urgent 


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Febrile Neutropenia 
Management/Next Dose for 
Ruxolitinib 
intervention indicated 
 
Table 6. Management recommendations for non-hematologic toxicities: 
 
Non-Hematologic 
Toxicities 
(non-Cardiac) 
Management/Next Dose for 
Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold* until ≤ Grade 1. 
Recommend resume at same dose 
level, but per investigator 
discretion. If the toxicity is deemed 
possibly, probably, or definitely 
related to ruxolitinib – and not 
reduced after the first occurrence - 
a dose reduction should be 
considered after a second 
recurrence, if still deemed 
possibly, probably, or definitely 
related. 
Grade 3 
Hold* until ≤ Grade 1. Resume at 
one dose level lower ** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >2 weeks should go off 
protocol therapy. 
**Patients requiring > two dose reductions should go off 
protocol therapy. 
Recommended management if diarrhea: loperamide 
antidiarrheal therapy 
Dosage schedule: 4 mg at first onset, followed by 2 mg 
with each loose motion until diarrhea-free for 12 hours 
(maximum dosage: 16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should 
be recorded when used. 
Recommended management if nausea/vomiting: anti- 
emetics 


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10. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
10.1 
Adverse events 
Anemia 
In Phase III MF clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia 
was 1.5 months. One patient (0.3%) discontinued treatment because of anemia. In patients 
receiving ruxolitinib mean decreases in Hgb reached a nadir of approximately 15 to 20 g/L 
below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new 
steady state that was approximately 10 g/L below baseline. This pattern was observed in patients 
regardless of whether they had received transfusion during therapy. In the randomized, 
placebocontrolled 
COMFORT-I study, 59.4% of ruxolitinib treated patients and 37.1% of patients 
receiving placebo received RBC transfusions during randomized treatment. In the COMFORTII 
study, the rate of PRBC transfusions was 51.4% in the ruxolitinib arm and 38.4% in the BAT 
arm. 
Over the randomized period in the RESPONSE and RESPONSE-2 studies, anemia was less 
frequent in PV patients (40.8%) versus 82.4% in MF patients. In the PV population, the CTCAE 
Grade 3 or Grade 4 events were reported in 2.7%, while in the MF patients, the frequency was 
of 42.5%. 
 
Thrombocytopenia 
In the Phase III MF clinical studies, in patients who developed Grade 3 or Grade 4 
thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia  
was generally reversible with dose reduction or dose interruption. The median time to recovery 
of platelet counts above 50 x 109/L was 14 days. Platelet transfusions were administered to 4.5% 
of patients receiving ruxolitinib and to 5.8% of patients receiving control regimens. 
Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients 
receiving ruxolitinib and 0.9% of patients receiving control regimens. Patients with a platelet 
count of 100 x 109/L to 200 x 109/L before starting ruxolitinib had a higher frequency of Grade 
3 or Grade 4 thrombocytopenia compared to patients with platelet count >200 x 109/L (64.2% 
versus 35.4%). 
Over the randomized period in the RESPONSE and RESPONSE-2 studies, the rate of patients 
experiencing thrombocytopenia was lower in PV (16.8%) compared to MF (69.8%) patients. 
The frequency of severe (i.e. of CTCAE Grade 3 or Grade 4) thrombocytopenia was lower in 
PV (2.7%) than in MF (11.6%) patients. 
 
Neutropenia 
In the Phase III MF clinical studies, in patients who developed Grade 3 or Grade 4 neutropenia, 
the median time of onset was 12 weeks. During the randomized period of the studies dose 
holding or reductions due to neutropenia were reported in 1% of patients and 0.3% of patients 
discontinued treatment because of neutropenia. 
Over the randomized period in the RESPONSE and RESPONSE-2 studies in PV, neutropenia 
was observed in 3 patients (1.6%) of which one patient developed CTCAE Grade 4 neutropenia 


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Urinary tract infections 
In Phase III MF clinical studies Grade 3 or Grade 4 urinary tract infection was reported for 1.0% 
of patients. Urosepsis was reported in 1.0% of patients and kidney infection was reported in one 
patient. 
Over the randomized period in the RESPONSE and RESPONSE-2 studies in PV, one (0.5%) 
Grade 3 or Grade 4 urinary tract infection was observed. 
 
Herpes zoster 
The rate of herpes zoster was similar in PV (4.3%) patients and MF patients (4.0%). There was 
one report of Grade 3 or Grade 4 post herpetic neuralgia amongst the PV patients. 
 
Tuberculosis 
In Phase III MF clinical studies tuberculosis (TB) (any grade) was reported in 0.7% of patients. 
Epidemiological data suggests hematological malignancies, corticosteroid use, diabetes, 
emphysema, body mass index (BMI) below 20 kg/m2, bronchitis, smoking and asthma are risk 
factors for TB in a general population (Jick et al 2006, Kamboj and Sepkowitz 2006). 
Although limited epidemiological data on the incidence of TB in the targeted population are 
available, the immune function of MF patients is known to be compromised due to disease and 
therapeutic measures, including corticosteroid therapy. 
The Phase III clinical trial sample size did not allow detection of a statistically significant 
difference in the incidence of TB between the treatment and control arms. 
Reports of TB continue to be received in ruxolitinib-treated patients in clinical trials. While the 
cumulative incidence of these TB reports appears to have declined since the original Phase III 
trials, given the potential impact of JAK1/JAK2 inhibition upon TB immune defense, the risk 
of TB is closely monitored. 
No cases of TB were seen in the RESPONSE and RESPONSE 2 studies in patients with PV. 
However, a case of TB was observed in a patient with PV in a non-interventional study. 
 
Increased blood pressure 
In the Phase III pivotal clinical studies in MF an increase in systolic blood pressure of 20 mmHg 
or more from baseline was recorded in 31.5% of ruxolitinib-randomized patients on at least one 
visit compared with 18.5% in the placebo arm and 21.7% in the BAT arm. In COMFORT-I the 
mean increase from baseline in systolic blood pressure was 0-2 mmHg on ruxolitinib versus a 
decrease of 2-5 mmHg in the placebo arm. In COMFORT-II mean values showed little 
difference between the ruxolitinib-treated and the control-treated patients. 
In the randomized period of Phase III clinical studies in PV (RESPONSE and RESPONSE-2), 
hypertension was noted to occur at 6.5% compared with 2.7% in BAT arm of RESPONSE and 
4.0% with the BAT arm of RESPONSE-2. 
 
Withdrawal effects 
Following interruption or discontinuation of ruxolitinib, symptoms of MF may return over a 
period of approximately one week. There have been cases reported of patients discontinuing 
ruxolitinib who sustained more severe events, particularly in the presence of acute intercurrent 
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Warnings and precautions 
Decrease in blood cell count 
Treatment with ruxolitinib can cause hematologic adverse reactions, including 
thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before 
initiating therapy with ruxolitinib. Complete blood counts should be monitored every 2-4 weeks 
until doses are stabilized, and then as clinically indicated and dose adjusted. 
It has been observed that patients with low platelet counts (<200 x 109/L) at the start of therapy 
are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was 
generally reversible and was usually managed by reducing the dose or temporarily withholding 
ruxolitinib. However, platelet transfusions may be required as clinically indicated. 
Patients developing anemia may require blood transfusions. Dose modifications or interruption 
for patients developing anemia may also be considered. 
Neutropenia (ANC <0.5 x 109/L) was generally reversible and was managed by temporarily 
withholding ruxolitinib. 
 
Infections 
Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred 
in patients treated with ruxolitinib. Patients should be assessed for the risk of developing serious 
infections. Physicians should carefully observe patients receiving ruxolitinib for signs and 
symptoms of infections and initiate appropriate treatment promptly. Ruxolitinib therapy should 
not be started until active serious infections have resolved. 
Hepatitis B viral load (HBV-DNA titer) increases, with and without associated elevations in 
ALT and AST, have been reported in patients with chronic HBV infections taking ruxolitinib. 
The effect of ruxolitinib on viral replication in patients with chronic HBV infection is unknown. 
Patients with chronic HBV infection should be treated and monitored according to clinical 
guidelines. 
 
Tuberculosis 
TB has been reported in patients receiving ruxolitinib for MF. Before starting ruxolitinib 
therapy, patients should be evaluated for latent or active TB as per local recommendations. This 
can include medical history, possible previous contact with TB, and/or appropriate screening 
such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. 
Physicians are reminded of the risk of false negative tuberculin skin test results, especially in 
patients who are severely ill or immunocompromised. 
 
Withdrawal effects 
Following interruption or discontinuation of ruxolitinib, symptoms of MF may return over a 
period of approximately one week. There have been cases reported of patients discontinuing 
ruxolitinib who sustained more severe events, particularly in the presence of acute intercurrent 
illness. 
 
Hepatic impairment 
In patients with any hepatic impairment the recommended starting dose based on platelet count 
should be reduced by approximately 50% (or as specified in country specific product labels). 


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Patients diagnosed with hepatic impairment while receiving ruxolitinib should be carefully 
monitored and may need to have their dose reduced to avoid ADRs. 
 
Dose adjustment with concomitant CYP3A4 inhibitors/inducers/substrates 
When ruxolitinib is administered with strong CYP3A4 inhibitors (such as, but not limited to, 
boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, 
voriconazole) as well as fluconazole (a dual inhibitor of CYP3A4 and CYP2C9, see also Section 
5.1.5.4), the dose should be reduced to approximately 50% of the dose rounding to the nearest 
dosage strength. The concomitant use of ruxolitinib with fluconazole doses of greater than 200 
mg daily should be avoided. More frequent monitoring of hematology parameters and clinical 
signs and symptoms of ruxolitinib related adverse reactions is recommended upon initiation of 
a strong CYP3A4 inhibitor. No dose adjustment is necessary when a mild or moderate CYP3A4 
inhibitor is used concomitantly with ruxolitinib. No dose adjustment is necessary when a 
CYP3A4 inducer (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, rifampicin, St. John’s) is used concomitantly with ruxolitinib. 
No dose adjustment is necessary when ruxolitinib is administered with a CYP3A4 substrate. 
Patients should be closely monitored and the ruxolitinib dose titrated based on safety and 
efficacy. 
 
Women of child-bearing potential 
Women of child-bearing potential must take appropriate precautions to avoid pregnancy during 
treatment. In case pregnancy occurs, risk-benefit evaluations must be carried out on an 
individual basis with careful counseling regarding potential risk to the fetus using the most 
recent data available. 
Embryo-fetal development studies with ruxolitinib in rats and rabbits did not indicate 
teratogenicity. Ruxolitinib was embryotoxic and fetotoxic in rats (increases in post-implantation 
loss and reduced fetal weights). The potential risk for humans is unknown. 
 
Breast-feeding 
Women taking ruxolitinib should not breast-feed. 
 
Overdosage 
There is no known antidote for overdoses with ruxolitinib. Single doses up to 200 mg have been 
given with acceptable acute tolerability. Higher than recommended repeat doses are associated 
with increased myelosuppression including leukopenia, anemia and thrombocytopenia. 
Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance 
the elimination of ruxolitinib. 
 
10.2 
Definitions 
Adverse Event: 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including abnormal sign, symptom or disease, temporally associated with the subject’s 
participation in research, whether or not considered related to the subject’s participation in the 


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research. Abnormal results of diagnostic procedures are considered to be adverse events if the 
abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires inpatient hospitalization/prolongation of existing hospitalization, unless: 
o routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, paracentesis, 
pain control) 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above/below and not resulting in hospital administrations 
o social reasons and respite care in the absence of any deterioration in the patient’s 
general condittion 
• 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-patient hospitalization or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious events should be regarded as 
non-serious adverse events. 
 
Unanticipated Problem: 
An unanticipated problem is any incident, experience or outcome involving risks to subjects or 
others in any human subjects research that meets all of the following criteria: 
• Unexpected (in terms of nature, severity or frequency) given (a) the research procedures 
that are described in the IRB-approval protocol and informed consent document, and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in such research (e.g., there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures 
involved in such research); and 


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• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic or social harm) than was previously known or recognized. 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures (e.g., after the first dose of study treatment) to the end 
of the study treatment (e.g., last dose of study treatment) and/or follow-up. For this study, the 
study treatment follow-up is defined as 30 days following the last administration of study 
treatment, or 30 days following the decision to remove the subject from study treatment, 
whichever is earliest. 
Baseline/Preexisting Condition 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the character of 
the condition worsens during the study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the 
following conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management (e.g., change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc.). 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol. Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 


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• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
10.3 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
Reporting of Serious Adverse Events 
 
10.4.1 
IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an unanticipated 
problem posing risk to subjects or others must be submitted to the IRB within one week (5 business 
days) following the occurrence of the unanticipated problem or the principal investigator’s 
acquiring knowledge of the unanticipated problem in accordance with IRB policy. Additionally, 
the sponsor-investigator will submit a summary of all Unanticipated problems that occurred since 
the beginning of the study at the time of continuing review. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Regulatory binder. 
 
10.4.2 FDA Notification by Sponsor-Investigator 
The Columbia University Medical Center Sponsor-Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. Columbia University Medical Center Sponsor- 
Investigator will report to the FDA, regardless of the site of occurrence, any adverse event that is 
serious, unexpected and there is evidence to suggest a causal relationship between the drug and 
the adverse event. These must be reported to the FDA and any affiliate sites as soon as possible, 
but in no case later than 15 calendar days after the sponsor determines that the information 
qualifies for reporting. The Sponsor-Investigator will also submit an IND annual report to the 


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FDA in accordance with 21.CFR 312.33. 
 
The Columbia University Medical Center Sponsor Investigator must report to the FDA and any 
affiliate site investigators as follows: 
• Any unexpected fatal or life-threatening event must be reported as soon as possible, but 
no later than 7 calendar days after the sponsor investigator initial receipt of the 
information 
• Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND, and whether or not conducted 
by the sponsor-investigator, that suggest a significant risk in humans exposed to the drug 
must be reported as soon as possible but no later than 15 calendar days after the sponsor- 
investigator determines that the information qualifies for reporting 
• Any findings from animal or in vitro testing whether or not conducted under an IND, and 
whether or not conducted by the sponsor-investigator, that suggest a significant risk in 
humans exposed to the drug must be reported as soon as possible but no later than 15 
calendar days after the sponsor-investigator determines that the information qualifies for 
reporting 
• Any clinically important increase in the rate of a serious suspected adverse reactions 
over that listed in the protocol or Investigator Brochure 
• Expected SAEs and AEs will be included in the IND Annual Reports. 
Follow-up information to a safety report should be submitted as soon as the relevant information 
is available. However, if the results of a sponsor’s investigation show that an adverse drug 
experience not initially determined to be reportable are so reportable, the sponsor investigator 
must report such experience as soon as possible, but no later than 15 calendar days after the 
determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
10.4.3 DSMC Reporting by the Sponsor Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the HICCC 
DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring at our 
institution or affiliate sites. 
 
Participating investigators must report each serious adverse event to the Columbia University 
Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence 
using the SAE Report Form. In the event that the participating investigator does not become 
aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), 
the participating investigator is to report the event within 24 hours after learning of it and 
document the time of his or her first awareness of the adverse event. Report serious adverse 
events by telephone, email or facsimile to: 
 
Richard D. Carvajal, MD 


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177 Fort Washington Avenue, MHB 6GN-435 
New York, NY 10032 
Telephone: 646-317-6354 
Fax: 212-305-3035 
Email address: CPDM_T5353@lists.cumc.columbia.edu 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the 
event has resolved or continues, if and how the event was treated, and whether the participant 
will continue or discontinue study participation. 
 
10.4.4 Reporting to Drug Manufacturer by Sponsor-Investigator 
SAE Reporting to Incyte 
The Sponsor-Investigator must report all Serious Adverse Events (SAEs) to Incyte within 24 
hours of learning of an event, regardless of the PIs causality assessment. This notification should 
be provided on a completed Serious Adverse Event (SAE) form. SAE reporting for each subject 
begins the day the informed consent is signed by the patient and within 30 days after subject has 
completed or discontinued from the study or has taken last dose of the study drug, or as 
described in the protocol. 
 
SAEs, occurring using Incyte Study drug, are reported in accordance with the effective 
protocol. SAEs occurring with any other commercial drug are reported to the manufacturer of 
that drug in accordance with regulations and protocol. 
 
Initial SAEs and/or subsequent follow-up reports should be reported via email to 
SafetyReporting@Incyte.com or fax (+) 1-866-981-2057. SAE reports should be for a single 
subject. SAE forms should be sent with a cover sheet and any additional attachments. 
 
All adverse event information is reported to Incyte on the Principal Investigator’s/Institution’s 
Adverse Event Report Form, or a CIOMS-I or MedWatch Form FDA 3500A, or on an Adverse 
Event Report Form which may be provided by Incyte upon request. The Principal Investigator 
does not provide medical records (e.g., discharge summary) to Incyte, unless specifically 
requested. 
 
 
Reporting of Pregnancy to Incyte 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 within 24 hours of discovery of a 
pregnancy of a subject who has taken the Incyte product or the pregnancy of a partner for a 
subject who has taken the Incyte product. The “Follow-up Pregnancy Report Form” or 
equivalent must be completed and emailed to SafetyReporting@Incyte.com or faxed to (+) 1- 
866-981-2057 within 30 days after delivery, so that Incyte is provided with information 
regarding the outcome of the pregnancy. If the pregnancy results in any events which meet the 
serious criteria (i.e., miscarriage or termination), the SAE reporting process needs to be followed 
and the timelines associated with a SAE should be followed. 


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The Sponsor-Investigator will report to investigational agent manufacturer any serious adverse 
events that meet the reporting criteria to the Institutional Review Board as described in section 
10.4and/or to the FDA as described in section 10.4 within 24 hours of becoming aware of it, so 
that these reports can be evaluated and included in the Investigator’s Brochure and for IND 
safety submissions per regulations. Reporting will occur by sending the reporting form along 
with any additional documentation sent to the regulatory authorities. 
 
At the time of IRB renewal or at the request of the manufacturer, the Sponsor- Investigator will 
submit a summary of all Serious Adverse Events that have occurred inclusive of all sites to 
manufacturer. 
 
10.4 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting Form, or in a narrative format. If supplied as in a narrative format, the minimum 
information to be supplied is noted above at the beginning of section 10. 
 
 
11. 
PHARMACEUTICAL INFORMATION 
11.1 
Description 
Ruxolitinib phosphate is a kinase inhibitor with the chemical name (R)-3-(4-(7H- 
pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate and a 
molecular weight of 404.36. 
 
Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous 
buffers across a pH range of 1 to 8. Ruxolitinib tablets are for oral administration. Each tablet 
contains ruxolitinib phosphate equivalent to 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ruxolitinib 
free base together with microcrystalline cellulose, lactose monohydrate, magnesium stearate, 
colloidal silicon dioxide, sodium starch glycolate, povidone and hydroxypropyl cellulose. 
 
11.2 
Treatment Regimen 
Ruxolitinib is an orally-administered tablet. Patients with adequate hematologic counts will be 
started on a dose of 10mg twice daily. Dosing will be adjusted for safety as delineated. 
Treatment will consist of 28-day cycles. Treatment will continue until disease progression or 
severe toxicity requiring cessation. 
 
11.3 
Method for Assigning Subjects to Treatment Groups 
 
Not applicable 
 
11.4 
Preparation and Administration of Study Drug 
Doses will be taken orally with approximately 8 oz. of water. Study drug should be taken at 
approximately the same times of day. Study drug should be swallowed whole and not crushed, 
chewed, or dissolved in water. 


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Missed doses (outside of a 4 hour dosing window) should be skipped and not administered as a 
double dose at the next administration. Subjects who vomit their dose should be instructed not to 
make up that dose. Doses that are vomited should not be replaced. 
 
11.5 
Subject Compliance Monitoring 
Subject compliance will be monitored with the aid of a “Patient Pill Diary” (Appendix D) which 
will be reviewed by the study team at each visit. Subjects who are non-compliant with protocol 
schedule or filling out the pill diary will be removed from the study at the discretion of the study 
investigator. 
 
11.6 
Packaging 
Ruxolitinib tablets (5 mg) are manufactured, packaged, and labeled according to GMP and GCP 
at the following address: 
 
DSM Pharmaceuticals, Inc. 
Greenville, NC 27834 
 
11.7 
Blinding of Study Drug 
Not applicable 
 
11.8 
Receiving, Storage, Dispensing and Return 
11.8.1 
Receipt of Drug Supplies 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug 
receipt log filled out and signed by the person accepting the shipment. It is important that the 
designated study staff counts and verifies that the shipment contains all the items noted in the 
shipment inventory. Any damaged or unusable study drug in a given shipment (active drug or 
comparator) will be documented in the study files. The investigator must notify agent 
manufacturer of any damaged or unusable study treatments that were supplied to the 
investigator’s site. 
 
11.8.2 
Storage 
Ruxolitinib tablets should be stored at room temperature or as described in detail  in  the 
current Investigator’s Brochure. Subjects should be requested to store the study drug at the 
recommended storage conditions noted on the label. 
 
11.8.3 
Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form, and 
signed and dated by the study team. 
 
11.8.4 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation 


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form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented 
prior to return or destruction of the study drug. 
 
11.9 
Other Agent(s) 
Not applicable 
 
12. 
STUDY EVALUATIONS 
12.1 
Screening Phase 
The screening phase will be up to 28 days. Screening is the interval between the signing of the 
informed consent form (ICF) and the day the subject receives the first dose of treatment in the 
study (Cycle 1 Day 1). Informed consent must be obtained before performing any study-specific 
procedures not considered standard of care. Assessments that are required to demonstrate 
eligibility may be performed over the course of 1 or more days during this phase. 
 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or the administration of study drug. Tests with results that fail eligibility requirements 
may be repeated during the screening phase if the investigator believes the results to be in error. 
Additionally, a subject who fails screening may repeat the screening process 1 time if the 
investigator believes there has been a change in eligibility status (eg, after recovery from an 
infection). 
 
See Section 13 for detailed list of screening procedures. 
12.2 
Treatment Phase 
The treatment period will continue every 28 days and may continue as long as subjects are 
receiving benefit from treatment and have not met any criteria for study withdrawal. 
 
See Section 13 for list and schedule of procedures while on treatment. 
12.2.1 
Clinic Visits 
 
During Cycle 1, patients will be seen every 2 weeks for vitals, physical exam, assessment of 
adverse effects, and appropriate laboratory tests and procedures (Section 13) Starting Cycle 2 
and onward, patients will be seen on Day 1 of each cycle for vitals, physical exam, assessment of 
adverse effects, and appropriate laboratory tests and procedures. Patients may be seen for 
additional unscheduled visits as needed at the discretion of the investigator. 
 
12.2.2 
General laboratory assessment 
 
See Section 13 for detailed laboratory tests and timing of these tests. 
 
12.2.3 
Schedule of Disease monitoring 


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A CT scan of the chest, abdomen, and pelvis with contrast will be obtained to evaluate disease 
status. A scan will be obtained at baseline (within 28 days of first study drug dose), then every 8 
weeks for the first 32 weeks. After week 32, a CT chest, abdomen, pelvis with contrast will be 
performed every 12 weeks until disease progression, withdrawal from study, or ongoing disease 
control at 2 years (defined as at least stable disease at this point). For patients who achieve 
ongoing disease control at 2 years, subjects will be observed with a CT chest, abdomen, pelvis 
with contrast every 12 weeks. In patients who are unable to get a CT scan with contrast due to 
renal function (or any other reason), an MRI with and without contrast may be used instead. If 
the patient develops disease progression during this observation time, they will have the option 
of restarting study treatment at that time. 
 
Table 7: Schedule of Disease Monitoring. 
 
Baseline scan 
Baseline scan within 4 weeks prior to first treatment 
Weeks 1 – 32 
Every 8 weeks +/- 1 week (at weeks 8, 16, 24, 32) 
Weeks 33 – until disease 
progression 
Every 12 weeks +/- 1 week (at weeks 44, 56, 68, 80, 92, 104) 
2 years 
If subjects achieve ongoing disease control at 2 years, patients 
will be continued on study treatment and observed with 
imaging every 12 weeks +/- 2 weeks. 
 
12.2.4 
Collection of Tumor Biopsies and Blood for Correlative Studies 
 
A minimum of 10 subjects must undergo pre- and on-treatment research tumor biopsies. Subjects 
in whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the 
opinion of the investigator, may be exempted from the biopsy requirement with discussion with 
the principal investigator. Use of outside archived tumor tissue for a baseline biopsy is not 
permitted. Biopsies will be collected at baseline and between C2D1 and C2D8 of therapy for 
correlative studies. An optional research biopsy at the time of progression will also be discussed 
with these patients, however, is not mandatory. 
 
Whole blood will be requested as outlined in section 13.2 for peripheral blood mononuclear cell 
(PBMC) and circulating tumor DNA (ctDNA) collection to evaluate the effect of ruxolitinib on 
circulating immune cell populations before and during treatment and to further evaluate ctDNA 
as a potential biomarker of disease response. 
 
 
12.2.5 
Adverse Events Monitoring 
 
Adverse events will be monitored from the time the subject receives the first dose of study 
treatment. Subjects will be instructed to report all AEs during the study and will be assessed for 
the occurrence of AEs throughout the study. All AEs (serious and nonserious) must be recorded 
on the source documents and eCRFs regardless of the assumption of a causal relationship with 
the study drug. The definition, reporting, and recording requirements for AEs are described in 


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Section 10. 
 
All AEs of unknown etiology associated with ruxolitinib exposure should be evaluated to 
determine if it is possibly an irAE. 
 
 
12.3 
End of Treatment 
If a decision is made that the subject will permanently discontinue study drug, the EOT visit 
should be conducted. If the EOT visit coincides with a regular study visit, the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT page in 
the eCRF. The subject should be encouraged to return for the follow-up visits. 
 
 
12.4 
Follow-up Phase 
12.4.1 
Safety Follow-up 
 
The safety follow-up phase is the interval between the last dose of study treatment and the 
scheduled safety follow-up visits, which should occur on days 30 (+/- 7 days) after the EOT visit. 
Adverse events and SAEs must be reported up until at least 90 days after the last dose of study 
drug, or until study drug-related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longer. If a subject initiates a new anti-cancer therapy within 90 days after the last 
dose of study treatment, the next scheduled safety follow-up visit must occur before the first dose 
the new therapy. Once new anti-cancer therapy has been initiated, the subject will move into the 
survival follow-up phase. 
 
12.4.2 
Follow-up (patients taken off treatment for reasons other than POD) 
 
Subjects who discontinue study treatment for a reason other than disease progression (including 
patients who achieve stable disease control at 2 years) will move into the follow-up phase and 
will be assessed every 12 weeks by radiologic imaging to monitor disease status. 
 
For patients who achieved stable disease at 2 years, re-treatment on study may be allowed at the 
time of disease recurrence or progression with permission of the study PI. 
 
Every effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression, death, and end of the study. 
 
12.4.3 
Survival Follow-up 
 
Once a subject has confirmed disease progression or starts a new anticancer therapy, the subject 
moves into the survival follow-up phase and should be contacted by telephone, email, or visit 
every 12 weeks (+/- 2 weeks) to assess survival status. Clinical notes for patients currently being 
treated at Columbia University Medical Center (or collaborating medical center) will also suffice 


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as follow up. Overall survival will be followed until death, withdrawal of consent, or the end of 
the study, whichever occurs first. 
 
12.5 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted. Any assessments 
performed at those visits should be recorded in the eCRF. 
 
 
13. 
STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy. Scans 
and x-rays must be done <4 weeks prior to the start of therapy. In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
13.1 
Safety Lead-In Calendar: 
Screening 
C1D1 
C1D15 
+/- 3d 
C2D1 
+/- 3d 
Ruxolitinib (daily) 
X 
X 
X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Height 
X 
X 
Weight 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
Serum Liver Function Testsb 
X 
X 
X 
X 
EKG (as indicated) 
X 
Adverse event evaluation 
X 
X 
X 
Tumor measurements 
X 
Radiologic evaluation 
X 
Serum B-HCGc 
X 
Tumor Biopsy (10 patients) 
X 
X 
Research blood collection 
X 
X 
Survival Follow-up 
X 
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 


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creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium 
b: Albumin, alkaline phosphatase, total bilirubin, AST, ALT 
c: Perform only in women of child-bearing potential 


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13.2 
Study Calendar 
Screening 
C1D1 
C1D15 
+/- 3d 
C2D1 
+/- 3d 
C3D1 ± 3d 
(and D1 ± 3d of 
every 
subsequent 
cycles) 
End of 
Treatment 
(Within 
30d 
of last 
treatment) 
Survival 
follow- 
up 
Ruxolitinib 
X 
X 
X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Concurrent meds 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
Serum Liver Function Tests 
b 
X 
X 
X 
X 
X 
X 
EKG (as indicated) 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
Tumor measurements 
X 
X 
(every other 
cycle) 
X 
Radiologic evaluation 
X 
X 
(every other 
cycle) 
X 
Serum B-HCG c 
Xb\ 
Tumor Biopsy (10 patients 
X 
X (between 
D1 and D8) 
Research blood collection 
X 
X 
X 
X 
Survival Follow-up 
X 
a: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium 
b: Albumin, alkaline phosphatase, total bilirubin, AST, ALT 
c: Perform only in women of child-bearing potential 
 
14. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
14.1 
Collection of samples for correlative studies 


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14.1.1 
Tumor biopsy samples 
 
Pre- and on-treatment tumor biopsies are mandatory in a minimum of 10 subjects. Subjects in 
whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the 
opinion of the investigator, may be exempted from the biopsy requirement, with discussion with 
the principal investigator. 


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Timing of Biopsy Samples: 
A fresh biopsy must be obtained at the following time-points: 
• Prior to treatment (anytime during the screening period) (mandatory) 
• On-treatment (between C2D1 and C2D8 treatment dose)) (mandatory) 
• At the time of disease progression (optional) 
Collection & Processing Instructions: 
Collection and processing instructions are the same for all of the specified tumor biopsy time 
points. 
 
A goal of at least 3 cores and up to 8 cores, if safe to obtain, will be obtained at each collection 
time point. 
 
14.1.2 
Blood samples 
 
Whole blood will be requested as outlined in section 13.2 for peripheral blood mononuclear cell 
(PBMC) and circulating tumor DNA (ctDNA) collection to evaluate the effect of ruxolitinib on 
circulating immune cell populations before and during treatment and to further evaluate ctDNA 
as a potential biomarker of disease response. 
 
 
See laboratory manual for detailed processing and shipping instructions for all correlative study 
specimens. 
 
Shipping Instructions: 
Shipments will be sent to the Schwartz laboratory by batch shipments when possible. 
Owens Laboratory 
1130 Saint Nicholas Avenue 
ICRC Room 207 
New York, NY 10032 
 
The 
analyzing 
laboratories 
should 
be 
notified 
by 
email 
(Study 
listserv 
email: 
CPDM_T5353@lists.cumc.columbia.edu) the day the samples are sent. The email wirell contain 
the following information: 
• Subject ID number 
• Subject Initials 
• Date of collection 
• Time point (e.g. baseline, Cycle 2 Day 1, end of treatment, etc) 
• Name of study center 
• Shipment date 
• Contents of shipment 


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All samples should be directed to the address listed above. Samples should be shipped via courier 
so that the package is tracked appropriately (specifically Federal Express or UPS). The samples 
should be shipped for morning delivery, Monday through Thursday for optimal processing. 
 
Samples will be tracked through a Microsoft Excel tracker. 
 
 
15. 
MEASUREMENT OF EFFECT 
 
15.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks 
weeks. In addition to a baseline scan, confirmatory scans should also be obtained 4 of weeks 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
15.2 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with ruxolitinib. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
15.3 
Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for 
nodal lesions) as >20 mm by chest x-ray, as >10 mm with CT scan or MRI, or >10 mm with 


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calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan or MRI (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. Cystic lesions thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
15.4 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 


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never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ³10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 


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next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy/Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. 
 
Cytology/Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG- 
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 


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15.5 
Response Criteria 
15.5.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
15.5.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
15.5.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 


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Table 8. Response Criteria for Patients with Measurable Disease (e.g., Target Disease) 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
PD/not evaluated 
No 
PR 
SD 
Non-CR/Non- 
PD/not evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
For Patients with Non-Measurable Disease (e.g., Non-Target Disease) 
Non-Target Lesions New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
15.6 
Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 


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measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
 
15.7 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
15.8 
Response Review 
All responses will be reviewed by an expert independent of the study at the study’s completion. 
All imaging will be stored at Columbia University Irving Medical Center 
 
15.9 
Unblinding Procedures 
Not applicable 
 
15.10 
Stopping Rules 
 
Not applicable 
 
16. 
DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10.0 
(Adverse Events: List and Reporting Requirements). 
 
16.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS for data entry. The system has full auditing capabilities which is web-based 
and housed on a server in a fully HIPAA compliant server room with restricted access and video 
camera monitoring. All users must login with their own application username and password. 
Users off campus must first access the Virtual Private Network with their assigned campus 
username and password and then use their application credentials. Users are only able to see 
study information if they are indicated as study personnel in our electronic IRB system. Users are 
limited to access based on the role assigned in their corresponding protocol. Subject data is 
entered directly into the system, which (in the case of Columbia subjects) confirms the correct 
identity of patients via an interface with the electronic medical patient index. Staff with the 


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appropriate IRB defined roles can run reports within the system for reporting purposes. 
 
16.2 
Data Reporting 
Case Report Forms will be completed for each subject enrolled into the clinical study through the 
CTMS. It is the investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the corresponding CRFs are complete, accurate and authentic. 
 
16.3 
Data and Safety Monitoring Committee 
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUMC-IRB policy and guidelines. The committee is chair is appointed by the HICCC Director. 
The committee consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety monitoring 
reports to the DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. All 
study data reviewed and discussed during these meetings will be kept confidential. 
 
For multicenter research, the principal investigator will assure that there is a mechanism in place 
to distribute the report to all participating investigators for submission to their local IRB. The 
report will document that a review of data and outcomes across all centers took place on a given 
date. It will summarize the DSMC’s review of the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm. It will also inform site 
investigators of the study the DSMC’s conclusion with respect to progress or need for 
modification of the protocol. 
 
16.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC. Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, statistical endpoints (e.g., stopping 


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rules), etc. for the full DSMC membership at the regularly scheduled meetings. 
Internal On-site Monitoring: 
• Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote 
clinical sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 
o The study Monitoring Visit Log will be completed and signed by the monitor 
and the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 
• The Compliance Coordinator will communicate with the site coordinator/Site Principle 
Investigator to schedule the monitoring visit and arrange for access to study materials 
and documentation. 
 
• The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first subject is enrolled and throughout the life of the study to ensure that the study is 
being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the PI and CRNP/CRN/CRC of upcoming monitor visits and convey what 
information and documentation will be required for the visit(s). The Compliance 
Coordinator is responsible for verifying that informed consent is properly obtained, 
eligibility is met (via the central registration process), and all study procedures are 
conducted according to the study protocol. The Compliance Coordinator will also verify 
that the data reported in the CRF’s accurately reflect source documents, that all toxicities 
have been reported to date, and that all SAE’s/UPs/deviations/violations have been 
reported according to local IRB and HICCC DSMC requirements. The Compliance 
Coordinator will issue queries and ensure resolution in a timely and efficient manner. 
The Compliance Coordinator will also monitor for applicable regulatory compliance and 
research pharmacy compliance (if applicable) and communicate any deficiencies as 
appropriate. 
 
16.5 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (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 


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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 (e.g., that the subject is alive) 
at the end of their scheduled study period. 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator and study staff will have access to the file. 
16.6 
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. 
 
16.7 
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 missing data must be explained. If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”. 
If the item is not applicable to the individual case, write “N/A”. 
 
16.8 
Records Retention 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 
CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies 
whether or not any subjects were enrolled in the study. 
If the research is FDA regulated, records should be retained for at least two years after approval 
of the investigational agent by FDA; if it is not approved, records should be retained at least two 
years after the study is terminated and FDA is notified (note the additional requirement below for 
clinical research studies); 
Clinical records, including consent forms that document clinical intervention or clinical 
diagnostic procedure research-related procedures, must be retained in medical records by the 
institution for at least seven years, per CUMC and NYP policy which is based on state law. 
 
 
17. 
STATISTICAL CONSIDERATIONS 
 
17.1 
Study Design and Sample Size 
This is a multi-center, non-randomized, open-label phase 2 trial to evaluate the efficacy and 
safety of ruxolitinib in post-transplant patients with advanced cutaneous squamous cell 
carcinoma. The primary endpoint is overall response rate, defined as the best response confirmed 


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within the 24 weeks of the start of study therapy. 
 
We will use a Simon Two-Stage Min-Max  design  with  a  target  overall  response  rate  of 
20% (alternative hypothesis), compared to a historical response rate of 5% (null hypothesis) with 
chemotherapy, with one-sided probability of a type I error set at 0.10 and power of 90%. In the 
first stage, 18 patients will be accrued. If less than 1 patient achieves a response among the 
initial 18 patients, the study will be declared negative and terminated. If at least 1 patient 
achieves a response, an additional  14 patients  will  be  accrued  to  the  second  stage  for  a 
total of 32 evaluable patients. Overall, if 4 or fewer responses are seen, the study will be 
declared negative. If at least  5  total  patients  achieve  a response, that treatment will be 
declared positive for attaining the primary endpoint. There is a 40% chance of stopping at Stage 
1 if the true confirmed response rate is at most 5% (null hypothesis). Accounting for 10% 
dropout, we will plan to enroll a total of 35 patients unless a second safety lead-in is required, in 
which case the the maximum potential accrual will be 41 patients. 
 
17.2 
Study Endpoints and Analytic Plan 
All subjects who receive at least one dose of study drug will be considered evaluable and 
included in the efficacy and safety analysis. 
 
Definition of primary outcome/endpoint: 
The primary endpoint is the overall response rate defined as the best response within the first 24 
weeks of the start of study therapy using RECIST v. 1.1 that has been confirmed at a subsequent 
time point (≥4 weeks). 
 
Definition of secondary outcomes/endpoints: 
PFS is defined as time from enrollment to time of clinical or radiographic disease progression as 
defined by RECIST v.1.1 criteria. OS is defined as time from enrollment to time of death from 
any cause. 
 
Analytic plan for primary objective: 
The overall response rate will be summarized using point estimates and 95% confidence 
intervals. 
 
Analytic plan for secondary and exploratory objectives: 
• We will estimate the survival distribution for both PFS and OS endpoints using the 
Kaplan Meier method. The log rank test will be used to examine differences between 
survival curves using prognostic markers. 
• For correlative studies we will apply either the Fisher’s exact test or Wilcoxon Rank 
Sum test to examine the associations between response status and changes in markers 
expression for categorical and continuous variables, respectively. Because of the 
limited sample size, the biomarker data analysis is for exploratory research only. 
• Toxicity data will be summarized by type, frequency, and severity according to the 
NCI CTCAE criteria v4.0. 


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• Pharmaocokinetic and pharmacodynamic parameters will be summarized using 
descriptive statistics and graphical methods (individual profile plots). 
 
 
17.3 
Size/Accrual Rate 
The planned accrual size is 35 patients. Each participating site will aim to accrue  1 
patient every 2 months month. 
 
17.4 
Stratification Factors 
Not applicable 
 
 
17.5 
Reporting and Exclusions 
17.5.1 Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study 
drug. 
 
17.5.2 Evaluation of response 
All patients included in the study will be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) will be included in the main analysis of the response rate. Patients 
in response categories 4-9 should be considered to have a treatment failure (disease progression). 
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific. 
 
All conclusions will be based on all eligible patients. Subanalyses may then be performed on the 
basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided. 
 
18. 
PROTECTION OF HUMAN SUBJECTS 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 


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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 obtained 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 or legally acceptable surrogate, as outlined in the IRB approved protocol, 
and the investigator-designated research professional obtaining the consent. 
 
19. 
STUDY FINANCES 
19.1 
Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a Committee- 
sanctioned conflict management plan that has been reviewed and approved prior to participation 
in this study. All CUMC investigators will follow the University conflict of interest policy. 
 
20. 
PUBLICATION PLAN 
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-investigator. 
Any investigator involved with this study is obligated to provide the sponsor-investigator with 
complete test results and all data derived from the study. 
 
21. 
GUIDELINES FOR AFFILIATE INSTITUTIONS IN MULTICENTER 
STUDIES 
21.1 
Multi-site Communication 
The CPDM Office at CUMC provides administration, data management, and organizational 
support for the affiliate sites in the conduct of a multicenter clinical trial. The CPDM Office will 
coordinate regularly scheduled conference calls with affiliate sites. 
The following issues will be discussed, as appropriate: 
• Enrollment information 
• Response assessments 
• Adverse events (e.g., new adverse events and updates on unresolved adverse events 
and new safety information) 
• Protocol violations 
• Other issues affecting the conduct of the study 
21.2 
New Protocol Distribution, IRB Submission, Modifications, and Annual Renewals 


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• Protocol specific documents are distributed to affiliate sites once CUMC IRB approval 
has been obtained. 
• The affiliate site must submit a draft of site specific revisions to protocol and/or consent 
form documents for review and approval by the sponsor-investigator prior to 
submission to the local IRB. Draft documents should be sent to the study specific email 
address. The site will be provided confirmation that they are approved to submit to their 
local IRB. 
• Protocol amendments must be approved by the affiliate site’s local IRB within 90 days 
of distribution to the site by the sponsor-investigator. 
21.3 
Regulatory Documents 
Prior to Site Initiation: 
Sponsor-Investigator will ensure that proper requests are made of sites and that the following 
documentation is collected, prior to the initiation of an affiliate site. 
 
• CV of PI, Co-I’s and other research staff listed on FDA 1572 (signed and dated copy 
within 2 years) 
• Medical Licenses of PI and Co-I’s (current copy) 
• Human subjects training certificates for PI and Co-I’s 
• CLIA/Laboratory Certifications for Local Laboratories listed on FDA 1572 
• Local Laboratory Director’s CV and License 
• Local Laboratory Reference Ranges 
• IRB roster or statement of compliance 
• FDA Form 1572, if applicable (wet ink originals required) 
• Financial Disclosure forms for all members listed on FDA 1572 (wet ink originals 
required) 
 
Ongoing Regulatory Documentation: Sponsor-Investigator will ensure that proper requests are 
made of sites and that the following documentation is collected throughout the course of the study. 
• IRB approval letters for all protocol modifications and all renewals 
• IRB-approved consent forms 
• Current IRB roster, if statement of compliance is not provided as part of site initiation 
• FDA Form 1572, if applicable as updates are required 
• Updated investigator and site information where relevant (e.g., CV, medical licensure 
and Financial Disclosure for new sub-investigator, local laboratory information) 
 
Regulatory documents may be sent to CPDM_T5353@lists.cumc.columbia.edu or to the following 
address: 
 
Clinical Protocol & Data Management Office 
161 Fort Washington Ave. 
Herbert Irving Pavilion 


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Mezzanine Level, M-203 
New York, NY 10032 
 
21.4 
Site activation 
Columbia University will schedule a site initiation visit once IRB approval has been submitted 
from the affiliate site. 
 
21.5 
Central Registration Procedures- Affiliate Institution Research Participant 
Registration Process 
All Affiliate Institutions must register subjects with the coordinating center (CUMC) prior to any 
administration of study drug/intervention/local institution registration. Please see instructions 
below: 
1. Within 48 hours of obtaining consent (excluding holidays and weekends), the Affiliate 
Institution CRN and/or CRC is required to submit the following documents to the 
coordinating center’s designee (CUMC Multicenter Core) via the study listserv 
CPDM_T5353@lists.cumc.columbia.edu. The coordinating center’s designee will review 
the documents for accurateness, and subsequently submit the documents to the CPDM 
Central Registration Office via email at CPDMRegistration@columbia.edu (or via fax at 
212.305.5292), with a request to register the patient “pending eligibility.” The title of the 
email should read, “Pending Subject Registration Request (PHI)”. The following 
documents should be submitted with the pending registration request, as applicable: 
a. Redacted Completed/signed IRB approved/stamped Informed Consent Forms, 
including additional study ICFs (e.g., tissue, DNA, etc.), as applicable 
b. Redacted Signed HIPAA (or institutional equivalent) 
c. MCT CPDM Velos Note to File form 
 
2. The Affiliate Institution’s investigator/research nurse/data manager/coordinator must 
contact the coordinating center’s designee (CUMC Multicenter Core) via telephone or 
email to communicate the following: 
a. Notify of pending registration request 
b. Confirm method of registration request submission (email or fax) 
c. Communicate expected time-line of registration request submission (e.g., same 
day, next day, within the hour, etc.) 
 
3. To complete registration, the Affiliate Institution’s investigator/research nurse/data 
manager/coordinator should then submit the following documents to the CUMC study 
specific designee: 
a. A signed Affiliate Site Eligibility Checklist (signed by the investigator) 
b. Copies of redacted source documentation necessary for each item to be verified on 
the CUMC specific Eligibility Checklist, including but not limited to: 
i. Copy of required laboratory test and procedure reports (e.g., hematology, 
serum chemistry, pregnancy test when applicable, MRI reports, CT/bone 
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ii. Copy of pathology and surgical reports 
iii. Copy of clinic note(s) capturing the consent process information, along with 
providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms. 
(e.g., positive investigator statements of unique eligibility items not 
captured via other direct source documentation, concomitant medication 
lists, etc.) 
iv. Protocol deviation/waiver approvals (if applicable) 
c. Please note: subject line of email or fax should include the following: “AAAT5353 
Complete Subject Registration Request (PHI)”. 
 
4. Upon receipt of the above mentioned documents, the designated study specific Clinical 
Research Coordinator will review all documents and verify patient eligibility. If any questions 
arise during the review process, queries in the form of emails will be addressed to the 
applicable affiliate site study team personnel for clarification prior to enrollment. Upon 
verification, the CUMC Multicenter Core will then forward all documents to the CPDM 
Central Registration Office for central registration (as described above). The CPDM Central 
Registration Registrar will review all applicable documents and communicate to the CUMC 
study specific designee in order to clarify any items. The CUMC study specific designee will 
communicate with the applicable site study team personnel for additional clarifications 
necessary prior to enrollment. 
 
5. Upon receipt of the subject registration notification email, the CUMC Multicenter Core will 
forward the notification email (which will include the study specific patient ID) to the affiliate 
site’s Principal Investigator, Consenting Professional, and applicable research personnel. 
This notification should be filed in the patient research binder accordingly. Protocol therapy 
may not be initiated prior to receipt of this notification from the coordinating center. 
6. All screenfail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration Office 
in a manner analogous to the procedures noted above. Applicable source documentation will 
be required within the corresponding submissions. 
 
21.6 
Protocol Deviation/Subject Waiver request for Affiliate Sites: 
The Affiliate site MUST submit a prospective deviation request to the CUMC lead PI for review 
and submission to the HICCC DSMC and CUMC IRB. Approvals must be obtained from all 
entities prior to implementation at the Affiliate site. If a prospective protocol deviation request is 
submitted for review (from an Affiliate site), the PI/site memo(s), HICCC DSMC approval(s) and 
correspondence and CUMC IRB approval letter(s)/equivalent should be forwarded to the Affiliate 
site for documentation. The Affiliate site is also required to obtain prospective local IRB approval 
as per institutional policies/procedures prior to implementing the proposed deviation and 
registering/enrolling the subject via CUMC Central Registration. All documents and 
determinations must be clearly documented in the study subject’s medical record, research chart 
and regulatory binder, as described. Please note that the HICCC DSMC and PRMC do not approve 


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eligibility deviations. If eligibility deviations are submitted, they will not be approved. 


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21.7 
Guidelines for Affiliate Site Monitoring 
On-Site MCT Monitoring: 
1. Initial, recurrent, and close-out on-site monitoring visits will also be conducted at Affiliate 
sites, as appropriate/feasible. Other sites will have monitoring performed remotely (see 
below for further details). 
a. The study Monitoring Visit Log will be completed and signed by the monitor and 
the PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
2. The Compliance Coordinator will communicate with the Affiliate site coordinator/Site 
Principle Investigator to schedule the monitoring visit and arrange for access to study 
materials and documentation. 
3. The Compliance Coordinator will monitor Investigator Initiated Trial (IIT) within 1 month 
after the first subject is enrolled at the Affiliate site and throughout the life of the study to 
ensure that the study is being conducted in accordance with the protocol, GCP, applicable 
federal and local regulations, and per all applicable SOPs. The Compliance Coordinator is 
responsible to notify the participating site PI and CRNP/CRN/CRC of upcoming monitor 
visits and convey what information and documentation will be required for the visit(s). 
The Compliance Coordinator is responsible for verifying that informed consent is properly 
obtained, eligibility is met (via the central registration process), and all study procedures 
are conducted according to the study protocol. The Compliance Coordinator will also 
verify that the data reported in the CRF’s accurately reflect source documents, that all 
toxicities have been reported to date, and that all SAE’s/UPs/deviations/violations have 
been reported according to Coordinating Center, local IRB and HICCC DSMC 
requirements. The Compliance Coordinator will issue queries and ensure resolution in a 
timely and efficient manner. The Compliance Coordinator will also monitor for applicable 
regulatory compliance and research pharmacy compliance (if applicable) and communicate 
any deficiencies as appropriate. 
 
4. An SIV (or) teleconference will be scheduled and conducted prior to study drug being made 
available (if applicable) and before any subjects are enrolled on a study at the Affiliate site. 
 
Remote MCT Monitoring: 
• When necessary (due to logistical constraints), Affiliate sites will be monitored remotely 
by a designated Compliance Coordinator. Sites will be informed of this remote monitoring 
process on a site by site basis. 
• Affiliate sites will be monitored by the Compliance Coordinator on both a regulatory level, 
as well as a clinical data/source documentation review level. 
• Redacted source documents (applicable to supporting the protocol specific CRF data 
requirements) will be sent to the designated Compliance Coordinator via fax or secure 
email for all subjects enrolled at Affiliate sites. Timelines for submission procedures will 
be defined on a case by case basis. 
• The Compliance Coordinator will review all submitted redacted source documents against 
the data entered on the protocol specific CRFs. The Compliance Coordinator will issue 
queries when/if necessary. 


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• The Affiliate site research staff will respond to queries within 30 days. If queries remain 
outstanding, the Compliance Coordinator will send a delinquent query reminder for the 
outstanding items. 
• The remote monitoring procedures will include review of applicable redacted source 
documentation and supporting applicable documents to determine compliance regarding: 
a. Informed consent procedures 
b. Eligibility criteria 
c. Protocol specific treatment compliance 
d. Protocol specific toxicity/outcome documentation/compliance 
e. Protocol specific schedule of events (e.g., baseline visits, pre-treatment, on study, 
follow-up) 
f. Participating site IRB documents (e.g., IRB amendment approvals, annual 
renewals, SAE/UP submissions, violation/deviation submissions, INDSR 
submissions, etc). 
g. Required specimen submissions (e.g., tissue specimens, research blood specimens, 
etc.) 
h. Pharmacy accountability records 
i. Adherence to the CRF submission timeframes to CUMC (within the protocol 
specified timeframes) 
• Affiliate site remote monitoring reports will be sent to the lead PI, HICCC DSMC, and 
Affiliate sites after each remote monitoring review. Reports will include information 
regarding data submission timeliness/accuracy, protocol adherence items, query resolution 
status, regulatory status, and overall Affiliate site performance. These reports will be 
generated by the Compliance Coordinator and reviewed with the Compliance Core 
Manager prior to dissemination. 
 
21.8 
Adverse event reporting 
Sponsor reporting: Notifying participating investigators at affiliate sites of adverse events 
It is the responsibility of the study sponsor-investigator to notify all affiliate sites, in a written IND 
safety report, of any adverse event associated with the use of the drug that is both serious and 
unexpected, as well as any finding from tests in laboratory animals that suggest a significant risk 
for human subjects. Additionally, sponsor-investigators are also required to identify in IND safety 
reports all previous reports concerning similar adverse events and to analyze the significance of 
the current event in light of the previous reports. 
 
Serious Adverse Event Reporting 
Each participating investigator is required to abide by the reporting requirements set by Columbia 
University Irving Medical Center. The study must be conducted in compliance with FDA 
regulations, local safety reporting requirements, and reporting requirements of the principal 
investigator. 
 
Participating investigators must report each serious adverse event to the Columbia University 


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Medical Center Overall Principal Investigator within 24 hours of learning of the occurrence using 
the SAE Report Form. In the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment elsewhere), the participating 
investigator is to report the event within 24 hours after learning of it and document the time of his 
or her first awareness of the adverse event. Report serious adverse events by telephone, email or 
facsimile to: 
 
Richard D. Carvajal, MD 
177 Fort Washington Avenue 
New York, NY 10032 
Telephone: 212-305-2055 
Fax: 212-305-3035 
Email: CPDM_T5353@lists.cumc.columbia.edu 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether the event 
has resolved or continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation. 
 
Follow-up information is sent to the same person to whom the original SAE Report Form was sent, 
using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and 
giving the date of the original report. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. The 
follow-up information should describe whether the event has resolved or continues, if and how it 
was treated, and whether the subject continued or withdrew from study participation or if study 
drug was interrupted or discontinued. 
 
If the SAE is not previously documented in the Investigator’s Brochure for the study drug (new 
occurrence) and is thought to be related to the investigational agent, the sponsor-investigator may 
urgently require further information from the investigator for reporting to Health Authorities. 
 
Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the Columbia University Medical Center Overall 
Principal Investigator on the toxicity Case Report Forms. 
 
Reporting to the Institutional Review Board (IRB) and the Data and Safety Monitoring Committee: 
 
All Unanticipated Problems (UPs) will be reported to the CUMC IRB. SAEs not constituting UPs 
will reported to the HICCC DSMC. 
 
Each affiliate site will be responsible for safety reporting to their local IRB. Investigators are 
responsible for complying with their local IRB’s reporting requirements, though must submit the 
required reports to their IRB no later than 7 calendar days following the occurrence of the UP or 
the Principal’s Investigator’s acquiring knowledge of the UP. Copies of each report and 


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documentation of IRB notification and receipt must be included in the regulatory binder. 
Expected or unexpected AEs must be reported at the time of continuing review of a protocol. 
Guidelines for Processing IND Safety Reports 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. The CUMC Principal Investigator 
will review all applicable IND Safety Reports and has the responsibly for forwarding the IND 
Safety Reports to the Affiliate Institutions. The Affiliate Institution investigators are to review, 
send a copy to their IRB according to their local IRB’s policies and procedures, and file a copy 
with their regulatory documents. All Affiliate site INDSR submissions, along with IRB 
acknowledgment (per local policies and procedures) are to be forwarded to CUMC for placement 
within the trial master file. 
 
Reporting to Hospital Risk Management 
Affiliate Site investigators will report to their local Risk Management Office any subject safety 
reports or sentinel events that require reporting according to institutional policy. 
21.9 
Efficacy analysis/ correlative analysis 
Efficacy analysis: 
Imaging will be reviewed by a site radiologist and interpreted according to response criteria 
detailed in section 12.4 for primary and secondary endpoint analysis. Imaging studies may be 
requested from participating centers for central radiology review. 
 
Correlative analysis: 
All tissue and blood samples collected at each site will be sent to Columbia University Medical 
Center for storage and correlative studies described above. 
 
21.10 
Confidentiality 
Each affiliate site will be assigned a site number. Each subject that signs consent should be 
assigned a unique code number consisting of site number followed by a number with each new 
subject being assigned the next sequential number (e.g., 04-10). All sites will be required to enter 
their data in the Velos eResearch, the Clinical Trial Management System used for all Cancer- 
related clinical research at CUMC. All users must login with their own application username and 
password. Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials. 
 
Subject confidentiality must be maintained according to HIPAA regulations and GCP 
recommendations. 


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Except when required by law, study information shared with persons and organizations outside of 
Columbia University Medical Center must not identify the patient by name, social security 
number, address, telephone number, or any other direct personal identifier. 
 
If the results of this research project are published or presented at a scientific or medical meeting, 
the patient not be identified. Otherwise, all results will be kept confidential and will not be divulged 
(except as required by law) without permission. 
 
21.11 
Data Reporting Plan 
Columbia University Medical Center (CUMC) is deeply committed to research integrity and 
strong credibility when it comes to the discovery of new treatment concepts, implementation of 
new clinical research techniques, and acceptance of its researcher's findings by the medical 
establishment. In accord with these ethics, CUMC encourages and supports its investigators in the 
sharing of final research data and/or details of newly developed clinical treatments. 
 
CUMC's policies that pertain to patient data sharing conform to CUMC IRB rules, local and state 
laws, and HIPAA privacy regulations. The primary reason for this is to protect the privacy of 
patients who participate in clinical trials. The data can be made available for continuing review by 
federal agencies upon request and for ongoing study safety reviews by the Principal Investigator, 
Statistician, Data Safety and Monitoring Board (DSMC), and, in other instances, the CUMC IRB. 
 
Data collected during the course of this clinical trial will primarily be shared with other 
investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred 
to other collaborators. Prior to transfer, the data collected must comply with, and must be limited 
by, the CUMC's guidelines for Protecting the Rights and Privacy of Human Subjects. 
 
21.12 
Data Acquisition and Submission 
Informed consent, including HIPPA authorization, must be obtained on all subjects prior to their 
participation. Always keep the original signed and dated consent form, with the redacted source 
documents and eligibility checklist. Velos eResearch will be used as the electronic clinical trials 
and data management system. Affiliate sites will enter data directly into Velos eResearch via 
customized case report forms for the study. The research staff will generate reports from Velos 
eResearch to ensure timely submission of data by affiliate sites. This resource allows for the timely 
analysis of particular data sets for safety analysis. 
 
21.13 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity, and use by subjects, as well as written records of the disposition of the 
drug when the study ends. 
 
The Principal Investigator is required to prepare and maintain adequate and accurate case histories 
that record all observations and other data pertinent to the investigation on each individual 


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administered the investigational drug or employed as a control in the investigation. Case histories 
include the case report forms and supporting data including, for example, signed and dated consent 
forms and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, CHR correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 


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22. 
REFERENCES 
1. 
Berg, D. and C.C. Otley, Skin cancer in organ transplant recipients: epidemiology, 
pathogenesis, and management. Journal of the American Academy of Dermatology, 
2002. 47(1): p. 1-20. 
2. 
Euvrard, S., J. Kanitakis, and A. Claudy, Skin cancers after organ transplantation. New 
England Journal of Medicine, 2003. 348(17): p. 1681-1691. 
3. 
Euvrard, S., et al., Subsequent skin cancers in kidney and heart transplant recipients after 
the first squamous cell carcinoma. Transplantation, 2006. 81(8): p. 1093-100. 
4. 
Wisgerhof, H.C., et al., Subsequent squamous- and basal-cell carcinomas in kidney- 
transplant recipients after the first skin cancer: cumulative incidence and risk factors. 
Transplantation, 2010. 89(10): p. 1231-8. 
5. 
Lott, D.G., et al., Aggressive behavior of nonmelanotic skin cancers in solid organ 
transplant recipients. Transplantation, 2010. 90(6): p. 683-687. 
6. 
Martinez, J.C., et al., Defining the clinical course of metastatic skin cancer in organ 
transplant recipients: a multicenter collaborative study. Arch Dermatol, 2003. 139(3): p. 
301-6. 
7. 
Karia, P.S., J. Han, and C.D. Schmults, Cutaneous squamous cell carcinoma: estimated 
incidence of disease, nodal metastasis, and deaths from disease in the United States, 
2012. J Am Acad Dermatol, 2013. 68(6): p. 957-66. 
8. 
Migden, M.R., et al., PD-1 Blockade with Cemiplimab in Advanced Cutaneous 
Squamous-Cell Carcinoma. N Engl J Med, 2018. 379(4): p. 341-351. 
9. 
Fisher, J., et al., Immune checkpoint inhibitor therapy in solid organ transplant 
recipients: A patient-centered systematic review. J Am Acad Dermatol, 2019. 
10. 
Sidaway, P., Cemiplimab effective in cutaneous SCC. Nat Rev Clin Oncol, 2018. 15(8): 
p. 472. 
11. 
Sadek, H., et al., Treatment of advanced squamous cell carcinoma of the skin with 
cisplatin, 5-fluorouracil, and bleomycin. Cancer, 1990. 66(8): p. 1692-6. 
12. 
Khansur, T. and A. Kennedy, Cisplatin and 5-fluorouracil for advanced locoregional and 
metastatic squamous cell carcinoma of the skin. Cancer, 1991. 67(8): p. 2030-2. 
13. 
Maubec, E., et al., Phase II study of cetuximab as first-line single-drug therapy in 
patients with unresectable squamous cell carcinoma of the skin. J Clin Oncol, 2011. 
29(25): p. 3419-26. 
14. 
Foote, M.C., et al., Phase II study of single-agent panitumumab in patients with incurable 
cutaneous squamous cell carcinoma. Ann Oncol, 2014. 25(10): p. 2047-52. 
15. 
Schwartz, D.M., et al., Type I/II cytokines, JAKs, and new strategies for treating 
autoimmune diseases. Nat Rev Rheumatol, 2016. 12(1): p. 25-36. 
16. 
Bachelor, M.A., Y. Lu, and D.M. Owens, L-3-Phosphoserine phosphatase (PSPH) 
regulates cutaneous squamous cell carcinoma proliferation independent of L-serine 
biosynthesis. J Dermatol Sci, 2011. 63(3): p. 164-72. 
17. 
Deepak Roshan, V.G., et al., Cyclin D1 overexpression associated with activation of 
STAT3 in oral carcinoma patients from South India. J Cancer Res Ther, 2018. 14(2): p. 
403-408. 
18. 
Abikhair Burgo, M., et al., Ruxolitinib inhibits cyclosporine-induced proliferation of 
cutaneous squamous cell carcinoma. JCI Insight, 2018. 3(17). 


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19. 
Hurwitz, H.I., et al., Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo 
in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for 
Whom Therapy With Gemcitabine Has Failed. Journal of Clinical Oncology, 2015. 
33(34): p. 4039-4047. 
20. 
Hurwitz, H., et al., Two randomized, placebo-controlled phase 3 studies of ruxolitinib 
(Rux) + capecitabine (C) in patients (pts) with advanced/metastatic pancreatic cancer 
(mPC) after failure/intolerance of first-line chemotherapy: JANUS 1 (J1) and JANUS 2 
(J2). Journal of Clinical Oncology, 2017. 35(4_suppl): p. 343-343. 
21. 
Harrison, C.N., et al., Long-term findings from COMFORT-II, a phase 3 study of 
ruxolitinib vs best available therapy for myelofibrosis. Leukemia, 2016. 30(8): p. 1701-7. 
22. 
Bollag, G., et al., Clinical efficacy of a RAF inhibitor needs broad target blockade in 
BRAF-mutant melanoma. Nature, 2010. 467(7315): p. 596-9. 


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23. 
APPENDIX 
23.1 
Appendix A: ECOG Performance Status Criteria. 
 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. 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 
In bed <50% of the time. 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 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 


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23.2 Appendix B: Appropriate contraceptive methods for study subjects. 
The following methods have been determined to be more than 99% effective (<1% failure rate 
per year) when used consistently and correctly35 and are permitted under this Protocol for use by 
the subject and his/her partner: 
• Complete abstinence from sexual intercourse 
• A barrier method (male or female condom) in addition to one of the following: 
o Diaphragm or cervical cap with spermicide 
o Intrauterine device (IUD) 
o Birth control patch or vaginal ring 
o Oral, injectable, or implanted contraceptives 
 
23.3 
Appendix C: Strong CYP3A4 and 2C8 Inhibitors and Inducers 
 
Strong Inhibitors 
Strong Inducers 
Protease Inhibitors: 
• Ritonavir 
• Indinavir 
• Nelfinavir 
Anticonvulants, mood stabilizers: 
• Phenytoin 
• Carbamazepine 
• Oxcarbazepine 
Macrolide antibiotics: 
• Erythromycin 
• Telithromycin 
• Clarithyromycin 
Non-nucleoside reverse transcriptase 
inhibitors: 
• Efavirenz 
• Nevirapine 
• Etravirine 
Azole antifungals: 
• Fluconazole 
• Ketoconazole 
• Itraconazole 
Others: 
• Phenobarbital 
• Rifampicin 
• Modafinil 
• Hyperforin (constituent of St Johns 
Wort) 
• Cyproterone (antiandrogen, progestin) 
Others: 
• Chloramphenicol 
• Nefazodone 
• 
Bergamottin (constituent of 
grapefruit juice) 
• Aprepitant 
• Verapamil 
• Gemfibrozil 
• Trimethoprim 


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• Thiazolidinedione 
• Montelukast 
• Quercetin 


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23.4 
Appendix D: Pill Diary 
An Open-label, Multi-center, Phase II Study of Janus-Associated Kinase 1 and 2 
(JAK1/2) Inhibition with Ruxolitinib in Solid Organ Transplant Recipients with Advanced 
Cutaneous Squamous Cell Carcinoma 
Patient Name:  
Study ID:  
MRN:  
 
(To be Completed by RN) 
Number of Ruxolitinib Tablets Given:  
Pill Bottle(s) returned: Circle Yes or No 
Total Daily Dose of Ruxolitinib:  
Number of Ruxolitinib Tablets returned:  
 
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT. 
SPECIAL INSTRUCTIONS 
1. Ruxolitinib should be taken at approximately the same time twice daily with a full 
glass (8 oz.) of water. Ruxolitinib should not be crushed, chewed, or dissolved in 
water. 
2. If you forget to take a dose, you can take that dose up to 2 hours after the scheduled 
dosing time. However, if it is greater than 2 hours after your scheduled dosing time, t 
he dose should be skipped and considered a missed dose. Missed doses should be 
skipped and not taken as a double dose at the next dosing time. If you vomit your 
dose, DO NOT make up that dose. 
3. Ruxolitinib tablets should be stored at room temperature. 
WEEKS 
CYCLE #: 
# of 
 
Day 
Medication 
Date 
Time 
# Capsules 
taken 
Comments 
Example 
Ruxolitinib 
1/1/2020 
9:00AM 
9:00PM 
1 
1 
Ruxolitinib 
2 
Ruxolitinib 
3 
Ruxolitinib 
4 
Ruxolitinib 
5 
Ruxolitinib 
6 
Ruxolitinib 
7 
Ruxolitinib 
8 
Ruxolitinib 
9 
Ruxolitinib 
10 
Ruxolitinib 
11 
Ruxolitinib 
12 
Ruxolitinib 
13 
Ruxolitinib 
14 
Ruxolitinib 
15 
Ruxolitinib 


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16 
Ruxolitinib 
17 
Ruxolitinib 
18 
Ruxolitinib 
19 
Ruxolitinib 
20 
Ruxolitinib 
21 
Ruxolitinib 
22 
Ruxolitinib 
23 
Ruxolitinib 
24 
Ruxolitinib 
25 
Ruxolitinib 
26 
Ruxolitinib 
27 
Ruxolitinib 
28 
Ruxolitinib 
 
 
Patient Signature: 
Date: 
Consenting Professional/Research RN Signature: 
Date: 
Consenting Professional/Research RN Comments: