Pharmacodynamic Effects and Predictive Biomarkers of Janus Kinases (JAK)/Signal Transducer and Activator of Transcription (STAT) Inhibition With Ruxolitinib in Operable Head and Neck Cancer: a Window Trial
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: University of California, San Francisco

Proprietary and Confidential
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws. Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed.
Pharmacodynamic effects and predictive biomarkers of 
JAK/STAT inhibition with ruxolitinib in operable head and 
neck cancer: a window trial
Protocol Number:  CC # 16201
Study Drug:  Ruxolitinib
Version Number:  6.3
Version Date:  03-22-2023
IND Number:  Exempt
Principal Investigator (Sponsor-Investigator)
William Ryan, MD
University of California San Francisco
 
Telephone:  
E-mail: 
Co-Principal Investigator
Patrick Ha, MD
University of California San Francisco
Telephone: 
E-mail: 
Statistician
Jimmy Hwang, PhD 
Revision History
Version 6.3
Date: 03-22-2023
Version 6.2
Date: 11-08-2019
Version 6.1
Date: 09-13-2019
Version 6.0
Date: 04-08-2019
Version 5.0
Date: 06-05-2018
Version 4.0 
Date: 04-13-2017
Version 3.0
Date: 12-15-2016
Version 1.0 
Date: 06-09-2015
NCT# 03153982

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Protocol Signature Page
Protocol No.: 16201
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Institutional Review Board (IRB), and Data Safety Monitoring 
Committee (DSMC).
2.
I will conduct the study in accordance with applicable IRB requirements, Federal 
regulations, and state and local laws to maintain the protection of the rights and welfare 
of study participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or 
Manufacturer’s Brochure) regarding the risks and potential benefits. I agree to conduct 
the protocol in accordance with Good Clinical Practices (ICH-GCP), the applicable 
ethical principles, the Statement of Investigator (Form FDA 1572), and with local 
regulatory requirements. In accordance with the FDA Modernization Act, I will ensure the 
registration of the trial on the www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, 
Federal, state and local laws and regulations.
UCSF Principal Investigator / Study Chair
William Ryan, MD
Printed Name
Signature
Date

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Protocol Signature Page – Participating Sites
Protocol No.: 16201
Participating Site(s)
Principal Investigator Name: Julie Bauman, MD, MPH 
Institution Name: University of Arizona Cancer Center
Address:  
Telephone:  
E-mail:  
 
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 
1572), Institutional Review Board regulations, and all national, state and local laws and/or 
requirements of the pertinent regulatory requirements. 
Principal Investigator
Julie Bauman, MD, MPH
Site
University of Arizona
Printed Name
Institution Name
Signature
Date

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Abstract
Title
Pharmacodynamic effects and predictive biomarkers of JAK/STAT inhibition with 
ruxolitinib in operable head and neck cancer: a window trial
Patient 
population
Patients with de novo or recurrent stage I-IVa head and neck squamous cell 
carcinoma (HNSCC) who are planned for definitive surgery. 
Rationale for 
Study
Head and neck squamous cell carcinoma (HNSCC) is responsible for over 11,500 
deaths in the United States alone each year, and despite advances in surgical, 
radiation, and chemotherapy treatment, overall survival rates have only increased 
incrementally over the past few decades. Aberrant STAT regulation is commonly 
seen in HNSCC, although direct pharmacologic targeting of this family of 
transcriptional factors has proven difficult. However, the Janus kinases (JAK) have 
been shown to modulate the activity of signal transducer and activator of 
transcription (STAT)-3 in HNSCC preclinical models, and small molecule JAK 
inhibitors have recently been developed. The potential utility of JAK modulation in 
HNSCC has not yet been tested.
Primary 
Objective

To identify baseline and/or pharmacodynamic biomarkers of response to 
ruxolitinib, based upon association with quantitative change in tumor size 
(ΔTumor size) following 14-21 days of neoadjuvant ruxolitinib in patients with 
operable HNSCC as determined by quantitative ΔTumor size
Secondary 
Objectives

To describe the tolerability of brief neoadjuvant exposure to ruxolitinib

To assess the effect of ruxolitinib on the tumoral Ki-67 proliferation index 

To evaluate additional candidate biomarkers of ruxolitinib response or 
resistance in HNSCC patients as determined by quantitative ΔTumor size, 
including:
o
Baseline activation and/or modulation of additional JAK/STAT3 signaling 
pathway proteins
o
Baseline SHP-2 overexpression
o
Reverse-phase protein array (RPPA) will be conducted on paired pre- and 
post-treatment tissue as a source of unbiased biomarker discovery
Study Design
This is a multicenter cohort study designed to assess the effect of the JAK 1/2 
inhibitor ruxolitinib on tumor proliferation, size, and biomarker expression.
Number of 
patients
Projected accrual is 45 patients for this study, for a total of 23 biomarker-evaluable 
patients.
Duration of 
Therapy
Patients may continue treatment for up to 4 weeks from the time of study entry to 
time of planned surgery.
Duration of 
Follow up
12-weeks post-operation, as deemed clinically necessary.
Duration of 
study
The study will reach completion 24 months from the time the study opens to 
accrual.
Study Drugs
Ruxolitinib, JAKAFI®, INCB018424 (JAK 1/2 inhibitor) 20mg (or 15mg) PO BID. 
Safety 
Assessments
The safety of this window intervention will be reported descriptively, including 
tabulation of toxicities according to NCI CTCAE v.4, surgical complications, and 
length of hospital stay.
Efficacy 
Assessments
Efficacy of neoadjuvant ruxolitinib in patients with operable HNSCC as determined 
by quantitative ΔTumor size reflective of a 35% reduction.

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List of Abbreviations
AE
adverse event
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CSF
cerebral spinal fluid
CT
computerized tomography
CTCEA
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTMS
Clinical Trial Management System
DFS
disease-free survival
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECOG
Eastern Cooperative Oncology Group
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HGB
hemoglobin
ICH
International Conference on Harmonization
IND
investigational new drug application
IRB
Institutional Review Board
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
ORR
overall response rate
PD
disease progression
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PR
partial response
PRC
Protocol Review Committee (UCSF)
QOL
Quality of Life
RBC
red blood cell (count)
SD
stable disease
WBC
white blood cell (count)

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Table of Contents
Protocol Signature Page...............................................................................................................2
Protocol Signature Page – Participating Sites ..............................................................................3
Abstract
4
List of Abbreviations......................................................................................................................5
Table of Contents..........................................................................................................................6
1
Introduction ..........................................................................................................................9
1.1
Background on Indication......................................................................................9
1.2
Background on Ruxolitinib....................................................................................9
1.3
Rationale for the Proposed Study ........................................................................16
1.4
Correlative Biomarker Analysis ..........................................................................21
1.4.1 Primary Analysis..................................................................................................21
1.4.2 Additional Analysis .............................................................................................21
2
Objectives of the Study......................................................................................................22
2.1
Primary Objective................................................................................................22
2.2
Secondary Objectives ..........................................................................................22
2.3
Endpoints .............................................................................................................22
2.3.1 Primary Endpoint.................................................................................................22
2.3.2 Secondary Endpoints ...........................................................................................23
3
Study Design .....................................................................................................................23
3.1
Characteristics......................................................................................................23
3.2
Number of Participants........................................................................................24
3.3
Eligibility Criteria................................................................................................24
3.3.1 Inclusion Criteria .................................................................................................24
3.3.2 Exclusion Criteria ................................................................................................25
3.4
Duration of Therapy.............................................................................................26
3.5
Duration of Follow Up.........................................................................................26
3.5.1 Procedures for discontinuation ............................................................................26
3.6
Study Timeline.....................................................................................................27
3.6.1 Primary Completion.............................................................................................27
3.6.2 Study Completion ................................................................................................27
4
Study Drugs .......................................................................................................................27
4.1
Description, Supply and Storage of Investigational Drugs..................................27
4.1.1 Ruxolitinib (JAKAFI®, INCB018424) ...............................................................27
4.2
Drug Accountability ............................................................................................29
4.3
Drug Ordering......................................................................................................29
4.4
Packaging and Labeling of Study Drugs .............................................................29
5
Treatment Plan ..................................................................................................................29
5.1
Dosage and Administration .................................................................................29
5.2
Dose De-escalation Rule......................................................................................29
5.3
Procedures in Case of Overdose..........................................................................30
5.4
Procedures in Case of Pregnancy.........................................................................30

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5.5
Dose Modifications and Dosing Delays ..............................................................31
5.6
Monitoring and Toxicity Management................................................................31
6
Study Procedures and Observations .................................................................................33
6.1
Study Calendar.....................................................................................................34
6.2
Participant Registration........................................................................................36
6.3
Schedule of Procedures and Observations...........................................................36
6.3.1 Screening Period..................................................................................................36
6.3.2 Treatment Period..................................................................................................37
6.3.3 End-of-Treatment/Final Study Visit Procedures .................................................39
6.4
Usage of Concurrent/Concomitant Medications..................................................40
6.4.1 Dietary Restrictions .............................................................................................40
6.4.2 Prohibited Medications........................................................................................40
7
Reporting and Documentation of Results ..........................................................................40
7.1
Evaluation of Efficacy: Antitumor Effect – Solid Tumors..................................40
7.1.1 Definitions ...........................................................................................................40
7.1.2 Disease Parameters ..............................................................................................40
7.1.3 Methods for Evaluation of Measurable Disease..................................................41
7.1.4 Response Criteria.................................................................................................41
7.2
Evaluation of Safety.............................................................................................43
7.3
Definitions of Adverse Events.............................................................................43
7.3.1 Adverse Event......................................................................................................43
7.3.2 Adverse Reaction.................................................................................................43
7.4
Recording of an Adverse Event...........................................................................45
7.5
Follow-up of Adverse Events ..............................................................................46
7.6
Adverse Events Monitoring.................................................................................46
7.7
Expedited Reporting ............................................................................................47
8
Statistical Considerations and Evaluation of Results.........................................................48
8.1
Study Endpoints...................................................................................................48
8.2
Determination of Sample Size and Accrual Rate ................................................48
8.2.1 Sample Size and Power Estimate.........................................................................48
8.2.2 Replacement Policy .............................................................................................48
8.2.3 Safety Lead-in......................................................................................................48
8.2.4 Accrual Estimates ................................................................................................49
8.3
Interim Analyses and Stopping Rules..................................................................49
8.4
Analyses Plans.....................................................................................................49
8.4.1 Analysis Populations............................................................................................49
8.4.2 Primary Analysis (or Analysis of Primary Endpoints)........................................50
8.4.3 Secondary Analysis (or Analysis of Secondary Endpoints)................................50
8.4.4 Other Analyses/Assessments...............................................................................51
8.5
Evaluation of Safety.............................................................................................51
9
Study Management............................................................................................................51
9.1
Pre-study Documentation ....................................................................................51
9.2
Institutional Review Board Approval..................................................................52
9.3
Informed Consent ................................................................................................52
9.4
Changes in the Protocol.......................................................................................52

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9.5
Handling and Documentation of Clinical Supplies .............................................52
9.6
Case Report Forms (CRFs)..................................................................................52
9.7
Oversight and Monitoring Plan............................................................................53
9.8
Record Keeping and Record Retention ...............................................................53
9.9
Coordinating Center Documentation of Distribution ..........................................54
10
Protection of Human Subjects ...........................................................................................54
10.1
Protection from Unnecessary Harm.....................................................................54
10.2
Protection of Privacy ...........................................................................................54
11
References ........................................................................................................................55
Appendix 1
Performance Status Criteria...............................................................................58
Appendix 2
Multicenter Institutional Studies Data and Safety Monitoring Plan for a 
Multicenter Study (Phase II or III study).............................................................59
Appendix 3
Prohibited Medications.......................................................................................63
Appendix 4
Study Drug Diary................................................................................................64
Appendix 5
Specimen Collection and Processing ................................................................65

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1
Introduction
1.1
Background on Indication
Head and Neck Cancer
HNSCC is the sixth leading cancer worldwide, with more than 600,000 cases anticipated in 
2012.1,2 In the United States, the 2012 disease burden included 52,600 new cases and 11,500 
deaths.2 Despite advances in surgical and radiotherapy techniques, as well as integration of 
chemotherapy into multimodality treatment paradigms, HNSCC is frequently lethal. Five-year 
overall survival (OS) is 40-60% and has increased only incrementally since 1990.3 Improved 
prognosis is largely attributable to the emerging epidemic of oral human papillomavirus (HPV) 
infection. An increasing proportion of oropharyngeal HNC is driven by oncogenic HPV, rather 
than the classic risk factors of tobacco and alcohol; HPV etiology is associated with improved 
survival after conventional treatments.4,5 Although two distinct causes of HNSCC exist, 
environmental carcinogenesis or transformation by HPV oncogenes, both etiologies are 
associated with aberrant STAT 3 signaling.6-8 The association of STAT3 hyperactivation with 
poor prognosis9 and resistance to standard therapies makes it a compelling target in HNSCC.
1.2
Background on Ruxolitinib
JAKAFI®, INCB018424
Despite the importance of STAT function in a number of pathologic processes, direct 
pharmacologic inhibition of STAT is difficult. However, inhibition of upstream regulators of STAT 
function via the JAK proteins has met with more success. A number of JAK inhibitors have 
progressed to various stages of drug development, including a handful that have gained FDA 
approval. One molecule, ruxolitinib, is an inhibitor of JAK1 and JAK2, and has been approved 
by the FDA for treatment of myelofibrosis.
Preclinical Anti-tumor Activity
Ruxolitinib represents a novel, potent, and selective inhibitor of JAK1 and JAK2. Ruxolitinib 
potently inhibits JAK1 and JAK2 [half maximal inhibitory concentration (IC50) 0.4 to 1.7 nM], yet 
it does not significantly inhibit (< 30% inhibition) a broad panel of 26 kinases when tested at 200 
nM (approximately 100 times the average IC50 value for JAK enzyme inhibition) and does not 
inhibit JAK3 at clinically relevant concentrations. Pharmacological data obtained in in vivo model 
systems support the potential utility of orally administered INCB018424 in the treatment of 
malignancies, including myeloproliferative disorders such as PMF, PPV-MF and PET-MF. 
Ruxolitinib retains activity against the JAK2V617F mutant and is effective in reducing spleen 
size in mice inoculated with cells carrying this mutation. 
Preclinical Toxicology
The toxicologic and toxicokinetic profiles of ruxolitinib were characterized in single and repeat 
oral dose studies of up to 6 months in duration in rats and dogs. Genetic toxicology, safety 
pharmacology, and embryo-fetal toxicology studies have also been conducted. 
In a 6-month study in rats, doses up to 60 mg/kg/day were evaluated. An adverse decrease in 
body weight was noted in male, but not in female rats. A dose related decrease in lymphocytes 
was noted. Minimal-to-mild lymphoid depletion in spleens and in mandibular lymph nodes was 
noted at the 60 mg/kg/day dose level; at lower doses, lymphoid tissues were within normal 
histologic limits. The no-observed-adverse-effect level (NOAEL) for oral administration of 
ruxolitinib for 26 weeks was 30 mg/kg/day for the males (unbound AUC 0.119 μM*h), related to 

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adverse effects on body weight at 60 mg/kg/day, and 60 mg/kg/day for female rats (unbound 
AUC 4.64 μM*h). (Lower parent drug levels in male rats are related to male rat specific 
isozymes 2C11, 2C13 and CYP3A2 that metabolize ruxolitinib to active metabolites). 
In the 6 month dog study, doses studied included 0.5, 2.5, 5, and 10 mg/kg/day. Demodectic 
mange, lymphopenia, eosinopenia, decreases in erythron parameters, moderate to severe 
cellular depletion of lymphoid tissues, bacterial pneumonia, viral-induced papillomas, 
microscopic invasive demodectic mange, and prostate hypoplasia/atrophy were seen in dogs 
that received high doses. Deaths attributed to bacterial pneumonia occurred in 3 of 14 dogs 
given 10 mg/kg/day. Demodectic mange was observed in several animals given 5 mg/kg/day 
and, microscopically, in one animal given 2.5 mg/kg/day. These events most likely reflect a 
response to the immunosuppressive effects of ruxolitinib. All tissues were normal in the 0.5 
mg/kg/day group. The NOAEL dose was defined at 2.5 mg/kg/day (unbound AUC 0.76 μM*h) 
due to minimal findings, which were not present in recovery animals. The low dose, 0.5 
mg/kg/day, was defined as the no-observed effect-level (NOEL). Additional details regarding 
dog toxicology studies are available in the Investigator Brochure (IB). 
Ruxolitinib was not genotoxic in the bacterial mutagenicity assay, the in vitro chromosome 
aberration assay, or the in vivo micronucleus assay in rats. In embryo-fetal assessments in rat 
and rabbit, maternal toxicity and minimal embryo-fetal toxicity were noted at the highest doses 
evaluated. Ruxolitinib was not teratogenic in either rat or rabbit. The NOAEL dose for the rat 
and rabbit study was 30 mg/kg/day. Additional toxicology and safety pharmacology information 
is available in the IB. 
Clinical Pharmacokinetics (PK)
Following oral, single-dose administration of ruxolitinib capsules in the fasting state, ruxolitinib 
was absorbed rapidly, typically attaining peak plasma concentrations within 1 to 3 hours after 
administration for all doses. After attaining Cmax, the ruxolitinib plasma concentrations declined 
with a mean terminal-phase disposition (t 1/2) of approximately 3-5 hours. The mean ruxolitinib 
Cmax and AUC increased with approximately linear proportionality to dose for the entire dose 
range evaluated of 5 to 200 mg. There was no significant food effect on absorption or exposure. 
Therefore, ruxolitinib can be dosed without regard to meals. 
No accumulation was seen following administration of repeated oral doses of 15 to 50 mg 
ruxolitinib twice daily (BID), and 50 to 100 mg ruxolitinib once daily for 10 days. PK parameters 
were similar to those seen following the administration of single doses. Ruxolitinib is 
metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme system, 
predominantly by the 3A4 isozyme. The effects of the potent CYP3A4 inhibitor ketoconazole on 
the pharmacokinetics (PK) and pharmacodynamics (PD) of ruxolitinib administered as single 
oral doses shows that with concomitant dosing of ketoconazole, the observed AUC increase is 
approximately 2-fold, and the calculated Equivalent Constant Concentration (ECC) for the 
pSTAT3 PD effect was also increased approximately 2-fold. Thus, a dose reduction of ~ 50% 
for ruxolitinib is appropriate for participants who take ketoconazole or other potent CYP3A4 
inhibitors as concomitant medication (see Section 9.8.1). A more modest effect on the PK 
parameters of ruxolitinib was demonstrated with concomitant dosing of the moderate CYP3A4 
inhibitor erythromycin. No dose adjustments were necessary when ruxolitinib was co-
administered with erythromycin, or by extension, with other moderate or weak inhibitors of 
CYP3A4, including grapefruit juice. 

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An open-label study to assess the effect of CYP3A4 inducers on ruxolitinib pharmacokinetics 
and pharmacodynamics revealed that, as expected, rifampin significantly decreased the 
exposure to ruxolitinib. However, essentially no difference in cytokine-induced STAT3 
phosphorylation was observed with or without rifampin induction. This suggests that CYP3A4 
induction with rifampin results in metabolism of ruxolitinib to active metabolites that also inhibit 
JAKs. Increased levels of active metabolites were seen with rifampin dosing. These data 
indicate that the dose of ruxolitinib need not be modified when dosed with CYP3A4 inducers. 
However, during the study, use of potent CYP3A4 inducers (rifampin and St. John’s Wort) is 
prohibited. Use of moderate CYP3A4 inducers (rifabutin, carbamazepine, phenytoin) is 
discouraged, and investigators should seek alternatives where possible. No dose adjustment 
will be used when these moderate CYP3A4 inducers are co-administered with study drug or 
open label ruxolitinib. Any concomitant use of CYP3A4 inducers must be documented. 
Ruxolitinib was given as a single 25 mg dose to participants with varying degrees of renal 
function, including normal (calculated creatinine clearance (CrCl) >80 mL/min), mild (CrCl 50-80 
mL/min), moderate (CrCl 30-49 mL/min) and severe (CrCl <30 mL/min) renal impairment as well 
as participants on dialysis and the PK and PD parameters measured. There was no statistically 
significant effect of mild to severe impairment of renal function on the PK or PD parameter; 
participants requiring dialysis showed decreased ruxolitinib clearance. Participants with serum 
creatinine exceeding 1.5 times the institutional upper limit of normal (ULN) will be excluded from 
the study. 
Randomized Studies
Two randomized Phase 3 studies (Studies 1 and 2) were conducted in patients with 
myelofibrosis (either primary myelofibrosis, post-polycythemia vera myelofibrosis or post-
essential thrombocythemia-myelofibrosis). In both studies, patients had palpable splenomegaly 
at least 5 cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) 
or high risk (3 or more prognostic factors) based on the International Working Group Consensus 
Criteria (IWG). 
The starting dose of ruxolitinib was based on platelet count. Patients with a platelet count 
between 100 and 200 X 109/L were started on ruxolitinib 15 mg twice daily and patients with a 
platelet count greater than 200 X 109/L were started on ruxolitinib 20 mg twice daily. Doses were 
then individualized based upon tolerability and efficacy with maximum doses of 20 mg twice 
daily for patients with platelet counts between 100 to less than or equal to 125 X 109/L, of 10 mg 
twice daily for patients with platelet counts between 75 to less than or equal to 100 X 109/L, and 
of 5 mg twice daily for patients with platelet counts between 50 to less than or equal to 75 X 
109/L. 
Study 1 
Study 1 was a double blind, randomized, placebo-controlled study in 309 patients who were 
refractory to or were not candidates for available therapy. The median age was 68 years (range 
40 to 91 years) with 61% of patients older than 65 years and 54% were male. Fifty percent 
(50%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 
18% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients 
had red blood cell transfusions within 8 weeks of enrollment in the study. The median 
hemoglobin count was 10.5 g/dL and the median platelet count was 251 X 109/L. Patients had a 
median palpable spleen length of 16 cm below the costal margin, with 81% having a spleen 
length 10 cm or greater below the costal margin. Patients had a median spleen volume as 

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measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2595 cm3 
(range 478 cm3 to 8881 cm3). (The upper limit of normal is approximately 300 cm3). 
Patients were dosed with ruxolitinib or matching placebo. The primary efficacy endpoint was the 
proportion of patients achieving greater than or equal to a 35% reduction from baseline in 
spleen volume at Week 24 as measured by MRI or CT. 
Secondary endpoints included duration of a 35% or greater reduction in spleen volume and 
proportion of patients with a 50% or greater reduction in Total Symptom Score from baseline to 
Week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 
diary. 
Study 2 
Study 2 was an open-label, randomized study in 219 patients. Patients were randomized 2:1 to 
ruxolitinib versus best available therapy. Best available therapy was selected by the investigator 
on a patient-by-patient basis. In the best available therapy arm, the medications received by 
more than 10% of patients were hydroxyurea (47%) and glucocorticoids (16%). The median age 
was 66 years (range 35 to 85 years) with 52% of patients older than 65 years and 57% were 
male. Fifty-three percent (53%) of patients had primary myelofibrosis, 31% had post-
polycythemia vera myelofibrosis and 16% had post-essential thrombocythemia myelofibrosis. 
Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of 
enrollment in the study. The median hemoglobin count was 10.4 g/dL and the median platelet 
count was 236 X 109/L. Patients had a median palpable spleen length of 15 cm below the costal 
margin, with 70% having a spleen length 10 cm or greater below the costal margin. Patients had 
a median spleen volume as measured by MRI or CT of 2381 cm3 (range 451 cm3 to 7765 cm3). 
The primary efficacy endpoint was the proportion of patients achieving 35% or greater reduction 
from baseline in spleen volume at Week 48 as measured by MRI or CT. 
A secondary endpoint in Study 2 was the proportion of patients achieving a 35% or greater 
reduction of spleen volume as measured by MRI or CT from baseline to Week 24. 
Study 1 and 2 Efficacy Results 
Efficacy analyses of the primary endpoint in Studies 1 and 2 are presented in Table 1 below. A 
significantly larger proportion of patients in the ruxolitinib group achieved a 35% or greater 
reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and 
best available therapy in Study 2. A similar proportion of patients in the ruxolitinib group 
achieved a 50% or greater reduction in palpable spleen length. 
Table 1: Percent of Patients with 35% or Greater Reduction from Baseline in Spleen 
Volume at Week 24 in Study 1 and at Week 48 in Study 2 (Intent to Treat) 
Study 1
Study 2
Ruxolitinib 
(N=155)
Placebo
(N=154)
Ruxolitinib 
(N=146)
Placebo 
(N=73)
Time Points
Week 24
Week 48
Number (%) of Patients with Spleen 
Volume Reduction by 35% or More
65 (41.9)
1 (0.7)
41 (28.5)
0
P-value
<0.0001
<0.0001

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Figure 1 shows the percent change from baseline in spleen volume for each patient at Week 24 
(ruxolitinib N=139, placebo N=106) or the last evaluation prior to Week 24 for patients who did 
not complete 24 weeks of randomized treatment (ruxolitinib N=16, placebo N=47). One (1) 
patient (placebo) with a missing baseline spleen volume is not included. 
Figure 1: Percent Change from Baseline in Spleen Volume at Week 24 or Last 
Observation for Each Patient (Study 1) 
In Study 1, myelofibrosis symptoms were a secondary endpoint and were measured using the 
modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. The modified MFSAF 
is a daily diary capturing the core symptoms of myelofibrosis (abdominal discomfort, pain under 
left ribs, night sweats, itching, bone/muscle pain and early satiety). Symptom scores ranged 
from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” 
symptoms. These scores were added to create the daily total score, which has a maximum of 
60. 
Table 2 presents assessments of Total Symptom Score from baseline to Week 24 in Study 1 
including the proportion of patients with at least a 50% reduction (i.e., improvement in 
symptoms). At baseline, the mean Total Symptom Score was 18.0 in the ruxolitinib group and 
16.5 in the placebo group. A higher proportion of patients in the ruxolitinib group had a 50% or 
greater reduction in Total Symptom Score than in the placebo group, with a median time to 
response of less than 4 weeks. 
Table 2: Improvement in Total Symptom Score 
Ruxolitinib 
(N=148)
Placebo 
(N=152)
Number (%) of Patients with 50% or Greater Reduction in Total 
Symptom Score by Week 24 
68 (45.9)
8 (5.3)
P-value 
< 0.0001

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Figure 2 shows the percent change from baseline in Total Symptom Score for each patient at 
Week 24 (ruxolitinib N=129, placebo N=103) or the last evaluation on randomized therapy prior 
to Week 24 for patients who did not complete 24 weeks of randomized treatment (ruxolitinib 
N=16, placebo N=42). Results are excluded for 5 patients with a baseline Total Symptom Score 
of zero, 8 patients with missing baseline and 6 patients with insufficient post-baseline data. 
Figure 2: Percent Change from Baseline in Total Symptom Score at Week 24 or Last 
Observation for Each Patient (Study 1) 

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Figure 3: Proportion of Patients With 50% or Greater Reduction in Individual 
Symptom Scores at Week 24
Safety of Ruxolitinib in Clinical Studies
The safety of ruxolitinib was assessed in 617 patients in six clinical studies with a median 
duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 
studies. 
In these two Phase 3 studies, patients had a median duration of exposure to ruxolitinib of 9.5 
months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 
24.6% treated for more than 12 months. One hundred and eleven (111) patients started 
treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. 
In a double blind, randomized, placebo-controlled study of ruxolitinib, 155 patients were treated 
with ruxolitinib. The most frequent adverse drug reactions were thrombocytopenia and anemia. 
Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent 
non-hematologic adverse reactions were bruising, dizziness and headache. 
Figure 3. The proportion 
of patients with at least a 
50% improvement in 
each of the individual 
symptoms that comprise 
the Total Symptom 
Score indicating that all 
6 of the symptoms 
contributed to the higher 
Total Symptom Score 
response rate in the 
group treated with 
ruxolitinib.

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Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients 
treated with ruxolitinib and 10.6% of patients treated with placebo. 
Following interruption or discontinuation of ruxolitinib, symptoms of myelofibrosis generally 
return to pretreatment levels over a period of approximately 1 week. There have been isolated 
cases of patients discontinuing ruxolitinib during acute intercurrent illnesses after which the 
patient’s clinical course continued to worsen; however, it has not been established whether 
discontinuation of therapy contributed to the clinical course in these patients. When 
discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of 
ruxolitinib may be considered.
Table 3 presents the most common adverse reactions occurring in patients who received 
ruxolitinib in the double blind, placebo-controlled study during randomized treatment. 
Table 3: Adverse Reactions Occurring in Patients on Ruxolitinib in the Double blind, 
Placebo-controlled Study during Randomized Treatment
Jakafi (N=155)
Placebo (N=151)
Adverse Reactions
All Gradesa 
(%)
Grade 3 
(%)
Grade 4 
(%)
All Grades 
(%)
Grade 3 
(%)
Grade 4 
(%)
Bruisingb 
23.2
0.6
0
14.6
0
0
Dizzinessc 
18.1
0.6
0
7.3
0
0
Headache 
14.8
0
0
5.3
0
0
Urinary Tract Infectionsd 
9.0
0
0
5.3
0.7
0.7
Weight Gaine 
7.1
0.6
0
1.3
0.7
0
Flatulence 
5.2
0
0
0.7
0
0
Herpes Zosterf 
1.9
0
0
0.7
0
0
aNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 
bincludes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site 
hematoma, increased tendency to bruise, petechiae, and purpura 
c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis 
dincludes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria 
urine, bacteria urine identified, nitrite urine present 
eincludes weight increased, abnormal weight gain 
f includes herpes zoster and post-herpetic neuralgia 
1.3
Rationale for the Proposed Study
Cumulative preclinical data implicate STAT 3 as a critical target in HNSCC; however, as with 
other transcription factors, STAT3 has been challenging to selectively and directly target. The 
recognition that hyperactivated STAT3 may result from increased upstream JAK signaling 
caused us to investigate JAK 1/2 inhibitors, including AZD1480 and ruxolitinib, in HNSCC 
preclinical models as described above. Promising preclinical results parallel findings from 
multiple solid tumors, where AZD1480 abrogated IL-6 dependent STAT3 signaling,10 justifying 
translation of JAK 1/2 targeting into human clinical trials. Novel insights into the genomic and 
epigenetic mechanisms of HNSCC tumor STAT3 activation raise the exciting possibility of 
biomarker-selection of patients most likely to respond to JAK 1/2 inhibition.
Ruxolitinib is an ATP-competitive, oral, small molecule inhibitor of the JAK1 and JAK2 kinases; 
it is the first JAK family inhibitor approved by the U.S. Food and Drug Administration (Incyte, 

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myelofibrosis, 2011).11 Inhibition of wild type JAK1 and JAK2 respectively has an enzyme IC50 of 
3.3 (+/- 1.2) and 2.8 (+/- 1.2) nM, concentrations easily achieved by the approved clinical 
dose.12 To date, ruxolitinib duplicates the findings of AZD1480 in our HNSCC preclinical models 
(Figures 4-8), as would be expected from its similar JAK inhibitory and pharmacokinetic profile. 
In this study, ruxolitinib will be administered for a short period of 2-3 weeks prior to planned 
surgical resection of HNSCC. The dose will be the FDA-approved dose in myelofibrosis, as 
determined by baseline platelet count: 1) Patients with a platelet count ≥ 200,000 will take 20 
mg bid (four 5mg tablets in the morning and four 5mg tablets in the evening); 2) participants with 
a platelet count ≥ 150,000 and < 200,000 will take 15 mg bid (three 5 mg tablets in the morning 
and three 5 mg tablets in the evening). The brief treatment duration is within the expected 
window of time that elapses from initial patient evaluation by a surgeon to performance of 
surgery. In the phase 0 or window trial model, a paired specimen analysis permits ex vivo 
evaluation of target modulation and pharmacodynamic changes in downstream or parallel 
molecular pathways.13 This study design is optimal in order to assess the biochemical and 
immunomodulatory effects of ruxolitinib on HNSCC. Furthermore, predictive biomarkers can be 
developed as related to a clinical endpoint (ΔTumor size) or a biochemical, pharmacodynamic 
endpoint (Δ Ki-67).
Ki-67 is a nuclear non-histone protein first characterized in 1991, which is expressed in 
proliferating human tissue.14 Down-modulation of Ki-67 is a validated surrogate biomarker in 
neoadjuvant studies of targeted therapy in breast cancer.15,16 Changes in Ki-67 observed in a 
neoadjuvant endocrine therapy study predicted the ultimate long-term disease-free survival 
advantage in the larger, adjuvant trial, whereas clinical response did not.16,17 In HNSCC window 
trials, Ki-67 modulation has not been evaluated directly against clinical outcome.18-20 An 
alternate surrogate biomarker to Ki-67, the TUNEL apoptotic index, was evaluated as the 
primary endpoint in a randomized window trial of lapatinib vs. placebo, prior to standard 
chemoradiotherapy in HNSCC.18 Although apoptosis was increased by lapatinib, the increase 
was not significant against that seen in the placebo group. Notably, the Ki-67 proliferation index 
was significantly decreased by lapatinib vs. placebo. This is in line with results from our first 
window study in HNSCC evaluating erlotinib, erlotinib-sulindac or placebo – where Ki-67 
reduction was significantly greater in the erlotinib arms vs. placebo.21  Collectively, these data 
suggest that proliferation is a worthwhile secondary endpoint for evaluation of biomarker 
correlations. 
The Jak/STAT pathway in Head and Neck Cancer
The STAT family of transcription factors is the central mediator of cellular response to cytokines 
and growth factors. Aberrant regulation of STAT3 and STAT1 in HNSCC underlies both 
malignant behavior and immune escape. STAT3 is an oncogenic transcription factor that is 
hyperactivated (phosphorylated) in a wide variety of malignancies. Studies from UPCI and other 
laboratories have shown that STAT3 transforms human epithelial cells, thereby meeting the 
definition of an oncogene. In HNSCC, STAT3 facilitates tumor growth and survival, and 
mediates resistance to standard therapies including chemoradiation and blockade of the 
epidermal growth factor receptor (EGFR).22-26
While cumulative evidence implicates STAT3 as an important target for cancer treatment, as 
with other transcription factors, STAT3 has proven challenging to inhibit selectively in humans. 
Few drugs have been amenable to clinical development. For example, an intra-operative phase 
0 trial of a STAT-3 oligonucleotide decoy in HNSCC was completed at UPCI, which reduced 

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target gene expression; however, the limited half-life and requirement for local injection impede 
broader clinical development.19 Increasing insight into the mechanisms of STAT3 
hyperactivation in human cancer raises the possibility of new therapeutic avenues, and may 
identify biomarkers for patient selection.
Although STAT3 is constitutively phosphorylated, activating mutations are not described in 
HNSCC27,28 or other human epithelial cancers. Thus, hyperactivated STAT3 likely results from 
excess activation of positive regulators and/or inactivation of negative regulators. STATs are 
phosphorylated by upstream growth factor receptors including Src and Janus kinases (JAK), 
and de-phosphorylated by protein tyrosine phosphatase receptors (PTPR). The activating JAK 
mutations identified in myeloproliferative disorders are not found in HNSCC.27,28 In HNSCC, IL-6 
stimulates tyrosine phosphorylation of STAT3 through JAK 1 and 2.29 The recent clinical 
development of JAK inhibitors, including ruxolitinib, raises the therapeutic plausibility of blocking 
this autocrine loop. For example, the JAK 1/2 inhibitor, AZD1480, abrogated IL-6 induced 
STAT3 phosphorylation and 
suppressed the growth of human 
solid tumor xenografts with 
constitutive STAT3 activity.10 
Moreover, a strategy for patient 
selection is emerging. While 
activating mutations in JAK or 
STAT3 are not found in HNSCC, our 
recent comprehensive mutational 
profiling of HNSCC detected 
mutations in the PTPR family of 
genes in nearly one-third of tumors.27 
Analysis of the 347 HNSCC tumors 
sequenced to date under the 
auspices of The Cancer Genome 
Atlas (TCGA) and our group, 
confirmed this high incidence of 
PTPR mutations (104/347, 30%). 
Further analysis demonstrated that 
PTPR genes are mutated in a wide array of solid tumors sequenced to date under the auspices 
of the TCGA (see Table 1). Loss of function mutations in PTPRT and PTPRD lead to increased 
STAT3 phosphorylation, suggesting a tumor suppressor role.30,31 Whole exome sequencing 
(n=374) and reverse-phase protein array data has been analyzed from 212 HNSCC tumors32. 
PTPR mutations were common and were associated with significantly increased phospho-
STAT3 expression. Expression of PTPRT mutant proteins induced STAT3 phosphorylation and 
cell survival, consistent with an oncogenic “driver” phenotype. Computational modeling revealed 
functional consequences of PTPRT mutations on phosphor-tyrosine-substrate interactions. In 
addition to genomic aberrations, PTPRT is commonly methylated in HNSCC tumors (60%, 
166/279 tumors analyzed to date in the TCGA); expression levels of PTPRT are significantly 
lower in these methylated tumors. Thus, silencing of key PTPR family genes may underlie 
STAT3 hyperactivation in HNSCC and other solid tumors. Identification and functional 
classification of these common genetic and epigenetic PTPR aberrations may permit companion 
biomarker development to select patients most likely to benefit from JAK inhibitors. 

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Figure 4: Decrease in pSTAT3Tyr705 expression with increase in concentration of 
Ruxolitinib
Recognition that 
hyperactivated STAT3 
likely results from increased signaling through upstream kinases, or loss of de-phosphorylation 
by silenced PTPRs, initially prompted investigation into the preclinical JAK1/2 inhibitor, 
AZD1480, in relevant HNSCC preclinical models. AZD1480 inhibited proliferation of eight 
HNSCC cell lines at low µM concentrations (data not shown). Ruxolitinib is an ATP-competitive, 
oral, small molecule inhibitor of the JAK1 and JAK2 tyrosine kinases. Inhibition of wild type 
JAK1 and JAK2 respectively has an enzyme IC50 of 3.3 (+/- 1.2) and 2.8 (+/- 1.2) nM.12 
Ruxolitinib blocked phosphorylation of pSTAT3 at Tyrosine 705 in dose-dependent fashion in 
the Cal33 HNSCC cell line (Figure 4). Furthermore, ruxolitinib inhibited growth of a FaDu 
HNSCC cell line xenograft, which harbors a loss-of-function PTPRT mutation, as compared to 
FaDu xenografts treated with vehicle control or ruxolitinib-treated PE/CA 34 HNSCC xenografts, 
which are wild type for PTPRT (Figure 4).
Figure 4. Cal 33 cells were 
treated with increasing 
concentrations of 
Ruxolitinib. After 24h, cells 
were harvested to obtain 
cell lysates. Forty 
micrograms of protein/lane 
were subjected to 
electrophoresis and 
immunoblotted for 
pSTAT3Tyr705 and total 
STAT3. Β-tubulin was 
used as a loading control.

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Figure 5: PTPRD or PTPRT mutations are found in 30% of HNSCC tumors. PTPRD and 
PTPRT mutations induce STAT3 activation, and increase sensitivity to JAK 1/2 inhibition.
The PTPRT/D mutations found in HNSCC tumors to date are shown below in Figure 6. 
Mutations in the PTP catalytic domains (PTPRT and PTPRD) and the fibronectin type 3 domain 
(PTPRD) have been reported to inhibit cellular functions of the phosphatase activity of these 
proteins.31,33 PTPRO was recently shown to behave as a tumor suppressor and decrease 
pSTAT3 in liver cancer.34 It is noteworthy that activating mutations of upstream mediators of 
STAT3 in HNSCC including EGFR, JAK, and Src were not detected in our HNSCC cohort. 
Furthermore, there was no evidence for association of PTPR mutations with HPV status. 
Published data32 illustrate that HNSCC tumors bearing PTPR mutations demonstrate higher 
pSTAT3 expression compared to PTPR wild-type. HNSCC cells transfected with a PTPRT 
mutation (A1022E or R1040L) demonstrate increased growth relative to EGFP-vector control or 
wild-type PTPR.

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Figure 6. Schematics showing mutations of PTPRT and PTPRD found in HNSCC patient 
tumors.
Figure 7. PTPR mutations correlate with STAT3 tyrosine phosphorylation in HNSCC 
tumors and enhance survival and STAT3 phosphorylation in HNSCC cells.
Preliminary data show that HNSCC cells transfected with a PTPRD mutation (P311T) 
demonstrated increased baseline STAT3 activation compared to vector controls (data not 
shown), and decreased survival and STAT3 promoter activity when treated with AZD1480 
compared with controls (Figure 8). 
Figure 7. (A) Significant increase in p-
TAT3(Y705) expression (intensity plot in log2 
scale; protein array data from The Cancer 
Proteome Atlas) in HNSCC patient tumors 
harboring PTPRD/J/K/M/O/S/T mutation (n 
=37) vs. tumors without PTPRT mutation (n = 
171) (P = 0.0202*). (B) Serum-dependent 
PCI-52-SD1 cells stably expressing EGFP-
vector control, wild-type PTPRT, or 
PTPRT(A1022E) or (R1040L) mutants were 
assessed by MTT assay for growth in the 
absence of serum. Cumulative growth 
relative to vector control (n ≥ 9) is shown. (C) 
Stable expression of wild-type PTPRT 
reduced basal p-STAT3(Tyr705) expression 
in PCI-52-SD1 cells. Graph showing 
cumulative results of p-STAT(Y705) levels in 
these cells from five independent 
experiments. (D) CAL-33 cells were 
transiently transfected with a representative 
PTPase domain mutation (A1022E) and an 
FN3-domain mutation (P497T). Expression 
levels of p-STAT3 (Tyr705) were detected by 
Western blotting. The PTPase domain 
mutation, but not the FN3-domain mutation, 
increased p-STAT3(Tyr705) expression. 
Similar results were observed in three 
independent experiments.
Figure 6.  Keys: Blue: Meprin/A5/PTPmu domain (MAM); Green: Fibronectin type 3 domain (FN3); Orange: 
Protein tyrosine phosphatase catalytic domain (PTPc); Pink: immunoglobulin (Ig) or Ig-like domain.

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Figure 8. Expression of PTPRD mutant in HNSCC cells
Finally, PTPRT, the most commonly mutated PTPR in HNSCC is methylated in 60% of samples 
analyzed to date by the TCGA where tumors with methlyated PTPRT express significantly lower 
levels of this protein. Further investigation in our lab showed that demethylation of a cell line 
with methylated PTPRT decreased pSTAT3 expression (data not shown)
1.4
Correlative Biomarker Analysis
1.4.1 Primary Analysis
Correlative biomarker analysis will be performed on paired pre-treatment specimens (tumor 
biopsies and blood) and post-treatment samples to determine the modulation of biomarkers by 
ruxolitinib. Most importantly, biomarkers within the JAK/STAT signaling pathway, including JAK 
and STAT phosphorylation, PTPR mutation and methylation, inflammatory cytokines and 
HLA/APM component expression will be assessed to determine their correlation with clinical 
response to ruxolitinib. Tissue microarrays will be generated from formalin-fixed, paraffin-
embedded (FFPE) specimens, and these will be used for immunohistochemistry to assess 
tissue histology, Ki67 labeling, and expression of JAK/STAT pathway proteins, including 
phosphorylated and non-phosphorylated forms of JAK1, JAK2, STAT1, STAT3, cyclin D1 and 
Src. PTPR mutations and methylation will be determined by Sanger sequencing/Sequenom31 
and methylation-specific PCR, respectively. Finally, HLA/APM component expression will be 
evaluated using IHC or intracellular flow cytometry for TAP1, TAP2, LMP2 and calreticulin, as 
described35. Remaining specimens after these studies have been completed will be used for 
additional analysis.
1.4.2 Additional Analysis
To determine if expression of serum proteins or DNA polymorphisms predict response to 
ruxolitinib targeting, paired serum (baseline, post-treatment) and baseline peripheral blood 
mononuclear cells (PBMCs) will be isolated. Blood will be processed for serum and isolation of 
PBMCs. Serum will be analyzed for proteomic markers using mass spectroscopy and luminex 
ELISA assays. DNA will be isolated from PBMC samples for SNP analysis. Tissue will be 
processed for DNA, fluorescence in situ hybridization (FISH), tissue microarrays, and 
Figure 8. UM-SCC-1 cells expressing mutant 
PTPRD (P1311T) or vector control were treated 
with AZD1480 (5 µM) or DMSO (vehicle) 
followed by MTT assay to determine % survival 
relative to vehicle control.  Results are mean +/- 
SEM, performed in triplicate.

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immunohistochemistry microarrays. Both uniplex and multiplex serum cytokine profile analysis, 
for correlation with other biomarkers and clinical responsiveness will be performed. For specific 
cytokines of interest, including IL-6, ELISA kits will be used. For multiplex analysis, the 
technology developed by Luminex Corporation (Austin, TX, http://www.luminexcorp.com) will be 
used. It enables a laboratory to simultaneously measure up to 100 analytes in a single 
microplate well, using very small sample volumes (less than 50 microliters). Previous studies 
have shown that a multi-marker panel offering the highest diagnostic power was comprised of 
22 biomarkers, including EGF, EGFR, Cyfra 21-1, AFP, IL-8, MMP-3, CA 72-4, CA 15-3, MMP-
2, TNF-RI, IL-7, HCGb, MIF, Mesothelin, MCP-1, IL-1Ra, FGFb, CEA, sVCAM-1 , tPAI 1, 
RANTES, IGFBP-1. Statistical analysis using our novel ADE algorithm resulted in a sensitivity of 
84.5%, specificity of 98%, and 92% of patients with active head and neck cancer correctly 
classified from a cross-validation serum set36. Further proteomic analysis will be performed 
using IHC microarrays. 
2
Objectives of the Study
2.1
Primary Objective
To identify baseline and/or pharmacodynamic biomarkers of response to ruxolitinib based upon 
association with quantitative change in tumor size (ΔTumor size) following 14-21 days of 
neoadjuvant ruxolitinib in patients with operable HNSCC. We hypothesize that ΔTumor size will 
correlate with five prioritized, predictive biomarkers which will be designated for specialized 
alpha spending: 1) baseline expression of pSTAT3; 2) change in expression of pSTAT3; 3) 
change in expression of the STAT3 target gene cyclin D1; 4) baseline silencing of protein 
tyrosine phosphatase receptors D or T (PTPRD or PTPRT) by mutation or methylation; 5) 
baseline elevation in peripheral inflammatory markers (C-reactive protein [CRP]).
2.2
Secondary Objectives

To assess preliminary efficacy of neoadjuvant ruxolitinib in patients with operable 
HNSCC as determined by quantitative ΔTumor size

To describe the tolerability of brief neoadjuvant exposure to ruxolitinib

To assess the effect of ruxolitinib on the tumoral Ki-67 proliferation index 

To evaluate additional candidate biomarkers of ruxolitinib response or resistance in 
HNSCC patients as determined by quantitative ΔTumor size, including:
o
Baseline activation and/or modulation of additional JAK/STAT3 signaling 
pathway proteins
o
Baseline SHP-2 overexpression
o
Reverse-phase protein array (RPPA) will be conducted on paired pre- and post-
treatment tissue as a source of unbiased biomarker discovery
2.3
Endpoints
2.3.1 Primary Endpoint

The primary efficacy endpoint of the study is clinical ruxolitinib response of 
quantitative ΔTumor size measured as a proportional percent (range -100% to +100%) 
from baseline to day 14-21. 

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2.3.2 Secondary Endpoints

The size of the tumor will be determined and net ΔTumor measurements used to 
determine the response.

The safety of this window intervention will be reported descriptively, including tabulation 
of toxicities according to NCI CTCAE v.4, surgical complications, and length of hospital 
stay.

The Ki-67 proliferative index will be measured in baseline and post-treatment tumor 
tissue as described, and will serve as a secondary endpoint (pharmacodynamic 
efficacy).21 The five prioritized biomarkers will be analyzed for correlations with ΔTumor 
size, as above. In addition, they will be analyzed for correlations with ΔKi-67. 

Non-prioritized biomarkers will also be evaluated for correlations with ΔTumor size and 
ΔKi-67. In order to assess biomarker response to ruxolitinib, we will test each 
component of the biomarker panel for within-patient differences between the pre-
treatment and post-treatment biospecimens (tumor tissue and blood) and compute the p-
values for each paired test (either a paired t test or the signed rank test). We anticipate a 
panel of 15 – 20 proteins will be tested for short-term modulation with TMAs. P values 
from paired data will be adjusted to control the expected false discovery rate by the 
method of Benjamini and Hochberg. Additional analyses of secondary endpoints will be 
conducted on an exploratory and hypothesis-generating bases using available material. 
These endpoints may include qualitative and semi-quantitative scoring of IHC in tissue 
arrays, gene microarrays and serum protein measures. 
3
Study Design
3.1
Characteristics
This is a multicenter cohort study designed to assess the effect of the JAK 1/2 inhibitor 
ruxolitinib on tumor proliferation, size, and biomarker expression.
Screening: Biopsies of the tumor and peripheral blood sample collection (see section 3.1)
After 14-21 days: Repeat CT scan and peripheral blood collection, followed by planned 
oncologic surgery with collection of post-treatment tumor specimen

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Schema of Proposed Clinical Trial
 
3.2
Number of Participants
45 patients will be accrued to achieve the target of 23 eligible patients demonstrating treatment 
compliance, and with quality paired tumor specimens.
3.3
Eligibility Criteria
Surgery will be the primary curative treatment for patients enrolled in this study. Patients should 
not require any standard induction treatment prior to surgery. Surgery will have to be the best 
treatment option as determined by the treating physician. Therefore, we will not be delaying 
chemoradiotherapy or other curative treatment. We plan to include any stage of HNSCC that will 
be managed by primary surgery, including patients with newly diagnosed disease or 
locoregional recurrence scheduled for surgical salvage. If surgery is unexpectedly cancelled, the 
patient will be removed from the study unless there is an accessible lesion for biopsy. Ideally, 
the pre-treatment biopsy and the intraoperative sample will be obtained from the same site 
(when there are multiple lesions). 
3.3.1 Inclusion Criteria
1.
Histologically or cytologically confirmed, primary or recurrent, head and neck squamous 
cell carcinoma, including variants. Patients must have at least one measureable lesion in 
accordance with RECIST 1.1 (tumor diameter ≥ 1 cm; short-axis lymph node diameter ≥ 
1.5 cm) OR by caliper measurement (tumor diameter ≥ 1 cm). Any diagnostic 
pretreatment biopsy sample is acceptable including FNA. 
2.
Primary tumors of any head and neck (oral cavity, oropharynx, hypopharynx, or larynx) 
site will be included. 
3.
Surgical resection of head and neck must be planned, either as primary treatment or 
salvage. Patients must have submitted adequate pre-treatment archival or fresh tissue.
4.
Age ≥ 18 years. 
5.
ECOG performance status 0-2 (See Appendix 1). 

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6.
Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
(sensitivity ≤ 25IU HCG/L) within 4 weeks prior to registration and will be repeated within 
72 hours prior to the start of study drug administration. 
7.
Persons of reproductive potential must agree to use and utilize an adequate method of 
contraception throughout treatment and for at least 12 weeks after study drug is stopped. 
Prior to study enrollment, women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors 
for an unintentional pregnancy.
8.
Adequate hematologic, renal and hepatic function, as defined by:
a) Absolute neutrophil count (ANC) ≥ 1,500/ul, platelets ≥ 150,000/ul.
b) Creatinine ≤ 1.5 x institutional upper limit of normal (ULN).
c)
Bilirubin ≤ 1.5 x ULN, AST or ALT ≤ 2.5 x ULN.
9.
Have signed written informed consent 
3.3.2 Exclusion Criteria
1.
Participants who fail to meet the above criteria. 
2.
Prior therapy for head and neck cancer is allowed, and the number of treatments is not 
limited. However, any systemic therapy should have been completed at least 30 days 
prior to study enrollment. Any radiation to the head and neck should have been 
completed at least 30 days prior to study enrollment. Palliative radiation outside of the 
head and neck does not require a washout. 
3.
Pregnancy or breastfeeding. Women (patients or partners of male patients) of 
childbearing potential (WOCBP) must practice acceptable methods of birth control to 
prevent pregnancy. All WOCBP MUST have a negative pregnancy test within 4 weeks 
prior to registration, and this must be repeated within 72 hours prior to first receiving 
ruxolitinib. If the pregnancy test is positive, the patient must not receive ruxolitinib and 
must not be enrolled in the study. 
4.
Any unresolved chronic toxicity ≥ grade 2 from previous anticancer therapy (except 
alopecia and anemia), according to Common Terminology Criteria for Adverse Events 
v4.0 (CTCAE).
5.
Current active infection requiring systemic antibiotic or antifungal therapy. 
6.
Acute hepatitis or known HIV.
7.
Treatment with a non-approved or investigational drug within 30 days prior to Day 1 of 
study treatment. 
8.
New York Heart Association (NYHA) Class III or IV heart disease. 
9.
History of thromboembolic event or other condition currently requiring anticoagulation 
with warfarin (Coumadin). Patients who are treated with low molecular weight heparin or 
fondaparinux are eligible. 
10. History of significant bleeding disorder unrelated to cancer, including: diagnosed 
congenital bleeding disorders (e.g., von Willebrand’s disease, diagnosed acquired 
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies, or ongoing or 
recent (≤ 3 months) significant gastrointestinal bleeding 

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11. Concomitant Medications, any of the following should be considered for exclusion: 
Strong CYP3A4 inhibitors: (Patients must discontinue drug 7 days prior to starting 
ruxolitinib), including but not limited to boceprevir, clarithromycin, conivaptam, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, or voriconazole. In addition, patients will be 
instructed to avoid grapefruit or grapefruit juice, starfruit, or Seville oranges.
12. Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or physical (e.g., infectious) illness. 
3.4
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment will only be during the pre-
operative window of 14-21 days or up to 28 days for delays in planned surgery or until:

Progressive disease at any time 

Any clinical adverse event, laboratory abnormality or intercurrent illness which, in the 
opinion of the Investigator, indicates that continued treatment with study therapy is not in 
the best interest of the participant 

Excessive toxicity 

Withdrawal of informed consent (participant’s decision to withdraw for any reason) 

Pregnancy 

All women of childbearing potential should be instructed to contact the 
Investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 

The Investigator must immediately notify Incyte in the event of a confirmed 
pregnancy in a patient participating in the study.

Study Closure or termination

Noncompliance
3.5
Duration of Follow Up
Patients will be followed for up to 12 weeks post-operation, as deemed clinically necessary or 
removal from study, or until death, whichever occurs first. Patients removed from study for 
unacceptable treatment related adverse event(s) will be followed until resolution or stabilization 
of all treatment related adverse events to Grade 2 or lower.
3.5.1 Procedures for discontinuation 
Participants who discontinue should, if possible, be seen and assessed by an investigator(s). 
The reason for withdrawal and the date of withdrawal must be documented. If possible, any 
diary cards and investigational products should be returned by the participant as soon as 
possible after study discontinuation. If patient had screening tissue samples obtained, has taken 
at least 14 days of drug, and has undergone response assessment, they are evaluable. 
If the reason for withdrawal from the trial is the death of the participant, the two options for 
categorizing withdrawal are either disease recurrence or an adverse event (AE; more than one 

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AE may be documented as a reason for withdrawal). Only one event will be captured as the 
cause of death. 
Note: death is an outcome and not an AE. All deaths that occur within the trial period or within 
30 days after administration of the last dose of trial drug must be reported to Incyte primarily for 
the purposes of serious adverse event (SAE) reporting; however, deaths due unequivocally to 
progression are not SAEs. 
3.6
Study Timeline
3.6.1 Primary Completion
The study will reach primary completion 24 months from the time the study opens to accrual.
3.6.2 Study Completion
The study will reach completion 36 months from the time the study opens to accrual.
4
Study Drugs
4.1
Description, Supply and Storage of Investigational Drugs
4.1.1 Ruxolitinib (JAKAFI®, INCB018424)
Ruxolitinib is dosed orally, every morning and every evening, and can be administered with or 
without food. If a dose is missed, the patient should not take an additional dose, but should take 
the next scheduled prescribed dose. In the case of emesis, the patient should not take an 
additional dose, but should take the next scheduled prescribed dose. For patients unable to 
ingest tablets, ruxolitinib can be administered through a nasogastric or percutaneous 
gastrostomy tube (8 French or greater) as follows: 

Suspend three or four 5 mg tablets (dose dependent according to platelet count, as 
described under “Study drug treatment” in section 5.2) in approximately 40 mL of water 
with stirring for approximately 10 minutes. 

Within 6 hours after the tablets have dispersed, the suspension can be administered 
through the feeding tube using an appropriate syringe. 
The tube should be rinsed with approximately 75 mL of water. The effect of tube feeding 
preparations on ruxolitinib exposure during administration through a nasogastric tube has not 
been evaluated. 
Participants will be asked to indicate on a drug diary (see Appendix 4) when doses of study drug 
are taken in order to monitor for compliance. Participants may also use the drug diary for 
notations on side effects and other treatment related events. The Investigational Pharmacy will 
maintain a drug accountability log to record ruxolitinib received, dispensed and/or destroyed. 
Unused drugs will be destroyed locally and will not be returned. 
NOTE: for current information, please see the most recent version of the Investigator Brochure
Classification

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Ruxolitinib is a Class I molecule under the Biopharmaceutical Classification System, with high 
permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib is 
rapidly absorbed after oral administration with maximal plasma concentration (Cmax) achieved 
approximately 1 hour post-dose
Mechanism of Action
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel, 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.
Metabolism
Ruxolitinib was eliminated predominantly by oxidative metabolism (leading to hydroxylated 
metabolites M7, M8, M14 and M18 and keto metabolites M14 and M18 (Figure 4-1), followed in 
some cases by limited subsequent glucuronidation in humans and animal species
Contraindications
Hypersensitivity to the active substance or any of the excipients.
Potential Drug-Drug Interactions
Ruxolitinib is primarily protein bound (97%) and is metabolized by CYP3A4 in the liver. 
Significant drug-drug interaction may occur when ruxolitinib is administered with inducers or 
inhibitors of CYP3A4. Concomitant administration of ruxolitinib with strong inhibitors of CYP3A4 
such as ketoconazole may lead to significant increases in Cmax, AUC, and half-life, thus such 
patients should not be included on study. No dose adjustment is recommended when ruxolitinib 
is administered with mild inhibitors or inducers of CYP3A4, although these patients should be 
carefully monitored. Grapefruit juice is also a potent CYP3A4 inhibitor, thus the consumption of 
grapefruit juice should be avoided during ruxolitinib treatment.
Warnings and Precautions
Based on clinical experience to date in myelofibrosis, the following adverse effects may be 
associated with ruxolitinib: thrombocytopenia, anemia, neutropenia, bruising dizziness, 
headache, urinary tract infection, weight gain, flatulence, and herpes zoster. Thrombocytopenia, 
anemia, and neutropenia are dose-related effects, which occur at a median of 8 weeks after 
initiation of ruxolitinib, and in studies of longer duration have been generally treated by 
withholding ruxolitinib. Occasionally patients with anemia may require a transfusion. Patients 
taking ruxolitinib may be at risk for infection and should be monitored for this. The incidence of 
clinically significant hematologic toxicity is expected to be very low in the current study 
population, due to the short ruxolitinib exposure, as well as the absence of a primary bone 
marrow malignancy predisposing to hematologic toxicity.
Some people who take ruxolitinib have developed certain types of non-melanoma skin cancers. 
Availability
All tablets are oval and white with “INCY” on one side and “25” on the other. Additional 
information regarding ruxolitinib can be found in the package insert.
Storage and handling

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In addition to the active ingredient, each ruxolitinib tablet contains microcrystalline cellulose, 
lactose monohydrate, magnesium stearate, colloidal silicone dioxide, sodium starch glycolate, 
povidone, and hydroxypropyl cellulose. Ruxolitinib will be supplied as 5 mg tablets in bottles 
containing 60 tablets each. Labels contain, at a minimum, the following information: product 
name, tablet strength, batch number, directions for use, storage conditions, and appropriate 
caution statements. Ruxolitinib tablets should be stored in a secure area at 25˚C (77oF); 
excursions permitted between 15˚-30˚C (59˚-86˚F). 
Side Effects
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and/or product package insert. 
4.2
Drug Accountability
The Investigational Pharmacist will manage drug accountability records. Damaged supplies will 
be destroyed at the study site and adequate records of the damaged supplies will be kept at the 
site. Study investigators will be responsible for drug accountability. 
4.3
Drug Ordering
Ruxolitinib will be supplied by Incyte Pharmaceuticals. 
4.4
Packaging and Labeling of Study Drugs
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws.
5
Treatment Plan
5.1
Dosage and Administration
Treatment will be administered on an outpatient basis.
Table 5.1
Regimen Description
Study Drug
Dose
Route
Schedule
Cycle Length
Ruxolitinib
20mg or 15mg 
dependent on baseline 
platelet count
PO
BID
Pre-operative window (14-21 
days) or up to 28 days for delayed 
surgery
5.2
Dose De-escalation Rule
A continuous monitoring rule for safety will be instituted, to guard against excess toxicity from 
pre-operative treatment with ruxolitinib at the FDA-indicated starting dose for patients with 
myelofibrosis (20 mg bid for patients with a platelet count ≥ 200,000 or 15 mg bid for patients 
with a platelet count ≥ 150,000 and < 200,000). See section 8.3.3 Safety Lead-In
Table 5.2 below describes the number of toxicity events per number of treated patients required 
to trigger the ruxolitinib de-escalation rule. Table 8 also shows the posterior probability that the 
rate exceeds 33%, and the binomial probability associated with the decision for an assumed 

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33% discontinuation rate. The prior probability has a beta distributions with parameters a = 1 
and b = 9, assumes a 10% mean with an approximate 80% mid-range of .0 to .22.
Table 5.2 Boundaries for the De-Escalation Rule
Participants
Treatment-Related 
Discontinuations
PP(π > 33%)*
Pr(X ≥ r|p = .33)
6
5
.629
.017
8
6
.685
.019
11
7
.673
.037
14
8
.664
.054
17
9
.657
.071
20
10
.650
.087
23
11
.645
.101
27
12
.594
.145
30
13
.592
.156
33
14
.590
.167
*π is the discontinuation rate. The minimum acceptable upper bound of a treatment-related discontinuation is 33%. 
PP(π > 33%) is the posterior probability that the discontinuation rate exceeds this 33% upper bound. This posterior 
probability of discontinuation is calculated from the prior distribution, the number of participants treated and the 
observed number of treatment-related discontinuations.
5.3
Procedures in Case of Overdose
There are no known antidotes for ruxolitinib. The treatment of AEs associated with overdose 
should be supportive for the underlying adverse symptoms.
Single doses up to 200 mg have been given with acceptable acute toxicity. Doses of study 
treatment in excess of that specified (20 mg twice daily) in the clinical study protocol are 
considered to be an overdose. Overdose, with or without associated symptoms, should be 
handled in the same way as a SAE. Signs or symptoms of an overdose that meet the criteria of 
SAE should be reported as a SAE in the appropriate manner and be documented as clinical 
sequelae to an overdose. 
5.4
Procedures in Case of Pregnancy
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive treatment. All reports of 
congenital abnormalities/birth defects are SAEs. Any SAE experienced during pregnancy must 
be reported on the SAE Report Form. Elective terminations for medical reasons, and any 
serious complications of pregnancy (including spontaneous miscarriage) should be reported as 
SAEs. Elective abortions without complications should not be handled as SAEs. 
The time period for collecting information on the occurrence of a pregnancy is from first 
administration of study treatment up to and including the follow up period. The outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality/birth defects) must be followed up and documented even if the participant was 
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5.5
Dose Modifications and Dosing Delays
The following dose modification rules will be used with respect to potential toxicity. Toxicity will 
be assessed according to the NCI Common Terminology Criteria for Adverse Events Version 
4.0 (CTCAE v4.0).
Ruxolitinib is approved for use in myelofibrosis at the dose of 20 mg po bid when the baseline 
platelet count > 200,000, 15 mg po bid when the baseline platelet count is > 100,000 but ≤ 
200,000, and 5 mg bid when the baseline platelet count is > 50,000 but ≤ 100,000. Ruxolitinib is 
approved in polycythemia vera at the dose of 10 mg po bid.
Dose reductions will not be allowed. Treatment delays up to 1 week are permitted as follows: 

If participants experience any grade 3-4 ruxolitinib-related non-hematologic toxicities in 
the neo-adjuvant window, the study drug will be discontinued and they will be removed 
from the study. (Exception: Patients with asymptomatic grade 3 electrolyte abnormalities 
manageable with repletion) Patients may also be removed from study for intolerable 
non-hematologic toxicities of any grade, which persist despite optimal medical 
management.

If participants experience grade ≥ 3 thrombocytopenia or neutropenia, ruxolitinib will be 
discontinued and they will be removed from the study.

Grade 3 anemia does not require discontinuation from protocol. Patients may be 
transfused per discretion of the treating physicians.

For mild or moderate (grade 1 or 2) side effects that are difficult to tolerate, treatment 
may be held for up to 1 week. Treatment may be resumed at the same dose, if there is 
improvement by at least one grade. Dose delays more than 1 week will not be permitted. 
If treatment is restarted, study physicians should aim for at least 3 days of ruxolitinib 
exposure prior to planned surgery.
In two Phase 3 clinical studies of ruxolitinib in myelofibrosis, the median time to onset of first 
CTCAE grade two or higher anemia was 6 weeks, and approximately 8 weeks until onset of 
grade 3 or 4 thrombocytopenia. In nearly all cases, ruxolitinib-induced anemia and 
thrombocytopenia could be reversed with dose reduction or interruption; occasionally red blood 
cell or platelet transfusions were required. Thus, given the short 2-3 weeks of treatment during 
this study, it is expected that few, if any, participants will develop hematologic abnormalities. 
Moreover, participants in the current study do not have a primary bone marrow malignancy 
which is the target of ruxolitinib and thus predisposes to hematologic toxicity. Any participants 
that experience anemia or thrombocytopenia may be transfused if deemed necessary by the 
treating physician.
Although clinically significant hematologic and non-hematologic toxicity is unexpected during the 
14-21 days of protocol treatment in patients with operable HNSCC, a continuous monitoring rule 
for excess toxicity will be instituted. Please see Section 5.6 below.
5.6
Monitoring and Toxicity Management
Each patient receiving ruxolitinib will be evaluable for safety. The safety parameters include all 
laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of 
adverse events reported to the investigator by patients.
Each patient will be assessed periodically for the development of any toxicity as outlined in 
Section 6 Study Procedures and Observations. Toxicity will be assessed according to the NCI 

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CTCAE v4.0. Dose adjustments will be made according to the system showing the greatest 
degree of toxicity. 
We will monitor for the following anticipated adverse events:
Anemia 
In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher 
anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of 
anemia. In patients receiving ruxolitinib, mean decreases in hemoglobin reached a nadir of 
approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually 
recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This 
pattern was observed in patients regardless of whether they had received transfusions during 
therapy. 
In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of 
patients receiving placebo received red blood cell transfusions during randomized treatment. 
Among transfused patients, the median number of units transfused per month was 1.2 in 
patients treated with ruxolitinib and 1.7 in placebo treated patients. 
Thrombocytopenia 
In the two Phase 3 clinical studies, in patients who developed Grade 3 or 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 4.7% of 
patients receiving ruxolitinib and to 4.0% 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 4 thrombocytopenia 
compared to patients with a platelet count greater than 200 X 109/L (16.5% versus 7.2%). 
Neutropenia 
In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped ruxolitinib because of 
neutropenia.
Table 5.6 provides the frequency and severity of clinical hematology abnormalities reported for 
patients receiving treatment with Jakafi or placebo in the placebo-controlled study.
Table 5.6 Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya 
Jakafi (N=155)
Placebo (N=151)
Laboratory 
Parameter
All Gradesb 
(%)
Grade 3 
(%)
Grade 4 
(%)
All Grades 
(%)
Grade 3 
(%)
Grade 4 
(%)
Thrombocytopenia 
69.7
9.0
3.9
30.5
1.3
0
Anemia 
96.1
34.2
11.0
86.8
15.9
3.3
Neutropenia 
18.7
5.2
1.9
4.0
0.7
1.3
a Presented values are worst Grade values regardless of baseline
b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 

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Additional Data from the Placebo-controlled Study 
25.2% of patients treated with ruxolitinib and 7.3% of patients treated with placebo developed 
newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The 
incidence of greater than or equal to Grade 2 elevations was 1.9% for ruxolitinib with 1.3% 
Grade 3 and no Grade 4 ALT elevations. 
17.4% of patients treated with ruxolitinib and 6.0% of patients treated with placebo developed 
newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The 
incidence of Grade 2 AST elevations was 0.6% for ruxolitinib with no Grade 3 or 4 AST 
elevations. 
16.8% of patients treated with ruxolitinib and 0.7% of patients treated with placebo developed 
newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 
cholesterol elevations was 0.6% for ruxolitinib with no Grade 3 or 4 cholesterol elevations. 
6
Study Procedures and Observations
The study-specific procedures and assessments are outlined in the Study Calendar – Section 
6.1.
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product. Any results falling outside of the reference ranges may be repeated at 
the discretion of the investigator.
All on-study visit procedures are allowed a window of ±5 days unless otherwise noted. 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation.

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6.1
Study Calendar
Table 6.1
Schedule of Study Procedures and Assessments
Treatment Period
Study Procedures
Screening
Days 1 thru 14 
to 21
Days 22 thru 28
(if surgery is 
delayed)
Pre-surgery visit
(within 5 days prior 
to surgery)
Surgery
(between 14-28 
days of ruxolitinib 
start)g
4-week 
post-op 
visit
Final study 
visit
(12-week post-
op)
Informed Consent
X
History and Physical 
Examinationa
X
X
X
X
Vital Signs, Weight
X
X
X
X
ECOG-PS
X
X
X
X
Pregnancy Testb
X
EKGc
X
Clinical Blood Testsd
X
X
X
X
Cross-sectional imaging 
studye
X
X
Research Blood 
Collectionh
X
X
Ruxolitinibf
X
X
X (take until morning 
of surgery)
Surgeryg
X
Tumor samplei
X
X
Archival tissue 
collection
X
a.
History and physical examination within 8 weeks prior to study entry. This should include surgical assessment of the primary tumor, including fiberoptic 
nasopharyngoscopy or examination under anesthesia as indicated per standard of care, and as determined by the treating surgeon. Patients will be 
reevaluated within 5 days prior to scheduled surgery. Toxicity and compliance as evidenced by pill count and patient diaries will be assessed. 
b.
Pre-menopausal women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test within 4 weeks of registration. A negative 
pregnancy test must then be documented within 72 hours of Day 1 of ruxolitinib treatment. 
c.
The standard of care EKG performed for pre-surgical evaluation should be used. EKGs performed within 12 weeks prior to study entry may be substituted, 
provided the patient has experienced no interval cardiac event.

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d.
Clinical blood tests include CBC with differential (to include total white blood cell count, absolute neutrophil count, hemoglobin, hematocrit and platelets), 
serum chemistries (to include sodium, potassium, chloride, HCO3, BUN, creatinine, glucose, magnesium and calcium), liver function tests (to include total 
bilirubin, AST, ALT, total protein, albumin and alkaline phosphatase), coagulation studies (PT/INR and PTT), and C-reactive protein (CRP). Clinical blood tests 
will be repeated once within 5 days prior to surgery, and at the 4-week and 12-week post-operative visits if clinically indicated according to the investigator. 
Coagulation studies are not required at the 4 week or 12 week post-surgical visits. 
e.
Within 6 weeks of study entry (within 4 weeks preferred), and again within 5 days prior to planned surgery, patients will undergo cross-sectional radiological 
evaluation using diagnostic contrasted CT, PET/CT (with diagnostic contrasted CT), or MRI of regions with radiologically or clinically identifiable tumor. The 
minimum cross-sectional evaluation is a diagnostic, contrasted computed tomography (CT) scan of the neck. PET/CT is the preferred modality, provided it 
includes a diagnostic, contrasted CT scan of the neck – however is not mandatory. For patients with severe allergy to iodinated contrast dye despite 
premedication, or in the case of physician preference, neck MRI may be substituted. The pre- and post-treatment imaging modality should be the same, i.e. if 
MRI was used at study entry, it should be used at the post-treatment, pre-surgical assessment. NOTE: in the event that a patient lacks a CT-measurable 
primary tumor or metastatic lymph node, measurable disease may also be established by caliper measurement of an oral cavity or oropharyngeal tumor (≥ 1 
centimeter). In this case, caliper measurement should be repeated within 5 days prior to planned surgery.
f.
The first day of ruxolitinib treatment will be considered Day 1. Ruxolitinib will be administered at 20 mg po bid, for 1421 days, and will be discontinued on the 
day of surgical resection (following the morning dose). If surgery is delayed, the study drug may be continued until surgery, for a maximum of 28 days. The 
interval between the last dose of ruxolitinib and surgery will be 2-24 hours.
g.
Surgery will be scheduled during days 14-21 of ruxolitinib treatment. For logistical reasons, surgery may be delayed by up to 7 days. Postoperative 
complications, hospital days, and ICU days will be noted for each patient. 
h.
Research blood samples will be obtained at screening and within the 5 days prior to scheduled surgery. One (1) purple top EDTA tube will be collected at 
each time point. Please refer to the laboratory SOPs for processing instructions.
i.
Archival tissue if available. If no archival tissue is available participants must undergo tissue biopsy at baseline. Research biopsies obtained at screening 
during planned surgery for resection of the tumor will be divided into fresh, fresh-frozen and paraffin specimens.
j.
Patients will be seen for a standard 4 week post-operative visit (+/- 2 weeks), and again for a standard 12-week post-operative visit (+/- 4 weeks). Clinical 
blood tests will be obtained as deemed clinically necessary. Thereafter, patients will be followed off study per standard of care.

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6.2
Participant Registration
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF will be given to the participant and a copy 
will be filed in the medical record. The original will be kept on file with the study records. 
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system is 
password protected and meets HIPAA requirements.
Each participating site is responsible for OnCore® registration of study participants consented at 
the site.
6.3
Schedule of Procedures and Observations
6.3.1 Screening Period
Pretreatment or Screening Evaluations (Baseline, within 4 weeks prior to study registration 
unless otherwise specified)
Required screening evaluations include: 

Tumor tissue sample:
o
Patients who have had research tissue procured under an omnibus tissue 
consent, who are determined to have sufficient fresh, fresh-frozen, and paraffin 
tissue for biomarker analysis, may substitute the archived tissue and do not need 
to undergo screening research biopsy provided no interval anti-neoplastic 
therapy was given.
o
Baseline research biopsy: If no archival tissue is available participants must 
undergo tissue biopsy at baseline (see below):

Examination under anesthesia (EUA) with triple endoscopy is strongly 
recommended, if not previously performed and/or if an appropriate 
standard of care for surgical staging. EUA may include direct 
laryngoscopy, bronchoscopy and esophagoscopy in order to fully 
evaluate the extent of primary tumor and rule out evidence of a second 
primary aerodigestive tract tumor. A thorough description of the 
anatomical extent of the head and neck primary tumor will be detailed by 
the surgeon in the EUA operative report. Biopsy of the primary tumor for 
diagnosis, if not already done, will be performed during the EUA 
according to standard pathologic procedures. Research biopsy of the 
primary tumor for biomarker studies during the EUA is required if no 
archival tissue is available. Alternately, patients for whom an in-office 
biopsy with local anesthesia is feasible may have the baseline research 
biopsy performed in the outpatient office of the otolaryngologist or head 
and neck surgeon.
o
Tissue for biomarker analysis will be processed according to procedures 
described in Appendix 5. 

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
Blood collection. The patient is required to undergo blood collection for biomarker 
assessment. For logistical purposes, research labs may be drawn simultaneous with 
blood labs required for standard clinical management.
o
Blood for biomarker analysis will be processed according to procedures 
described in Appendix 5.

History and physical examination, to include surgical and medical evaluation, within 8 
weeks prior to study registration, including a careful description of the location and 
extent of the primary lesion and nodal spread. Fiberoptic 
nasopharyngoscopy/laryngoscopy is recommended, unless fiberoptic exam is deemed 
unnecessary by the treating surgeon. 

Vital signs, weight, height within 8 weeks prior to study registration

ECOG Performance Status within 8 weeks prior to study registration 

Laboratory studies including CBC with differential (to include total white blood cell count, 
absolute neutrophil count, hemoglobin, hematocrit and platelets), serum chemistries (to 
include sodium, potassium, chloride, carbon dioxide, BUN, creatinine, glucose, 
magnesium and calcium), liver function tests (LFTs; to include total bilirubin, AST, ALT, 
total protein, albumin and alkaline phosphatase), coagulation studies (PT/INR and PTT), 
and C-reactive protein (CRP). 

Negative serum pregnancy test within 4 weeks of study registration in WOCBP. Note, 
the clinical research coordinator or treating investigator will document an additional 
negative pregnancy test within 72 hours of starting ruxolitinib treatment.

Cross-sectional radiologic evaluation within 6 weeks of study registration (within 4 weeks 
is preferred). The minimum cross-sectional evaluation is a diagnostic, contrasted 
computed tomography (CT) scan of the neck. PET/CT is the preferred modality, 
provided it includes a diagnostic, contrasted CT scan of the neck – however is not 
mandatory. For patients with severe allergy to iodinated contrast dye despite 
premedication, or in the case of physician preference, neck MRI may be substituted. If 
MRI is used for baseline imaging, it should also be used for response assessment (post-
treatment, pre-surgical imaging). This is standard of care for baseline assessment. The 
post treatment assessment is research.

EKG. The standard of care EKG performed for pre-surgical evaluation should be used. 
EKGs performed within 12 weeks prior to study registration may be substituted, provided 
the patient has experienced no interval cardiac event.
6.3.2 Treatment Period
Days 1-28; NOTE ruxolitinib treatment is planned for 14-21 days, however may be administered 
up to 28 days if required for logistical/scheduling purposes.
6.3.2.1 Day 1
Ruxolitinib will be administered at the FDA-approved dose in myelofibrosis, as determined by 
baseline platelet count: 1) Patients with a platelet count ≥ 200,000 will take 20 mg bid (four 5mg 
tablets in the morning and four 5mg tablets in the evening); 2) participants with a platelet count 
≥ 150,000 and < 200,000 will take 15 mg bid (three 5 mg tablets in the morning and three 5 mg 
tablets in the evening). Ruxolitinib will be discontinued on the day of surgical resection (following 
the morning dose). If surgery is delayed, the study drug may be continued until surgery, for a 

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maximum of 28 days. Fourteen days is the minimum required treatment for a patient to be 
considered evaluable. The interval between the last dose of ruxolitinib and surgery will be 2-24 
hours. 
Ruxolitinib will be dispensed as 5mg tablets. Participants with a platelet count ≥ 200,000 will 
take 20 mg bid (four 5mg tablets in the morning and four 5mg tablets in the evening). 
Participants with a platelet count ≥ 150,000 and < 200,000 will take 15 mg bid (three 5 mg 
tablets in the morning and three 5 mg tablets in the evening). 
Participants will be asked to indicate on a drug diary (see Appendix 4) when doses of study drug 
are taken in order to monitor for compliance. Participants may also use the drug diary for 
notations on side effects and other treatment related events.
6.3.2.2 Day 9-28 (inclusive of day of surgery)
Post-treatment, pre-surgical 
NOTE: all efforts should be made to schedule these evaluations on the day prior to or the day of 
surgery, however a 5 day window is provided for logistical purposes.

History and Physical Examination (Post-treatment, Pre-operative): Participants will be 
evaluated by history and physical examination by the treating physician within 5 days 
prior to planned surgery (including vital signs, weight, performance status). This visit will 
also include toxicity and compliance assessment. Compliance as evidenced by pill count 
and patient drug diary will be assessed. For logistical convenience, this visit may be 
scheduled in conjunction with blood collection and imaging as specified below. NOTE: 
Participants will continue to take ruxolitinib until the morning of planned surgery. If 
surgery is delayed, participants will continue to take ruxolitinib and this pre-operative 
history and physical examination does not need to be repeated.

Blood Collection (Clinical and Research Blood): Participants will undergo repeat CBC 
with differential, serum chemistries, LFTs, coagulation studies and C-reactive protein 
within 5 days prior to planned surgery. Research blood will be drawn simultaneously with 
these standard pre-operative labs. NOTE: Participants will continue to take ruxolitinib 
until the morning of planned surgery. If surgery is delayed, participants will continue to 
take ruxolitinib and these pre-operative blood tests do not need to be repeated.

Cross-sectional Imaging for Tumor Measurements (Research): Participants will undergo 
a repeat diagnostic CT scan of the neck with IV contrast within 5 days prior to planned 
surgery. If a neck MRI was performed in lieu of CT scan at baseline, then a MRI should 
be substituted at response assessment. NOTE: Participants will continue to take 
ruxolitinib until the morning of planned surgery. If surgery is delayed, participants will 
continue to take ruxolitinib and this pre-operative imaging does not need to be repeated.
NOTE: in the event that a patient lacks a CT-measurable primary tumor or metastatic 
lymph node, measurable disease may be established by caliper measurement of an oral 
cavity or oropharyngeal tumor (≥ 1 centimeter). In this case, caliper measurement should 
be repeated and documented within 5 days prior to planned surgery, as a substitute for 
cross-sectional imaging.

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6.3.2.3 Surgery (Occurring Between Days 14-28, Inclusive)
The nature of complete resection of the primary head and neck tumor, type of reconstruction, 
and levels of nodes to be dissected will be determined by the treating surgeon. Prior to surgery, 
dental evaluation is recommended, to allow for any necessary dental extractions to be planned 
in conjunction with surgery. Consultations with a Nutritionist and Speech and Language 
Pathologist are strongly recommended prior to surgery and as ongoing support. Placement of a 
nasogastric (e.g. Dobhoff) or gastrostomy feeding tube is at the discretion of the participant and 
the study physicians. Following 14-21 days (+ 7 days if required for logistical and scheduling 
purposes) of treatment prior to participant’s scheduled surgery, a surgeon will resect the 
participant’s tumor (days 14-28). Part of the tumor specimen will be sent to the research 
laboratory for mandatory biomarker analyses. If surgery is unexpectedly cancelled, the patient 
will be removed from the study unless the primary tumor is accessible for in-office biopsy in the 
judgment of the surgeon-investigator, in which case a tumor biopsy may be substituted for the 
operative specimen. Tissue collection procedures are described in Section 9.0. 
6.3.2.4 Post-operative therapy
After surgery, participants may receive adjuvant radiation or radiation plus chemotherapy in 
accordance with appropriate standards, as determined by the participant’s treating physicians.
6.3.3 End-of-Treatment/Final Study Visit Procedures
A standard history and physical examination and blood tests as clinically indicated (CBC, 
chemistries, liver function tests in accordance with investigator judgment) will be performed 4 
weeks (+/- 2 week) and 12 weeks (+/- 4 weeks) post-surgery. Additional non-protocol visits may 
occur during the 12-week post-operative period as deemed clinically necessary. Patients will be 
referred for adjuvant chemotherapy and radiation per standard of care, based upon pathologic 
findings. Once the first 12 weeks of follow-up have been completed, study follow-up will be 
discontinued and participants will continue standard treatment and surveillance in accordance 
with national guidelines. 
The standard post-operative visit which occurs 12 weeks post-op (+/- 4 weeks) will be 
considered the “final study visit.” 
Post-Therapy Radiologic Evaluation
Within 6 weeks prior to registration (within 4 weeks preferred), and again within the 5 days prior 
to planned surgery, patients will undergo cross-sectional radiological evaluation using diagnostic 
contrasted CT, PET/CT (with diagnostic contrasted CT), or MRI of regions with radiologically or 
clinically identifiable tumor. The minimum cross-sectional evaluation is a diagnostic, contrasted 
computed tomography (CT) scan of the neck. PET/CT is the preferred modality, provided it 
includes a diagnostic, contrasted CT scan of the neck – however is not mandatory. For 
patients with severe allergy to iodinated contrast dye despite premedication, or in the case of 
physician preference, neck MRI may be substituted. The pre- and post-treatment imaging 
modality should be the same, i.e. if MRI was used at study entry, it should be used at the post-
treatment, pre-surgical assessment. Modified Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1)37 criteria will be used to establish target lesions. 
NOTE: in the event that a patient lacks a CT-measurable primary tumor or metastatic lymph 
node, measurable disease may also be established by caliper measurement of an oral cavity or 

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oropharyngeal tumor (≥ 1 centimeter). In this case, caliper measurement should be repeated 
within 5 days prior to planned surgery.
6.4
Usage of Concurrent/Concomitant Medications
6.4.1 Dietary Restrictions
Patients will be instructed to avoid grapefruit or grapefruit juice, starfruit, or Seville oranges.
6.4.2 Prohibited Medications
Strong CYP3A4 inhibitors. For eligibility, patients must discontinue drug 7 days prior to starting 
ruxolitinib, including but not limited to boceprevir, clarithromycin, conivaptam, indinavir, 
itraconazle, ketoconazole, lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, or voriconazole.
7
Reporting and Documentation of Results
7.1
Evaluation of Efficacy: Antitumor Effect – Solid Tumors
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria (or International Workshop on Chronic 
Lymphocytic Leukemia [IWCLL]).
7.1.1 Definitions
Evaluable for toxicity
All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
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.)
7.1.2 Disease Parameters
Measurable disease
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung).
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters. 
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy.

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Target lesions
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline. Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.
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. It is possible to record multiple non-target lesions involving the same organ as a single 
item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”). Bone lesions may be measureable if ≥ 1 cm on MRI.  Measurements of these 
lesions are not required, but the presence or absence of each will be noted throughout follow-
up.
Non-measurable disease (Tumor Markers)
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan). 
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non-
measurable. (e.g., PSA, CA-125, CA19-9, CEA)
7.1.3 Methods for Evaluation of Measurable Disease
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment.
The same method of assessment and the same technique will 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 when both methods have been used to assess 
the antitumor effect of a treatment.
7.1.4 Response Criteria
Complete Response (CR)
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart. Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes). There 
can be no appearance of new lesions.

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Partial Response (PR)
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD. There can be no appearance of new lesions.
Progressive Disease (PD)
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started.
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).
Incomplete Response/Stable Disease (SD)
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.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression.
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 target lesion diameters (longest diameter of non-nodal 
lesions; short axis diameter of the target lymph nodes), /recurrence (taking as reference the 
baseline sum diameter.
Progressive Disease (PD)
At least a 20% increase in the sum of target lesion diameters (longest diameter of non-nodal 
lesions; short axis diameter of the target lymph nodes), taking as reference for progressive 
disease the smallest sum diameter measurements recorded since the baseline sum diameter 
measurements. 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. The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.

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Table 2.1
Response Criteria
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response for this Category 
Also Requires
CR
CR
No
CR
> 4 weeks confirmation
CR
Non-CR/
Non-PD
No
PR
PR
Non-PD
No
PR
> 4 weeks confirmation
SD
Non-PD
No
SD
documented at least once > 4 weeks 
from baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression
Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression.
7.2
Evaluation of Safety
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE v4.0 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events, see Appendix 2.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.
7.3
Definitions of Adverse Events
7.3.1 Adverse Event
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related. More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality. An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.3.2 Adverse Reaction
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event.
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 

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“reasonable possibility” indicates that there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree 
of certainty about causality than an adverse reaction.
7.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure. For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure.
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation. Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes.
7.3.2.3 Serious
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 

Death

Life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function

Congenital anomaly/birth defect
Important medical events that may not result in death, are life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.

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1.
In the event of a serious adverse event, the PI, the institutional review board (per 
institutional reporting requirements), and Incyte Corporation will be notified using the 
FDA Form 3500 MedWatch report. All events meeting the definition of a serious adverse 
event should be recorded on a MedWatch 3500 Form 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM163919.p
df ) and submitted to:DSMC
2.
Local IRB per institutional reporting requirements
3.
FDA
4.
Incyte

In addition to completing appropriate patient demographic and suspect medication 
information, the report should include as applicable the following information that is available 
at the time of report within the Event Description (section 5) of the MedWatch 3500 
form:CTCAE term(s) and grade(s) 

Current status of study drug

All interventions to address the AE (testing and result, treatment and response)

Hospitalization and/or discharge dates

Event relationship to study drug
7.3.2.4 Life-threatening
An adverse event or suspected adverse reaction is considered life threatening if, in the view of 
either the investigator or sponsor, its occurrence places the patient or participant at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
7.4
Recording of an Adverse Event
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug. Data about these events and their severity 
will be recorded using the NCI CTCAE v4.0. 
The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
Relationship 
Attribution 
Description 
Unrelated
The AE is clearly NOT related to the 
intervention 
Unrelated to investigational 
drug/intervention
Unlikely
The AE is doubtfully related to the 
intervention 
Possible
The AE may be related to the intervention 
Probable
The AE is likely related to the intervention 
Related to investigational 
drug/intervention
Definite
The AE is clearly related to the intervention 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE. When specific adverse events are not listed in the CTCAE, they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions:

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Grade 0
No AE (or within normal limits)
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL)
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
7.5
Follow-up of Adverse Events
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the participant with the investigational drug 
may be conducted if considered both safe and ethical by the Investigator.
Follow-up Reports:
Additional information may be added to a previously submitted report by adding to the original 
MedWatch 3500 report and submitting it as follow-up or creating supplemental summary 
information and submitting it as follow-up with the original MedWatch 3500 form.
7.6
Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above.
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board, 
the Institutional Review Board (IRB); and, when the study is conducted under an Investigational 
New Drug Application (IND), to the Food and Drug Administration (FDA) if it meets the FDA 
reporting criteria.
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
Comprehensive Cancer Center Site Committee on a weekly basis. The Site Committee will 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s).
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and the attribution of relationship of the adverse event to the administration of 
the study drug(s).
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks.

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For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 2.
7.7
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event. The contact may be by 
phone or e-mail.
Reporting to UCSF Institutional Review Board (Institutional Review Board)
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 5 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Reporting to Pharmaceutical Companies providing Study Drug
Incyte Corporation, Adverse Events Reporting (within 24 hours of learning of the SAE):
Phone: (855) 463-3463 

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8
Statistical Considerations and Evaluation of Results
8.1
Study Endpoints
This is a phase II open label study to identify baseline and/or pharmacodynamics biomarkers of 
clinical response to ruxolitinib based on quantitative change in tumor size following 14-21 days 
of neoadjuvant ruxolitinib in patients with operable HNSCC. Clinical response will be defined by 
the change of the ΔTumor size between two measurements during study windows. 
8.2
Determination of Sample Size and Accrual Rate
8.2.1 Sample Size and Power Estimate
The primary objective of the study is to identify baseline and/or pharmacodynamic biomarkers 
that might have predictive utility to determine the clinical response to ruxolitinib. As a biomarker 
study, the statistical design is to accrue a sufficient number of patients and provide 80% power 
to test one or any of 5 key hypotheses with a shared alpha of 0.15: 1) relationship between 
clinical response (ΔTumor size) and baseline STAT activation (pSTAT3 expression); 2) 
relationship between clinical response (ΔTumor size) and change in expression of pSTAT3; 3) 
relationship between responders (ΔTumor size) and change in expression of cyclin D1; 4) 
relationship between clinical response (ΔTumor size) and baseline genetic or epigenetic PTPRT 
or PTPRD silencing; 5) relationship between responders (ΔTumor size) and baseline C-reactive 
protein. An overall alpha of .15 will be shared equally among the five primary hypotheses. 23 
patients with complete biomarker data are needed to achieve 80% power for the 5 primary 
hypothesis and limit overall family wise error rate (FWER) to 15%. As estimated from our prior 
window trials, accounting for treatment compliance and quality paired tumor specimens, this will 
require enrollment of 45 patients. For each biomarker (baseline pSTAT3 expression, change 
from baseline of pSTAT3 expression, change from baseline of cycline D1 expression, baseline 
PTPRT or PTPRD silencing and baseline C-reactive protein), mean and standard deviation will 
be estimated and compared for significance between clinical responders and non-responders of 
ruxolitinib therapy using Wilcoxon rank tests. Our experience with our phase 0 clinical trial 
testing the STAT3 decoy also showed correlations between ΔKi-67 (the primary 
pharmacodynamic efficacy endpoint) and STAT3-target genes falling in the range of .50 to .67. 
Twenty-five patients will enable a two -tailed Spearman Correlation test at alpha = .03 to detect 
a true correlation of .56. For the expected 30% of patients with a PTPR mutation, a one-tailed 
Wilcoxon test will demonstrate increased sensitivity to ruxolitinib via a decrease in tumor size 
equal to 1.3 standard deviations with 23 patients (8 with a mutation). 
8.2.2 Replacement Policy
Because this is an open label study with limited number of patients, 23 accrued eligible patients 
with clinical tumor assessments and biomarkers measurements at baseline and the end of study 
window are required for the study. Additional patients will be enrolled to replace patients without 
clinical tumor assessments and completed biomarker measurements for both time points at 
least one of the five biomarkers of interest. However, all patients will be followed and included 
for safety assessments. 
8.2.3 Safety Lead-in
A continuous monitoring rule for safety will be instituted, to guard against excess toxicity from 
pre-operative treatment with ruxolitinib at the FDA-indicated starting dose for patients with 
myelofibrosis (20 mg bid for patients with a platelet count ≥ 200,000 or 15 mg bid for patients 
with a platelet count ≥ 150,000 and < 200,000). The first cohort of 6 patients will be treated at 
this starting dose. After enrollment of the 6th patient, we will continuously monitor the number of 

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patients who discontinue ruxolitinib and come off study for ruxolitinib-attributable toxicity. A 
qualifying toxicity must be at least possibly related to ruxolitinib, as judged by the treating 
investigator, and fulfill one of the following definitions:

Grade ≥ 3 non-hematologic toxicity, with the exception of asymptomatic electrolyte 
abnormalities manageable with repletion. 

Intolerable non-hematologic toxicities of any grade, which persist despite optimal 
medical management.

Grade ≥ 3 thrombocytopenia or neutropenia.
If the posterior probability of ≥ 33% toxicity rate exceeds 50% for patients having to discontinue 
window treatment due to qualifying toxicity, this would be considered unacceptable and would 
result in de-escalating the starting dose of ruxolitinib to 10 mg p.o. bid, the FDA-indicated 
starting dose in polycythemia vera, for all subsequent patients. This would be the starting dose 
in all patients with a qualifying platelet count for this study (≥150,000), including those with 
platelet count ≥ 150,000 and < 200,000 and those with platelet count > 200,000. (see section 
5.2 Dose De-Escalation Rule)
8.2.4 Accrual Estimates
Accrual of 2 evaluable patients per month is expected for total enrollment period of 
approximately 12 months.
8.3
Interim Analyses and Stopping Rules
This is an open label biomarkers study. No interim analysis is planned.
8.4
Analyses Plans
8.4.1 Analysis Populations
Safety Population
The safety population will include all enrolled patients who receive at least one dose of 
ruxolitinib and have the potential to complete pharmacodynamics biomarkers assessments at 
baseline and the end of study treatment window. Although the risk from specimen collections for 
biomarker assessment is limited and low, all patients will be evaluable for toxicity and safety 
assessment of ruxolitinib. Patients who are determined ineligible after enrollment or who are not 
evaluable for safety analysis (e.g. due to withdrawal of consent or failure of specimens 
collection as not related to tumor progression and not treatment-related toxicity) will be replaced 
(see section 8.2.2 for details).
Efficacy Population
The efficacy population for the primary endpoint of 35% or greater reduction in tumor size will 
include all enrolled patients who have measurable disease present at baseline and have 
completed tumor assessment at the end of study window. Patients who are determined 
ineligible after enrollment or who are not evaluable for safety analysis (e.g. due to withdrawal of 
consent or failure of specimens collection as not related to tumor progression and not treatment-
related toxicity) will be replaced (see section 8.2.2 for details).

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8.4.2 Primary Analysis (or Analysis of Primary Endpoints)
The primary objective of the study is to identify if one or any of the pharmacodynamics 
biomarkers of interest have predictive utility on the clinical tumor response to neoadjuvant 
ruxolitinib treatment in patients with operable HNSCC. The clinical response will be based on 
the reduction in Δtumor size from baseline to 14-21 days of ruxolitinib treatment: 
(1) Primary analysis using Spearman correlation between baseline pSTAT3 expression and 
%Change in tumor size will also be performed. As a supportive exploratory analysis, for 
clinical responders of patients who have achieved a 35% or greater on reduction in 
Δtumor size from baseline, descriptive statistics with mean, standard deviation and 95% 
CI will be calculated for baseline STAT activation (pSTAT3 expression) and Wilcoxon 
rank tests will be used to determine the significant difference on baseline pSTAT3 
expression between responders and non-responders.
(2) Primary analysis using Spearman correlation between change of pSTAT3 expression 
and %Change in tumor size will also be performed. As a supportive exploratory analysis, 
for clinical responders of patients who have achieved a 35% or greater on reduction in 
Δtumor size from baseline, descriptive statistics with mean, standard deviation and 95% 
CI will be calculated for change in STAT activation (pSTAT3 expression) from baseline 
and Wilcoxon rank tests will be used to determine the significant difference on change of 
pSTAT3 expression between responders and non-responders.
(3) Primary analysis using Spearman correlation between change of cyclin D1 expression 
and %Change in tumor size will also be performed. As a supportive exploratory analysis, 
for clinical responders of patients who have achieved a 35% or greater on reduction in 
Δtumor size from baseline, descriptive statistics with mean, standard deviation and 95% 
CI will be calculated for change in cyclin D1 expression from baseline and Wilcoxon rank 
tests will be used to determine the significant difference on change of cyclin D1 
expression between responders and non-responders.
(4) Primary analysis using Spearman correlation between baseline genetic or epigenetic 
PTPRT/PTPRD silencing and %Change in tumor size will also be performed. As a 
supportive exploratory analysis, for clinical responders of patients who have achieved a 
35% or greater on reduction in Δtumor size from baseline, descriptive statistics with 
mean, standard deviation and 95% CI will be calculated for baseline genetic or 
epigenetic PTPRT/PTPRD silencing and Wilcoxon rank tests will be used to determine 
the significant difference on baseline genetic or epigenetic PTPRT/PTPRD silencing 
between responders and non-responders.
(5) Primary analysis using Spearman correlation between baseline C-reactive protein level 
and %Change in tumor size will also be performed. As a supportive exploratory analysis, 
for clinical responders of patients who have achieved a 35% or greater on reduction in 
Δtumor size from baseline, descriptive statistics with mean, standard deviation and 95% 
CI will be calculated for baseline C-reactive protein level and Wilcoxon rank tests will be 
used to determine the significant difference on baseline C-reactive protein level between 
responders and non-responders.
8.4.3 Secondary Analysis (or Analysis of Secondary Endpoints)
For secondary endpoints, due to the limited sample size in the study, descriptive statistics with 
mean and 95% confidence intervals will be used. For continuous variables, descriptive statistics 
will include the number of non-missing values, mean, standard deviation, median, min and 

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maximum. For categorical variables, descriptive statistics will include counts and percentages per 
category. For comparison between subgroups, ANOVA and t-tests or non-parametric tests will be 
used when appropriate to determine the association of the efficacy endpoints and specific 
biomarkers. For example, descriptive statistics with mean, standard deviation and 95% CI will be 
calculated for the tumoral Ki-67 proliferation index and Wilcoxon rank tests will be used to 
determine the significant difference on the tumoral Ki-67 proliferation index between responders 
and non-responders. We will also performed additional analysis using Spearman correlation 
between the tumoral Ki-67 proliferation index and %Change in tumor size.
8.4.4 Other Analyses/Assessments
For continuous variables, descriptive statistics will include the number of non-missing values, 
mean, standard deviation, median, min and maximum. For categorical variables, descriptive 
statistics will include counts and percentages per category. 
Descriptive statistics with mean, standard deviation and 95% CI will be calculated for baseline 
JAK/STAT3 Signaling activation and Wilcoxon rank tests will be used to determine the 
significant difference on baseline JAK/STAT3 Signaling activation between responders and non-
responders.
Descriptive statistics with mean, standard deviation and 95% CI will be calculated for baseline 
and change in STAT1/STAT3 activation and Wilcoxon rank tests will be used to determine the 
significant difference on baseline and change in STAT1/STAT3 activation between responders 
and non-responders.
Descriptive statistics with mean, standard deviation and 95% CI will be calculated for baseline 
SHP-2 overexpression and Wilcoxon rank tests will be used to determine the significant 
difference on baseline SHP-2 overexpression between responders and non-responders.
8.5
Evaluation of Safety
Analyses will be performed for all patients having received at least 14 days’ worth of study drug. 
The study will use the NCI CTCAE v4.0.
9
Study Management
9.1
Pre-study Documentation
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, participant 
recruitment materials, and any other written information to be provided to participants before 
any protocol related procedures are performed on any participants. 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 

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The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements.
9.2
Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB. Prior to obtaining IRB approval, the protocol must be approved by 
the Helen Diller Family Comprehensive Cancer Center Site Committee and by the Protocol 
Review Committee (PRC). The initial protocol and all protocol amendments must be approved 
by the IRB prior to implementation. 
9.3
Informed Consent
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation. Participants must 
sign the IRB-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file. 
9.4
Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation. 
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites.
9.5
Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs. The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included. The sponsor-
investigator will maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients. Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol.
9.6
Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 

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monitoring and data analysis. All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
UCSF personnel. All source documentation should be kept in separate research folders for each 
patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager.
9.7
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study. The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”. The DSMC will audit study-
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable. See 
Appendix 2 Multicenter Institutional Studies Data and Safety Monitoring Plan for a Multicenter 
Study (Phase 2 or 3 Study), for additional information.
9.8
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 participants, 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 administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data (e.g., signed and dated 
consent forms and medical records, such as 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.

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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.
9.9
Coordinating Center Documentation of Distribution
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.).
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt.
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received.
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed.
10
Protection of Human Subjects
10.1
Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all participants involved in human 
experimentation. This is accomplished through the CHR mechanism and the process of 
informed consent. The CHR reviews all proposed studies involving human experimentation and 
ensures that the participant’s rights and welfare are protected and that the potential benefits 
and/or the importance of the knowledge to be gained outweigh the risks to the individual. The 
CHR also reviews the informed consent document associated with each study in order to 
ensure that the consent document accurately and clearly communicates the nature of the 
research to be done and its associated risks and benefits. 
10.2
Protection of Privacy
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document.

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11
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Agrawal N, Frederick MJ, Pickering CR, et al. Exome Sequencing of Head and Neck 
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Hou J, Xu J, Jiang R, et al. Estrogen-sensitive PTPRO expression represses 
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Appendix 1 Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease
0
Normal activity
Fully active, able to carry on all 
pre-disease performance 
without restriction
90
Able to carry on normal activity; 
minor signs or symptoms of disease
80
Normal activity with effort; some 
signs or symptoms of disease
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)
70
Cares for self, unable to carry on 
normal activity or to do active work
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs
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
50
Requires considerable assistance 
and frequent medical care
40
Disabled, requires special care and 
assistance
3
In bed > 50% of the time
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking hours
30
Severely disabled, hospitalization 
indicated
Death not imminent
20
Very sick, hospitalization indicated
Death not imminent
4
100% bedridden
Completely disabled
Cannot carry on any self-care
Totally confined to bed or chair
10
Moribund, fatal processes 
progressing rapidly
5
Dead
0
Dead

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Appendix 2 Multicenter Institutional Studies Data and Safety Monitoring Plan for 
a Multicenter Study (Phase II or III study)
1.
Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for 
all HDF CCC institutional clinical studies. A summary of DSMC activities for this study includes: 

Review of patient data.

Review of serious adverse events.

Monitoring every six months (depending on patient accrual).

Minimum of a yearly regulatory audit.
2.
Monitoring and Reporting Guidelines
All institutional Phase II or III therapeutic studies are designated with a moderate risk 
assessment. The data is monitored by a DSMC Monitor twice per year with twenty percent of 
the patients monitored (or at least three patients if the calculated value is less than three).
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters.
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair.  
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites.  The Study Chair will conduct continuous review of data 
and patient safety and discuss each patient’s treatment at monthly UCSF Site Committee 
meetings.  The discussions are documented in the UCSF Site Committee meeting minutes.  
Multicenter communication
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites.  
The following issues will be discussed as appropriate:

Enrollment information. 

Adverse Events (i.e., new adverse events and updates on unresolved adverse events 
and new safety information).

Protocol Violations.

Other issues affecting the conduct of the study.
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® and eFlorence (a FDA 21 CFR part 11-compliant electronic data 
repository)  at the UCSF Coordinating Center and the participating sites as per the study-
specific guidelines.  The data (i.e., copies of source documents) from the participating sites will 

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be downloaded into the PC console of OnCore or from eFlorence prior to the monitoring visits in 
order for the DSMC to monitor the participating site’s compliance with the protocol and FDA 
regulations.
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All Grade 3-5 Adverse Events (AEs), regardless of being unexpected or considered to 
be associated with the use of the study drug will be entered into OnCore®, UCSF’s 
Clinical Trial Management System.  
Adverse Events are graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) as developed and revised by the Common Therapy Evaluation 
Program (CTEP) of the National Cancer Institute.  Adverse Events are further given an 
assignment of attribution or relationship to treatment or medical procedure.  Attribution 
categories are:

Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure.

Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure.

Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure.

Unlikely – The adverse event is doubtfully related to the investigational agent(s) or 
medical procedure.

Unrelated – the adverse event is clearly not related to the investigational agent(s) or 
medical procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis 
at the UCSF Site Committee meetings.  All adverse events entered into OnCore® will be 
reviewed on a monthly basis at the UCSF Coordinating Center Site Committee 
meetings.  All clinically significant adverse events must be reported to the UCSF 
Coordinating Center by the participating sites within 10 business days of becoming 
aware of the event or during the next scheduled monthly conference call, whichever is 
sooner.  The UCSF Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to the 
administration of the study drug(s) from the UCSF Coordinating Center and the 
participating sites. 
3.2
Serious Adverse Event Reporting 
By definition, an Adverse Event is defined as a Serious Adverse Event (SAE) according 
to the following criteria:

Death.

Life-threatening (i.e. results in an immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

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
Permanent or significant disability/incapacity.

Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed above.

Event occurring in a gene therapy study.

Event that changes the risk/benefit ratio of a study.

Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations 
and Code of Federal Regulation Title 21 Part 312.32.  The SAE will be reported on a 
Med Watch form.  
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm
Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All Serious Adverse Events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines) via iRIS®.  All SAEs, whether expected or unexpected, must be 
reported to the UCSF Coordinating Center within 1 business days of becoming aware of 
the event.  The SAEs are reviewed and monitored by the UCSF Data and Safety 
Monitoring Committee on an ongoing basis and discussed at DSMC meetings, which 
take place every six weeks.  The date the SAE was sent to all required reporting 
agencies will be documented in OnCore®. 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or 
definitely related either to the investigational drug or any research related procedure, the 
Study Chair at the UCSF Coordinating Center or the assigned designee must be notified 
within 1 business day from the participating site(s) and the Study Chair must then notify 
the DSMC Chair or qualified alternate within 1 business day of this notification.  The 
reporting procedure is by communication via phone or in person with written 
documentation of the one-on-one communication via e-mail, with a copy of the e-mail to 
the DSMC Director.
3.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Study Chair at 
the UCSF Coordinating Center is responsible for notifying the DSMC at the time the 
increased rate is identified.  The report will indicate if the incidence of adverse events 
observed in the study is above the range stated in the Investigator Brochure or package 
insert.

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If at any time the Study Chair stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Director must be notified within 1 business day and the IRB 
must be notified within 10 business days via an iRIS Reporting Form.
Data and Safety Monitoring Committee Contacts:
Thierry Jahan, MD
UCSF HDFCCC
San Francisco, CA 94158
DSMC Monitors 
UCSF HDFCCC
San Francisco, CA 94143
Revision #3 (12Nov2017)
Approved by NCI (09Feb2012)

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Appendix 3 Prohibited Medications
Drug
Trade name (if applicable)
Boceprivir:
Victrelis
Clarithrymycin
Biaxin
Conivaptam
Vaprisol
Indinavir
Crixivan
Itraconazole
Sporanox
Ketoconazole
Nizoral
Lopinavir
Kaletra
Mibefradil
Posicor
Nefazodone
Serzone
Nelfinavir
Viracept
Posaconazole
Noxafil
Ritonavir
Norvir
Saquinavir
Invirase
Telaprevir
Incivek, Incivo
Telithromycin
Ketek
Voriconazole
Vfend

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Appendix 4 Study Drug Diary
Study Drug Diary
Protocol #_______________________Name ______________________________________
Please check each day, AM and PM that you take your study medication. If you do not take your 
medication on the day it is scheduled, please write in the reason. Also write in any side effects 
that you experience. It is very important that you keep this calendar and bring it with you when 
you see your study doctor or nurse.
Month __________________________________
Year ______________________
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___
AM ___
PM___

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Appendix 5 Specimen Collection and Processing
Specimen Collection
Blood
Peripheral blood obtained by venipuncture will serve as a source of cells for laboratory testing. 
Blood will be collected at screening and within 5 days prior to planned surgery (up to and 
including the day of surgery). One (1) purple top EDTA tube will be collected at each time point. 
Please refer to the laboratory SOPs for processing instructions. 
Tissue
Biopsy material from pre-treatment and post-treatment tumor specimens will be taken from 
either archival tissue or the initial research biopsy and at the time of surgical resection of the 
primary tumor, respectively. On both occasions, tissue estimated to be equivalent to at least two 
4 mm punch biopsies or two 18 to 14 gauge core needle biopsies will be collected. Tumor 
samples are ideally to be processed within 5-15 minutes of surgical excision. The tumor 
samples will be separated into two parts and processed as follows: 1) A tissue sample will be 
placed in a formalin filled plastic container, then embedded into paraffin for further analysis 
(FFPE). The FFPE sample will be stored in the UCSF Head and Neck Tissue Repository with 
study identifiers. 2) A fresh tissue specimen will also be banked within this mechanism. 
Tissue Processing
FFPE: For head and neck tumors, construction of tissue microarrays (TMAs) and 
immunohistochemical staining of the patient specimens will be performed at the Pathology 
Facility of UCSF. These studies will be supervised by our head and neck pathologist, Dr. 
Annemieke VanZante who directs the Tissue Core of our HNC Specialized Program of 
Research Excellence (SPORE). Dr. VanZante is experienced in TMA construction and analysis 
of protein expression. Paraffin embedded tissue blocks will be sectioned at 5μm and stained 
with H&E for morphologic characterization and to serve as guide slides for TMA construction. 
For high throughput immunohistochemical analysis and standardization of staining conditions, 
tissue microarrays (TMAs) will be constructed from formalin fixed paraffin embedded tissue 
blocks from the tumor biopsies. Using a manual tissue arrayer, (MTA-1, Beecher Instruments, 
Sun Prairie, WI) 0.6 mm tissue cores will be extracted from each pre and post treatment tumor 
in triplicate and arrayed on 1-2 recipient paraffin blocks along with normal tonsillar controls. The 
newly constructed array block will then be warmed to 35-37°C for 10 minutes to allow annealing 
of donor cores to the paraffin wax of the recipient block and minimize core loss. Donor cores will 
range from 2-4 mm in length. Hence each TMA will yield an estimated 100 to 200 tissue 
sections (4μm thickness). For TMA quality assessment morphologic confirmation of tumor, 
throughout the entire thickness of the block, one hematoxylin and eosin stained slide will be 
prepared from every ten tissue sections. Immunohistochemical evaluation of the remaining 
deparaffinized sections will be performed using immunoperoxidase staining for proteins in the 
JAK/STAT pathway including the following antigens: JAK1, JAK2, STAT1, STAT3, cyclin D1 
and Src on paraffin sections cut from the TMAs using commercially available antibodies and 
standard methods. Sections will be deparaffinized with successive ethanol and xylene baths. 
These sections will then be subjected to an optimized antigen retrieval method individualized to 
each antibody. Signal amplification will be performed using a proprietary micropolymer 
peroxidase (ImmPRESSTM, Vector, Burlingame, CA) conjugated to an anti-mouse antibody. 
Immunoreactive cells will be visualized with the brown color resulting from incubation with 
diaminobenzidine (DAB) chromogenic substrate at room temperature for 5 minutes. Sections 

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will be counterstained blue with hematoxylin for 15 seconds and lithium carbonate for 5 seconds 
to provide morphologic detail. Immunohistochemical staining will be scored quantitatively for 
each core, based upon proportion of immunoreactive cells and staining intensity, with the 
assistance of computerized digital imaging (Aperio). When appropriate, separate scores for 
each case will be assigned for cytoplasmic and nuclear staining.