Clinical trial NCT01268579
Conditions: HEAD & NECK Cancer
Keywords: ribavirin VIRAZOLE tonsil base of tongue squamous cell carcinoma 10-218
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2010-12-28; Completion date: 2022-10-31
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Human papillomavirus (HPV-16) is an important factor in the development of many tonsil and/or base of tongue squamous cell cancers. Although HPV-16 is not thought to cause cancer by itself, it appears to contribute to the development of tonsil and/or base of tongue cancer in many patients. It is likely that treatment for many patients with tonsil and/or base of tongue cancer could be improved if effective therapy to control HPV-16 is developed. The investigators in this study want to learn if ribavirin shows evidence of activity against HPV-16.

Ribavirin is a pill therapy that is approved by the Food and Drug Administration (FDA) as part of the standard treatment for Hepatitis C. Laboratory experiments suggest that ribavirin might also be useful in the treatment of head and neck cancers. However, ribavirin has not yet been tested against head and neck cancer in patients. The purpose of this study is to find out the effects of ribavirin on tonsil and base tongue squamous cell cancer in patients.

The main purpose of this study is to see if ribavirin changes the expression of certain proteins related to HPV infection in the tumor. The study will also find out if ribavirin changes how the tumor appears in a PET/CT scan (positron emission tomography/computed tomography scan).

Detailed description:

Arms: arm 1: This will be a single institution non-randomized study for patients with tonsil and/or base of tongue squamous cell cancer. This is a pilot study to obtain pharmacodynamic data regarding the effects of ribavirin on tonsil squamous cell cancer.
Interventions: intervention 1: ribavirin
Intervention descriptions: intervention 1: The clinical intervention in this study is ribavirin therapy for approximately 14 days. Ribavirin 800 mg/day is administered in divided doses, 400 mg PO qAM and 400 mg PO qPM.

Protocol documents:
Prot_SAP_000.pdf: 
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Page 1 of 33 
 
 
A Pilot Study to Assess the Pharmacodynamic Effects of Ribavirin 
in Patients with Tonsil and/or Base of Tongue Squamous Cell 
Carcinoma 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
David Pfister, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Shrujal Baxi, MD 
Medicine 
Investigator(s)/Department: 
Eric Sherman, MD 
Alan Ho, MD PhD 
Nora Katabi, MD 
Heiko Schoder, MD 
Camelia Sima, MS 
Jatin Shah, MD PhD (Hon) 
Ashok Shaha, MD 
Jay Boyle, MD 
Bhuvanesh Singh, MD PhD 
Richard Wong, MD 
Snehal Patel, MD 
Ian Ganly, MD 
Luc Morris, MD 
Tim Chan, MD PhD 
Jonathan Schatz 
Medicine 
Medicine 
Pathology 
Radiology 
Epidemiology and 
Biostatistics 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Radiation Oncology 
Medicine 
Consenting Professional(s)/Department: 
David Pfister, MD 
Eric Sherman, MD 
Alan Ho, MD PhD 
Shrujal Baxi, MD 
Jatin Shah, MD PhD (Hon) 
Ashok Shaha, MD 
Jay Boyle, MD 
Bhuvanesh Singh, MD PhD 
Richard Wong, MD 
Snehal Patel, MD 
Ian Ganly, MD 
Luc Morris, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
 
Table of Contents 


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MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL .................................................................... 1 
Memorial Sloan-Kettering Cancer Center ....................................................................................... 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 4 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 6 
2.2 
Primary ............................................................................................................................... 6 
2.3 
Secondary .......................................................................................................................... 6 
3.1 
BACKGROUND AND RATIONALE .................................................................................... 6 
3.2 
HPV/p16-positive HNSCC is a distinct clinical and biological entity .............................. 6 
3.3 
Rationale for targeting eIF4E in HPV/p16-positive tumors .............................................. 7 
3.4 
Ribavirin is a broad-spectrum antiviral agent that inhibits eIF4E ................................... 9 
3.5 
Rationale for Tissue Pharmacodynamic Studies........................................................... 13 
3.6 
Summary and Future directions ..................................................................................... 13 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION .............................................................. 15 
4.2 
Design .............................................................................................................................. 15 
4.3 
Intervention ...................................................................................................................... 15 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS.............................................................................. 16 
5.2 Ribavirin .............................................................................................................................. 16 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 17 
6.2 
Subject Exclusion Criteria .............................................................................................. 18 
7.0 
RECRUITMENT PLAN ...................................................................................................... 19 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 19 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 20 
9.2 Immunohistochemistry (IHC) ............................................................................................. 20 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 21 
11.1 TOXICITIES/SIDE EFFECTS ................................................................................................ 23 
11.2 Hematologic Toxicity ........................................................................................................ 23 
11.3 2 Non-Hematologic Toxicity .............................................................................................. 23 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 24 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 24 
14.0 BIOSTATISTICS .................................................................................................................... 25 
15.0 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES26 
16.0 DATA MANAGEMENT ISSUES ........................................................................................ 26 
17.0 PROTECTION OF HUMAN SUBJECTS ........................................................................... 27 
18.0 INFORMED CONSENT PROCEDURES ............................................................................... 28 


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19.0 REFERENCES ....................................................................................................................... 30 
20.0 APPENDICES ........................................................................................................................ 33 


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1.1 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
1.2 Summary 
 
This will be a single-institution, non-randomized, pilot study for 7 patients at MSKCC 
Main Campus. 
 
We wish to study ribavirin in this patient population because: (1) eIF4E can function as an 
oncogene; (2)  we have recently found that expression of phosphorylated eIF4E is 
associated with p16-positive tonsillar squamous cell carcinoma (3) ribavirin has been shown 
to decrease eIF4E levels in vivo. 
 
The Primary Aim of this pilot study is to explore if ribavirin therapy for 2 weeks decreases 
tumor expression of phosphorylated eIF4E among patients with tonsillar and/or base of 
tongue squamous cell carcinoma. 
 
Subjects will have tonsil and/or base of tongue squamous cell carcinoma that is previously 
untreated. 
 
Subjects will not have a history of more than 10 pack-years of tobacco use.  Subjects will 
have had a prior diagnostic surgical or core needle biopsy.  Patients for whom definitive 
local-regional treatment (primary surgery or primary radiation therapy +/- chemotherapy, 
given sequentially or concurrently) is planned will be offered participation in the study. 
Subjects will take ribavirin 800 mg/day in divided doses for two weeks, which is a standard 
time frame for pre-operative planning.  Patients will be evaluated in clinic by the medical 
oncologist during week 1 and week 2. (For patients who undergo research biopsy, this will 
be performed in the clinics of the Head and Neck Disease Management Team.) 
 
Patients will be considered done with treatment at time of surgery and/or research biopsy. 
 
Post-surgical (or post research biopsy) management will be off protocol, according to 
established 
standards of care. 


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1.3 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Off-Study 
Patients are off-study as of Day of Surgery (or Research Biopsy) 
Post-operative (or post Research Biopsy) management is off 
protocol, 
per standards of care 
Approximately Day 15 
 
Surgery or Research Biopsy at MSKCC 
 
Discontinue Ribavirin 
Treatment 
 
Ribavirin 800 mg/day, in 2 divided doses, for approximately 14 days 
 
Day 1, Day8: H&P, CBC, comp panel 
New Diagnosis Tonsil and/or Base of Tongue SCC 
 10 unstained slides must be available from the initial diagnostic biopsy 
 Written Informed Consent 


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2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.2 
Primary: 
2.1.1 
To explore if ribavirin therapy for 2 weeks prior to tumor resection decreases tumor 
expression of phosphorylated eIF4E among patients with tonsillar and/or base of tongue 
squamous cell carcinomas that express phosphorylated eIF4E. 
 
 
2.3 
Secondary: 
2.2.1 
In pre- and post-treatment tumor samples, to explore the pharmacodynamic effects of 
ribavirin on molecules that may be regulated, directly or indirectly, by eIF4E (eg, p16, p21, 
EGFR, p53). 
 
2.2.2 
In pre- and post-treatment tumor samples, to explore if ribavirin reduces the expression of 
HPV-16 oncoproteins E6 and E7 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 
HPV/p16-positive HNSCC is a distinct clinical and biological entity 
 
HNSCC comprises at least two distinct clinical entities:  HPV-positive tumors and HPV- 
negative tumors (1).   Approximately half of oropharynx (tonsil, base of tongue) squamous 
cell carcinomas are HPV-positive, but tumors arising at other sites in the upper aerodigestive 
tract (i.e., oral cavity, hypopharynx, or larynx) generally are not associated with HPV (1). 
HPV-negative tumors typically occur in individuals with histories of tobacco abuse, whereas 
HPV-positive HNSCC usually is not associated with tobacco abuse (2, 3).  In a prospective 
randomized clinical trial of cisplatin plus concurrent radiation in HNSCC, HPV-positive 
squamous cell carcinomas arising in the oropharynx were associated with superior overall 
survival compared with HPV-negative oropharynx tumors (4). 
 
Potentially, differences in the molecular pathogenesis mechanisms of these tumors account 
for their distinct treatment responsiveness.  Landmark cytogenetic studies of HNSCC 
demonstrate frequent gene loss at the locus encoding p16 and p14 (CDKN2A), and 
amplification at the gene locus encoding cyclin D1 (5-7)  Whereas p16 loss and cyclin D1 
amplification characterize HPV-negative (tobacco-related) tumors, p16 overexpression and 
downregulation cyclin D1 typify HPV-positive tumors (8). The high p16/low cyclin D1 profile 
in HPV-positive tumors is due to loss of negative feedback on p16 when the E7 viral 
oncoprotein inactivates the pRB tumor suppressor protein (1, 9). Immunohistochemical 
detection of p16 is a marker for HPV-associated carcinogenesis in HNSCC (10-12). 
 
In summary, HPV-positive and HPV-negative head and neck cancers are distinct at the 
molecular pathology level. There are converse molecular profiles for HPV-positive tumors 


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(ie, overexpression of p14 and p16; downregulation of cyclin D1; p53 wildtype) and HPV- 
negative tumors (ie, overexpression of cyclin D1; downregulation p14, p16 and p21; p53 
mutant) (3, 8, 10, 13-15), and these molecular profiles can inform the development of clinical 
studies. 
 
3.3 
Rationale for targeting eIF4E in HPV/p16-positive tumors 
 
The translation initiation factor eIF4E is a central regulator of gene expression (16). eIF4E 
binds the 7-methyl guanosine (m7G) cap structure in the 5’ end of mRNAs, and selectively 
stimulates the translation of several oncogenic transcripts that are repressed under normal 
circumstances.  Malignancy related mRNAs that are regulated at the level of translation by 
eIF4E include cyclin D1, VEGF, bcl-2, MMP-9 and Pim-1 (16, 17). 
Wendel and colleagues 
demonstrated that eIF4E functions as an oncogene and confers resistance to therapeutic 
mTOR inhibition in a murine lymphoma model (18, 19). 
 
In 1999 clinicopathologic study of 65 HNSCC surgical cases, Nathan and colleagues reported 
that expression of eIF4E was detectable by immunohistochemistry in all of the tumors.  
Expression of eIF4E in histologically tumor-free margins was present in 55% of specimens, 
and was associated with a significantly increased risk of tumor recurrence (20).                 
This group subsequently demonstrated that antisense inhibition of eIF4E mRNA reduced the 
malignant properties of a HNSCC cell line (FaDu), as measured by increased contact 
inhibition, reduced growth in soft agar, and reduced tumor growth in xenograft mouse models 
(21). Growth inhibitory effects also were observed when another HNSCC cell ine 
(UMSCC22B) was subjected to eIF4E silencing with siRNAs (22). As further evidence of 
eIF4E’s central role in translation regulation in HNSCC cells, eIF4E-targeted suicide gene 
therapy in a murine model of HNSCC (SCC-7 cells) improved disease-free survival (23). 
 
Our current interest in eIF4E in head and neck cancer is an offshoot of our DMT’s research 
program into inhibitors of the PI3K/Akt/mTOR pathway (IRB 06-129, IRB 08-138, IRB 09- 
028, IRB 09-131).  To explore if expression levels of any proteins in this pathway are 
associated with p16 status, we constructed a tissue microarray (TMA) with 46 archived tonsil 
squamous cell carcinoma specimens (24). The TMA was interrogated with antibodies 
directed against proteins in this pathway and against p16.  The antibody panel included anti- 
eIF4ESer209, because phosphorylation of eIF4E appears to be essential for oncogenic activity 
(19, 25). 
 
We demonstrated that downstream components of the PI3K pathway, such as 
phosphorylated Akt and S6, are expressed in the majority of the specimens (24),  in 
agreement with the results of the Head and Neck Cancer Tissue Array initiative (26).  Sixty- 
five percent of the tumors expressed p16, the marker for HPV-driven carcinogenesis (10-12). 
The salient new finding was that p16 expression was associated with expression of 
phosphorylated eIF4E (p= 0.03, Table 1) (24). Expression of p16 also correlated with 
expression of p21 (p = 0,02, Table 1) (24), in agreement with the immunohistochemistry 
study of Hafkamp (8). There was no association between expression of p16 and 
phosphorylated S6 or phosphorylated 4E-BP1. In agreement with multiple reports regarding 
HPV-status and tobacco history (2, 3), we found a significant correlation between history of 
tobacco abuse (>10 pack/years) and absence of p16 expression (p = 0.01) (24). 


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Table 1.  Associations between anti-p16 and 8 other antibodies (24) 
 
Antigen 
Number p16 
positive 
Number p16 
negative 
P 
value* 
p21 
0.02 
Pos (%) 
25 (78) 
7 (22) 
Neg (%) 
5 (38) 
8 (62) 
PTEN 
0.02 
Pos (%) 
24 (77) 
7 (23) 
Neg (%) 
6 (40) 
9 (60) 
Phospho eIF4ESer209 
0.03 
Pos (%) 
26 (74) 
9 (26) 
Neg (%) 
4 (9) 
7 (91) 
Phospho 4E-BP1Thr37/46 
1.0 
Pos (%) 
20 (67) 
10 (33) 
Neg (%) 
9 (64) 
5 (36) 
Phospho AKTSer473 
0.12 
Pos (%) 
21 (75) 
7 (25) 
Neg (%) 
9 (50) 
9 (50) 
Phospho S6Ser240/244 
1.0 
Pos (%) 
19 (63) 
11 (37) 
Neg (%) 
10 (67) 
5   (33) 
Phospho S6Ser235/236 
0.75 
Pos (%) 
13 (65) 
7 (35) 
Neg (%) 
17 (71) 
7 (29) 
p53 
1.0 
Pos (%) 
11 (65) 
6 (35) 
Neg (%) 
19 (68) 
9 (32) 
*P values determined by Fisher’s exact test 
 
Note:  For the following antibodies, tumor sample was missing from the TMA for  one patient each:  p21, p53, 
phosphorylated S6Ser240/240.  Tumor sample was missing from the TMA for two patients each for:  phosphorylated 
4E-BP1Thr37/46 and phosphorylated S6Ser235/236 (24). 
 
 
The association between p16 and phosphorylated eIF4E expression has potential 
implications for clinical study.   In the context of the central role of eIF4E in the translation of 
proteins encoded by capped mRNAs (27), the association between p16 and phosphorylated 
eIF4E may reflect interplay between virus and cellular translational apparatus. In cells 
infected with herpes simplex virus-1 or vaccinia virus, phosphorylation of eIF4E by Mnk-1 is 
critical for viral protein synthesis and replication (28, 29).  It is not known if similar 
mechanism occurs in HPV-positive HNSCC, but HPV is associated with increased cap- 
dependent translation in differentiating cervical cancer cell lines (30), and eIF4E staining is 
increased in cervical neoplasia (31). 
 
In summary, several observations indicate that eIF4E is an attractive research target in 
HPV/p16 positive tonsillar squamous cell carcinoma: (1) eIF4E expression has prognostic 
significance in HNSCC (2) eIF4E knockdown in HNSCC cell lines is associated with reduced 
tumorigenicity (3) phosphorylated eIF4E is associated with p16 status in a tonsil squamous 
cell carcinoma tissue microarray (4) eIF4E is critical for viral protein synthesis in other 
systems. 


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3.4 
Ribavirin is a broad-spectrum antiviral agent that inhibits eIF4E 
 
In 1972, the guanosine ribonucleotide analogue ribavirin (Virazole®; 1-β-D-ribofuranosyl- 
1,2,4-triazole-3-carboxamide) was reported to have broad spectrum activity against both 
RNA and DNA viruses. The combination of ribavirin + peginterferon (PEG-IFN) α-2b is an 
effective treatment for chronic hepatitis C. The most common adverse events associated 
with ribavirin are mild anemia, cough, and rash. For patients treated with prolonged ribavirin, 
anemia usually is mild and hemoglobin remains in the normal range (32, 33).  Risk factors 
for moderate to severe anemia with ribavirin are advanced age, low body weight, hepatic or 
renal insufficiency, and baseline marrow dysfunction (34-36). In the current study, eligibility 
criteria exclude patients with factors that might put them at increased risk of anemia with 
ribavirin. 
 
The pivotal trial (n = 1530 subjects) establishing PEG-IFN α-2b + ribavirin efficacy against 
chronic hepatitis C showed that treatment for 48 weeks with PEG-IFN α-2b (1.5 µg/kg/week) 
and a flat dose of ribavirin (800 mg/day) was statistically superior to IFN α-2b or low-dose 
(0.5 µg/kg/week) of PEG-IFN α-2b and weight-based dose of ribavirin (1000 – 1200 mg/day) 
(37). A subsequent randomized clinical trial (n = 5027 subjects) demonstrated that a weight- 
based ribavirin (800 – 1400 mg/day) + PEG-INF α-2b was more effective than flat-dose 
ribavirin (800 mg/day) + PEG-IFN α-2b (38). However, the improvement in sustained 
virologic response was modest (44.2% for weight-based dosing versus 40.5% for flat dosing), 
and appeared to be restricted to patients with HCV genotype 1. Additionally, mean 
hemoglobin levels decreased to a lesser extent in the flat-dose group than in the weight 
based-group (38). In the current protocol, ribavirin will be given at flat dose of 800 mg/day to 
optimize patient safety. 
 
Ribavirin has been reported to have clinical activity against laryngeal papillomatosis (LP) in a 
small non-randomized pilot study (39). LP, a rare condition with an incidence of 
approximately 7.1 per million in the U.S., is an HPV-related disease in which the upper 
airway becomes progressively occluded with mucosal papillomas. Repeated laser surgery 
for removal of lesions has been commonly applied as a management strategy.  In the pilot 
study, patients (3 adults, 1 child) received pre-operative ribavirin (23 mg/kg daily) on the day 
of laser surgery, and continued oral ribavirin at the same daily dose for an additional 6 
months (only 3 months for the child). The viral strain was HPV-6 in the papillomas of three 
patients, and was HPV-11 in one patient. 
 
Treatment was generally well tolerated, with only one patient requiring a 25% dose reduction 
for anemia, which resolved with continued treatment at the reduced dose. Ribavirin 
treatment was associated a decrease in observable disease on follow up examinations, as 
determined by a previously described mapping score. Ribavirin treatment was associated 
with an increase in the time interval between successive required surgeries by a factor of at 
least 2 in all patients (39).  No pharmacodynamic correlates were done in this study. The 
efficacy of ribavirin against laryngeal papillomatosis was confirmed in a subsequent case 
report (40), and ribavirin is considered to be one treatment option for this uncommon entity 
(41). 
 
The mechanism of ribavirin’s antiviral activity is not conclusively established, and at least five 
potential mechanisms have been proposed (42).  For example, ribavirin is a potent 
competitive inhibitor of cellular inosine monophosphate dehydrogenase (IMPDH), thereby 
depleting GTP pools that are necessary for viral nucleic acid synthesis. Ribavirin also 
inhibits viral 7-methylguanosine (m7G) RNA cap synthesis in vaccinia virus (43, 44). These 
two mechanisms may be complementary:  by reducing levels of competing GTP, ribavirin 


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may be more effective as a capping inhibitor (42). The precise mechanism of ribavirin may 
be influenced by the particular virus and cell type, but the capping inhibition mechanism may 
be potentially relevant for those viruses that produce capped transcripts, such as HPV-16. 
 
In 2004, Borden and colleagues proposed that ribavirin competitively prevents eIF4E from 
binding the m7G cap of mRNAs, thereby inhibiting translation of proteins encoded by capped 
mRNAs (45). 
Because many capped mRNAs are important for oncogenesis, these findings 
suggested that ribavirin might potentially have activity against eIF4E-overexpressing cancers.  
However, this particular mechanism has been called into question as other labs hav               
e not been able to reproduce the finding that ribavirin mimics the m7G cap (46, 47), perhaps 
due to assay conditions (48). While the precise mechanisms of ribavirin require further  
study, subsequent clinical study in AML patients demonstrates that ribavirin decreases  
eIF4E levels in vivo (49). 
 
The in vivo demonstration of the impact of ribavirin on eIF4E levels was also reported by 
Borden and colleagues. They evaluated ribavirin in a proof-of-principle study for patients 
with relapsed or refractory AML, a disease which commonly overexpresses eIF4E (49). The 
starting dose of ribavirin was 1000 mg/day, with dose increases allowed for lack of response 
at 14 days. Treatment was well tolerated; no patient required dose reduction for toxicity. 
Among 13 enrolled patients, there was 1 complete response, 2 partial remissions, 2 blast 
responses, 4 stable diseases, 2 progressive diseases, and 2 patients were inevaluable (49). 
 
Ribavirin treatment  decreased levels of eIF4E mRNA (Table 2) and protein (Table 2, Figure 
1) in AML patients (49) (including Supplemental Data).   Prior to treatment, all patients 
evaluated had elevated eIF4E mRNA levels versus healthy controls. With a single 
exception, patients receiving 28+ days of therapy had a 2- to 10-fold drop in eIF4E RNA 
levels by day 28 (Table 2), and these levels remained reduced for the duration of treatment. 
Levels of eIF4E protein and other pathway proteins were assessed by Western blot in 
several patients, demonstrating decreases in eIF4E levels with ribavirin treatment in each 
case (Figure 1) (49).  Based on these encouraging studies, a follow-up clinical trial is 
underway in AML (www.clinicaltrials.gov; NCT01056523). Ribavirin is also being evaluated 
in advanced breast cancer (www.clinicaltrials.gov; NCT01055757), due to evidence of 
aberrant eIF4E activity in that disease (50, 51). 


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Table 2: eIF4E levels in AML before and after ribavirin treatment (49). 
 
 
 
Sample 
eIF4E mRNA 
Baselinea 
eIF4EmRNA 
Day 28b 
Pt1 
3.00 + 0.99 
0.50 + 0.25 
Pt3 
6.33 + 0.82 
0.32 + 0.32 
Pt6 
6.40 + 0.88 
0.64 + 0.10 
Pt9 
2.99 + 0.44 
1.66 + 0.32 
Pt10 
7.91 + 1.04 
0.24 + 0.09 
Pt12c 
5.06 + 0.68 
1.10 + 0.15 
Pt13 
3.34 + 0.79 
0.53 + 0.12 
eIF4E Protein 
Baseline 
eIF4E Protein 
Day 28 
Pt 7d 
6.38+ 0.17 
0.67 + 0.01e 
Pt 8d 
4.03+ 0.28 
N/A 
Pt 11d 
4.36+0.18 
0.26+0.04 
 
Note: 
RNA levels were quantified using quantitative real time PCR and 
normalized to multiple housekeeping genes to ensure that there were no errors 
due to unexpected changes in the normaliser genes. RNA levels are presented + 
standard deviations. 
 
aeIF4E RNA levels before treatment relative to normal controls 
beIF4E mRNA levels during treatment divided by baseline values 
cPatient 12 was treated for only 19 days. 
dFor patients 7, 8, and 11, there was no RNA available for analysis. Thus, analysis 
of the intensity of eIF4E immunostaining in micrographs was monitored. Analysis 
was done measuring pixel intensities over the same surface area of micrographs 
using Adobe Photoshop CS4 for the skin biopsy (patient 7) or bone marrow biopsy 
(patient 8) or by measuring average pixel intensity per cell for confocal micrographs 
(patient 11). 
eFor patient 7, eIF4E protein level was assessed in skin biopsy on day 100 of 
treatment (49). 


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Figure 1: eIF4E activity and levels are reduced by ribavirin treatment 
in 
AML.  Western blot analysis was carried out using the antibodies 
indicated (49) 
 
 
 
 
 
The demonstration of efficacy in AML motivates the exploration of ribavirin in other 
malignancies. Head and neck cancer is an obvious choice due to clinical and preclinical data 
demonstrating the eIF4E appears to play a significant role (20, 21, 52).   Additionally, 
ribavirin 
has potent antitumor activity against a HNSCC cell line (FaDu) that 
overexpresses eIF4E. In 
vitro, ribavirin inhibits phosphorylation of Akt and reduces   anchorage independent growth of FaDu 
cells (53). In a xenograft model using FaDu cells, 
20 days of treatment with ribavirin yielded a 6- 
fold reduction in mean tumor volume in 
treated animals, compared with the control group (45). 
The hypothesis that this growth 
inhibition may be mediated by ribavirin’s effect of eIF4E is 
supported by the observation  
that reduction of eIF4E expression in FaDu cells with antisense 
RNA also reduces the 
tumorigenic and angiogenic properties of FaDu cells (21). Taken 
together, we feel that these observations support a pilot study of ribavirin in head and neck cancer. 
In order to 
enrich for patient population that expresses the eIF4E target, the study is limited to 
never  smokers (or past oligo smokers) with tonsillar squamous cell cancer (see Table 1 above). 


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3.5 
Rationale for Tissue Pharmacodynamic Studies 
 
To obtain proof-of-principle regarding the hypothesis that ribavirin is an inhibitor of eIF4E (45, 
48, 49), we will compare pre and post treatment tumor levels of phosphorylated eIF4E by 
immunohistochemistry.  Expression of phosphorylated eIF4E is associated with p16 positive 
tonsil squamous cell carcinoma (24) [see Table 1 herein]. In AML, ribavirin therapy results in 
decreased levels of eIF4E mRNA and protein (49) [see Figure 1 and Table 2 herein].  eIF4E 
can function as an oncogene (18), and pharmacodynamic demonstration of downregulation 
of eIF4E would provide a mechanistic basis for further development of ribavirin in HPV- 
positive head and neck cancer. 
 
As a secondary endpoint, we will explore if ribavirin alters levels of selected proteins that are 
regulated by eIF4E at the translational level.  In a model system with primary human 
mammary epithelial cells (HMECs), eIF4E activates p16 and p21 and represses EGF 
receptor (17). This eIF4E-induced pattern of expression (high p16, high p21, and low EGFR) 
seen in HMECs (17) is very similar to the protein expression patterns seen in HPV-positive 
HNSCC (3, 8, 24).  The striking similarities between expression patterns induced by eIF4E  
in a HMEC model system and the expression patterns in HPV-positive HNSCC prompt 
exploratory pharmacodynamic assays involving pre and post-treatment tissue in this study. 
We wish to obtain pilot data to determine if ribavirin impacts expression of p16, p21, and/or 
EGFR in patient tumors in this study, which could strengthen the hypothesis that ribavirin is 
an inhibitor eIF4E activity. 
 
We also wish to explore if ribavirin treatment effects the expression of viral oncoproteins E6 
and E7.  HPV-16 uses a single promoter to drive expression of a bicistronic mRNA that 
encodes E6 and E7.  Synthesis of both E6 and E7 from the bicistronic transcript is 
dependent on an m7G cap structure on the 5’end of the mRNA (54). In view of the 
hypothesis that ribavirin may interfere with translation of cap-dependent mRNA transcripts 
(43-45), we wish to obtain pilot data regarding whether inhibition of production of E6 and E7 
might be a mechanism of action for ribavirin in HPV-positive tonsil squamous cell carcinoma. 
 
 
3.6 
Summary and Future directions 
 
In this study, up to 7 evaluable subjects will be treated with ribavirin for 14 days to 
evaluate the pharmacodynamic effects of ribavirin in HPV-positive  oropharynx SCC. We 
feel 
that 14 days is adequate to demonstrate the pharmacodynamic effects of ribavirin 
because (1) Ribavirin pharmacology is characterized by rapid absorption and rapid 
distribution (Section 5.1); (2) Ribavirin often causes mild anemia within 2 weeks, consistent 
with rapid onset clinical activity of the drug (61);  (3) For other targeted 
therapies with well- 
defined mechanisms of action in oncology, pharmacodynamic activity  is evident in 15 days or 
less (62, 63); (4) In the pilot study of ribavirin in AML, the first 
response assessment occurred at 
14 days (49). 
 
Squamous tumors of tonsil and base of tongue, both oropharynx subsites, share the same 
underlying molecular pathology in which HPV figures prominently in the development of 
malignancy (1).  Primary surgical resection or primary radiation +/- chemotherapy (concurrent 
or sequential) may be offered to patients with either tonsil or base of tongue   SCC. Because 
HPV-driven pathology is a shared characteristic of SCC at both of these subsites, we feel that 
it is appropriate to include both tonsil and base of tongue SCC in this study. 


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If the pilot data from this study is consistent with the hypothesis that ribavirin is an inhibitor or 
eIF4E, we would pursue further clinical studies of ribavirin in head and neck cancer. In view 
of the reported supra-additive effects of cisplatin + eIF4E inhibition against HNSCC cancer 
cell lines (22), we would consider a phase I/II study of ribavirin + low dose weekly cisplatin + 
external beam radiation therapy for patients with stage III/IVB HPV-positive HNSCC. The 
low-dose cisplatin regimen would likely be better tolerated than the current standard high- 
dose cisplatin regimens (64, 65). We would also wish to consider a phase I/II study of 
ribavirin + cisplatin + docetaxel as induction chemotherapy for patients with stage III/IVB 
HPV-positive HNSCC.   The use of 2 cytotoxic agents in this experimental induction regimen 
would likely be better tolerated than the current standard induction chemotherapy in HNSCC 
which is three cytotoxic agents (cisplatin, docetaxel, 5-fluorouracil) (66).  Another study 
option might be developed for patients who undergo primary surgery for head and neck 
cancer. In view of the report that expression of eIF4E in histologically tumor free margins is 
associated with increased risk of recurrence (20), a post-operative treatment regimen 
incorporating ribavirin would be an attractive study concept. Each of the study concepts 
outlined above would provide the opportunity to obtain adequate tumor tissue for correlative 
studies to further analyze the mechanistic effects of ribavirin. Finally, in view of the worldwide 
burden of cervical carcinoma which is also characterized by elevated eIF4E expression (31), 
these findings potentially could have implications beyond head and neck cancer clinical 
research. 


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4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This will be a single institution non-randomized study for patients with tonsil and/or base of 
tongue squamous cell cancer.  This is a pilot study to obtain pharmacodynamic data 
regarding the effects of ribavirin on tonsil and/or base of tongue squamous cell cancer. After 
patients provide informed consent, eIF4E expression in tumors will be measured by 
immunohistochemistry.  Those patients with tumors that express eIF4E ≥ 30% will be 
deemed eligible for the study and will self-administer ribavirin for approximately 14 days. 
The primary endpoint is to explore if ribavirin decreases tumor expression of phosphorylated 
eIF4E among patients with tonsil and/or base of tongue squamous cell carcinoma. 
Immunohistochemistry will be performed on pre-treatment pathology samples (e.g. 
diagnostic biopsy), as well as on the post-treatment pathology samples (e.g. definitive 
surgery or research biopsy, to describe the effects of ribavirin treatment on the expression of 
phosphorylated eIF4E. 
 
4.3 
Intervention 
 
Patients will self-administer ribavirin for approximately 14 days prior to surgery.   Patients will 
undergo safety assessments with clinic visits and routine laboratory studies at least once per 
week. On approximately day 15, patients will undergo planned surgical resection or research 
biopsy.  Patients will be considered done with treatment at time of surgery or research biopsy.  
Post-operative (or post research biopsy) management will be according to standards            
of care off protocol. 
 
For those patients who undergo research biopsy, this will be performed in the clinics of the 
Head and Neck Disease Management Team.  Research biopsy will be performed on easily 
accessible lesions. The phrase “easily accessible tumor” designates tumors that may be 
biopsied in an office setting with minimal risk of complication and discomfort to the patient. 
Common techniques for office biopsy include fine needle aspirate of malignant neck node, or 
forceps cut biopsy of primary tumor (with local anesthetic). The method used for research 
biopsy in the clinic is at the discretion of the investigator. 


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5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 Ribavirin 
 
Availability and Administration: 
Generic ribavirin is commercially available as 200 mg, 400mg, and 600 mg tablets, which will 
be orally administered by the patients themselves.  Ribavirin will be purchased from the 
hospital pharmacy. Tablets are supplied in bottles of 84 capsules (200 mg each). Ribavirin is 
available as blue-colored (shade depending on strength), capsule-shaped, film-coated 
tablets.  Medication labels will comply with US legal requirements and be printed in English. 
They will supply no clinical information about the patient on the labels. The storage 
conditions for study drug will be described on the medication label. Ribavirin tablet may be 
taken with food or on an empty stomach. 
 
Toxicities (> 10%): 
 
Hematologic:  anemia, thrombocytopenia, leukopenia, lymphopenia 
Gastrointestinal:  anorexia, nausea, diarrhea 
Hepatic:  elevated liver function tests 
Pulmonary:  dyspnea, cough 
Reproductive:  may be teratogen 
Constitutional: fatigue, musculoskeletal pain 
Dermatologic: alopecia, pruritis, rash 
Neurologic: headache, dizziness 
Endocrine and metabolic:  hyperuricemia 
 
 
Pharmacology: 
 
Ribavirin oral tablet administration is characterized by rapid absorption with a tmax of 
approximately 2 hours, followed by rapid distribution and long terminal phases. Mean γ- 
phase half-life has been reported to be in the range of approximately 30 - 61 hours after a 
single dose, and 274 - 296 hours following multiple doses. Mean bioavailability is 
approximately 30 - 50%. Apparent plasma clearance is approximately 20 L/h.  Population 
based pharmacokinetic models have identified factors associated with lower apparent 
clearance of ribavirin (female gender, higher age, and low body weight), but taken together 
these factors account for less than 30% of the variability in clearance (34, 67-69). 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
 
 
6.1 
Subject Inclusion Criteria 
 
1. Prior diagnostic surgical or core needle biopsy, with confirmation of tonsil and/or base of 
tongue squamous cell carcinoma that is positive for expression of p16 and phosphorylated 
eIF4E, as determined by the Department of Pathology at MSKCC. The biopsy may be 
either of the tonsil, base of tongue, and/or an involved neck node.  2 unstained slides 
and/or tissue block must be available from the initial diagnostic biopsy 
 
Positive expression p16 and phosphorylated eIF4E is defined as >=30% of tumor cells 
with cytological and/or nuclear staining 
 
2. Age ≥ 18 and ≤ 65 years of age 
 
3. Karnofsky Performance Status ≥ 80 
4. 
Adequate organ function, as follows: 
 
Adequate bone marrow reserve:  absolute neutrophil count (ANC) ≥ 1.5 X 109/L, 
platelets ≥ 160 X 109/L, hemoglobin ≥ 12 g/dL 
Hepatic:  total bilirubin within 1.5 X upper limit of normal (ULN) ; alkaline phosphatase 
(AP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 X ULN 
 
(Patients with Gilbert’s syndrome as the cause of hyperbilirubinemia may be eligible if 
total bilirubin ≤ 2.5 X UNL) 
 
Renal:  Serum creatinine ≤ 1.3 mg/dL.  Patients with serum creatinine > 1.3 mg/dL 
may be eligible if creatinine clearance (CrCl) ≥ 55 mL/min based on the standard 
Cockroft and Gault formula. 
 
 
5. Patients of childbearing potential must have a negative serum pregnancy test within 14 
days of treatment. Patients must agree to use a reliable method of birth control during and 
for 6 months following the last dose of study drug. 
 
6. Ability to swallow oral medication. 
 
7. Non-surgical patients: If primary radiation +/- chemotherapy (concurrent or sequential) is 
planned, patients must agree to undergo research biopsy after completion of ribavirin 
treatment. 


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6.2 
Subject Exclusion Criteria 
 
1. Prior chemotherapy or radiation for tonsillar or base of tongue squamous cell cancer 
 
2. More than 10 pack-years of tobacco use 
 
3. History of hemolytic anemia or thalassemia 
 
4. Active infection or serious underlying medical condition that would impair the patient’s 
ability to receive protocol treatment. 
 
5. Current therapeutic anticoagulation with Coumadin (warfarin) 
 
6. Current or prior treatment with ribavirin 
 
7. Known active Hepatitis B or C 
 
8. Any prior documented history of transient ischemic attack (TIA) or cerebrovascular 
accident (CVA) 
 
9. New York Heart Association (NYHA) Grade II or greater congestive heart failure 
 
10. Clinically significant peripheral vascular disease 
 
11. History of unstable angina or myocardial infarction (MI) within the last 3 years 


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7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team at Memorial Sloan-Kettering Cancer Center (MSKCC). 
 
Patient recruitment will occur in medical oncology clinics of the Head and Neck Disease 
management team at main campus.  If the investigator is a member of the treatment team, 
s/he will screen their patient’s medical records for suitable research study participants and 
discuss the study and their potential for enrolling in the research study. Potential subjects 
contacted by their treating physician will be referred to the investigator/research staff of the 
study. 
 
. 
 
8.1 
PRETREATMENT EVALUATION 
 
All pre-treatment evaluations should be within 21 days prior to therapy, unless otherwise 
specified in this Section. 
 
• 
Complete medical history including current medications, physical examination including 
evaluation of Karnofsky performance status. 
 
• 
Pathology review at MSKCC must confirm diagnosis of tonsil and/or base of tongue 
squamous cancer that is positive for expression of phosphorylated eIF4E, at any time 
prior to treatment.  Diagnostic biopsy may be of tonsil and/or involved neck node.  2 
unstained slides and/or tissue block must be available from the diagnostic biopsy 
 
• 
The following laboratory studies will be obtained within 21 days prior to therapy: 
Complete blood count with white blood cell differential and platelet counts; 
Comprehensive profile (including electrolytes, bicarbonate, blood urea nitrogen (BUN), 
creatinine, glucose, alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), total bilirubin, total protein, albumin, and glucose);  prothrombin 
time and activated partial thromboplastin time 
 
• 
Serum pregnancy test for women of childbearing potential within 14 days prior to therapy. 
 
• 
Electrocardiogram within 8 weeks prior to therapy 
 
• 
Baseline cross-sectional imaging of the neck (CT neck or MR neck) within 8 weeks prior 
to therapy 


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9.1 
TREATMENT/INTERVENTION PLAN 
 
9.2 Clinical Plan 
 
The clinical intervention in this study is ribavirin therapy for approximately 14 days. Ribavirin 
800 mg/day is administered in divided doses, 400 mg PO qAM and 400 mg PO qPM.  Details 
regarding evaluations during treatment are provided in Section 10. 
 
9.3 Immunohistochemistry (IHC) 
 
Each formalin-fixed and paraffin-embedded tissue specimen will be processed for IHC, 
consistent with established methods in our group (70). The time from tumor removal 
at 
surgery to formalin fixation should be 2 hours or less. 
 
The avidin-biotin immunoperoxidase technique will be employed.  Antigen retrieval with citric 
acid (0.01%) for 15 minutes under microwave treatment commonly precedes incubation with 
the primary antibody (usually overnight at 4oC). Primary antibodies to be used include anti- 
phospho eIF4ESer209 (rabbit polyclonal, Cell Signaling #9741), anti-p16 (mouse IgG, clone 
E6H4, Dako #K5334), anti-p21 (mouse IgG, clone EA10, Calbiochem #OP64), anti-EGFR 
(mouse IgG, clone 31G7, Ventana #28-005), anti-HPV16 E6 (mouse IgG, clone C1P5, Santa 
Cruz #sc-460), and anti-E7 (mouse IgG, clone 8C9, Invitrogen #28-0006).  Diaminobenzidine 
will be utilized as the final chromogen and hematoxylin will provide the nuclear counterstain. 
 
If limited tumor tissue is available, the top priority immunostain will be phosphorylated eIF4E. 
 
If sufficient tissue is available, exploratory analysis of additional biomarkers may be 
performed.   For example, if immunohistochemistry does not provide definitive data regarding 
levels of  E6,  E7, and p53, expression may be explored  with RT PCR using established 
methods (71, 72). 
 
Technical difficulty or inability to obtain results with certain antibodies or samples will not be 
considered a protocol violation. 


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10.1 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.2 Description of Evaluations 
 
Patients will be provided with a pill diary at the start of  treatment (Appendix A), and will be 
required to bring a updated pill diary to each clinic visit.  If patients miss any doses of 
ribavirin, this will not be considered a protocol violation but the investigator retains the 
discretion to remove patients from study for non-compliance. 
 
Every attempt will be made for patients to have clinic visits and laboratory tests on the 
indicated dates.  However, dates may need to be altered for medical or personal or logistical 
reasons. Clinic visits and laboratory studies may occur 3 days before or 3 days after the 
scheduled date, if need be. Additional clinical visits and laboratory studies may be 
scheduled if clinically necessary, per investigator discretion. 
 
• 
On Day 1, routine laboratory studies are obtained: complete blood cell count and 
comprehensive metabolic panel. Patients undergo history and physical. 
 
• 
Days 1 – 14, approximately: ribavirin 800 mg/day in divided doses, 400 mg q AM and 
400 mg q PM.  Typically, this will be administered as two 200 mg tablets qAM, and 
two 200 mg tablets qPM.  Use of one 400 mg tablet (instead of two 200 mg tablets) is 
also allowed, at the discretion of the investigator. 
 
• 
On Day 8, Routine laboratory studies are obtained: complete blood cell count and 
comprehensive metabolic panel. Patients undergo history and physical. 
 
• 
Day 15 (approximately):  Surgical plan is resection or research biopsy of the tonsil 
and/or base of tongue squamous cell carcinoma, possibly with neck dissection at the 
discretion of the surgeon.   Patients will be considered done with treatment at time of 
surgery or research biopsy.  As such, the surgical or biopsy procedure is considered 
off-protocol, and the surgery or research biopsy will be performed at the discretion of 
the investigator. The protocol provides no guidance nor places any restrictions 
regarding surgical management. 
 
While every attempt will be made to schedule surgery or research biopsy on Day 15, 
the exact timing of surgery or research biopsy will be at the discretion of the surgeon. 
No ribavirin will be given after surgery or research biopsy. 
 
• 
Post-operative (or post research biopsy) management will be per standard of care, off 
protocol. 


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10.3 Calendar of Events 
 
Baseline 
Day  a 
1 
Day 8 
Day 14 
Day 15 
History and Physical 
X 
X 
X 
CBC, comp panel 
X 
X 
X 
PT/aPTT 
X 
EKG 
X 
CT or MRI of neck 
X 
Ribavirin 
800 mg PO daily X 14 days 
Surgery or research 
biopsy 
X 
Adverse Events (AEs) 
Continuous Monitoring for AEs 
a 
This table shows approximate dates. Please see sections 9 and 10 for allowed variations in the 
timing of interventions and assessments 


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11.1 TOXICITIES/SIDE EFFECTS 
 
This section provides guidelines for the clinical management of adverse events. The 
toxicities of ribavirin are presented in Section 5, and are listed again here: 
 
Hematologic:  anemia, thrombocytopenia, leukopenia, lymphopenia 
Gastrointestinal:  anorexia, nausea, diarrhea 
Hepatic:  elevated liver function tests 
Pulmonary:  dyspnea, cough 
Reproductive:  may be teratogen 
Constitutional: fatigue, musculoskeletal pain 
Dermatologic: alopecia, pruritis, rash 
Neurologic:  headache, dizziness 
Endocrine and metabolic:  hyperuricemia 
 
 
Reporting requirements for adverse events are presented in Section 17.2. 
 
All toxicities will be assessed according to CTC version 4.  Dose reductions or drug stoppage 
are only required for those adverse events that the investigator feels are possibly, probably, 
or definitely related to ribavirin. 
 
Subjects who take < 10 days of ribavirin prior to surgery will be considered inevaluable and 
will be replaced. 
 
Any patient who requires dose reduction below 600 mg/day will be removed from study. 
 
11.2 Hematologic Toxicity 
 
The most common toxicity requiring dose reduction for ribavirin is anemia. 
 
For any patient who experiences a fall in hemoglobin of > 2 g/dL (from Day 1 value), ribavirin 
dose will be decreased to 600 mg/day (200 mg qAM, 400 mg qPM).   Any patients who 
develop a hemoglobin level of < 10 g/dL will be removed from study. 
 
Any patient who develops a platelet count of < 100 K/mcL will be removed from study. Any 
patient who develops an absolute neutrophil count of <1.0 K/mcL will be removed from study. 
Dose delays and dose reductions are not required for uncomplicated leukopenia or 
uncomplicated lymphopenia. 
 
11.3 Non-Hematologic Toxicity 
 
For any patient who develops grade 2 toxicity (felt to be definitely, probably, or possibly 
related to ribavirin), the investigator may either (a) reduce the dose of ribavirin to 600 
mg/day, or (2) remove the patient from study.  Any patient who develops toxicity of grade 3 
or greater will be removed from study. 
 
Even when the patient meets criteria for continued treatment at full dose per the protocol, 
the investigator retains the discretion to delay treatment and/or reduce dose (to 600 


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mg/day)  if there are safety concerns and/or logistical issues.  Any dose reductions not 
specified in the protocol should be discussed with the principal investigator. 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The primary objective of this study is based on immunohistochemistry (IHC), not a 
therapeutic or radiologic outcome. For details regarding IHC methods, see Section 9.2.   As 
a secondary endpoint, we wish to explore the feasibility of using pre and post treatment 
FDG-PET/CT scans to assess the metabolic effect of ribavirin in tonsillar and/or base of 
tongue squamous cell carcinoma. 
 
The volume(s) of interest (VOI) from the MRI neck (or CT neck) images will be matched to 
the FDG PET/CT images.  Matched VOIs will be analyzed by visual and semiquantitative 
analysis, using the attenuation-corrected PET emission images. For semiquantitative 
analysis, VOIs are placed over the areas of focal FDG uptake in the neck nodal metastases. 
The intensity of FDG uptake in these regions is measured using the standardized uptake 
value (SUV), normalized to body height. The maximum pixel SUV was recorded. The 
imaging data initially available in units of microcuries per milliliter per voxel are decay 
corrected to the time of injection and converted into SUV units (73). 
 
PET images will be reconstructed from the initial data set using iterative reconstruction 
software and will be reoriented into transaxial, coronal and sagittal slices. Attenuation 
corrected scans will be read. The images will be reviewed in all standard planes (3- 
dimensional computer display) and a maximum intensity projection (MIP) image.  At least 2 
parameters will be investigated as measures of tumor response to therapy: SUVmax and 
SUVmean. Changes in these parameters between the baseline and follow up scans will be 
used as a measure of effect of study drug. The data analysis equipment and software for 
nuclear medicine imaging is continuously changing and evolving. As new imaging analysis 
methods are developed, we will apply those that are optimal to the imaging purpose. 
 
13.1 CRITERIA FOR REMOVAL FROM STUDY 
 
 
• 
Patients may be removed from the study for protocol non-compliance. 
 
• 
If at any time the patient develops unacceptable toxicity he/she will be removed from 
study. 
 
• 
Participants can be removed from the study at any time if the study doctor feels that it is in 
their best interest to do so. 


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14.0 BIOSTATISTICS 
 
The primary endpoint of this pilot study is to explore if ribavirin therapy for 2 weeks 
decreases tumor expression of phosphorylated eIF4E among patients with tonsillar and/or 
base of tongue squamous cell carcinomas that expresses phosphorylated eIF4E. 
 
Decision Rule: We would consider ribavirin to be interesting for further study in this patient 
population if we observe at least 4 patients (among 7) in which positive baseline expression 
of phosphorylated eIF4E becomes negative after ribavirin treatment. 
 
Positive phosphorylated eIF4E overexpression is defined as ≥30% of cells with cytoplasmic 
and/or nuclear staining by IHC (19, 24).  With this 30% cutoff, the probabilities of observing 
at least 4 patients with negative post-treatment eIF4E expression among the 7 patients 
included in the study are listed below: 
 
True probability that 
ribavirin inhibits eIF4E 
expression 
Probability of observing the 
inhibition in at least 4 of the 7 
patients 
.40 
.29 
.50 
.52 
.60 
.71 
.70 
.87 
.80 
.97 
 
 
For each of the patients tested, we will tabulate pretreatment and posttreatment tumor 
expression of phosphorylated eIF4E, of molecules that are regulated by eIF4E (p16, p21, 
EGFR), HPV-16 oncoproteins (E6 and E7) and FDG-PET/CT scans, as well as percentage 
change between pretreatment and posttreatment levels. 
 
Toxicity data (AEs, laboratory data and vital sign data) will be collected and listed individually 
per patient according to CTCAE version 4.0. 
 
Subjects who take < 10 days of ribavirin prior to surgery (or research biopsy) will be 
considered inevaluable and will be replaced. The expected accrual rate is 1 to 2 patients per 
month, so we expect the study to be completed in 4 to 7 months. 
 
Note:  If the post-treatment tumor specimen cannot be obtained (eg, technical issues or 
patient withdraws consent) or if insufficient/inadequate material is available for 
immunostaining of phosphorylated eIF4E, the subject will be deemed inevaluable and 
will 
be replaced. If there is insufficient/inadequate tissue to perform the other immunostains discussed 
in the secondary aims, this would not be considered a protocol 
violation and the subject would 
not need to be replaced as long as the patient was evaluable for the primary endpoint of this pilot 
study. 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office at 
Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
16.1 DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team.  The data collected for this study will be entered into a secure 
database.  Source documentation will be available to support the computerized patient 
record. 
 
16.2 Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data.  Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. 
 
16.3 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 


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monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol is assessed for it’s level 
of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in- 
house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
17.1 PROTECTION OF HUMAN SUBJECTS 
 
Inclusion of Children in Research 
 
This protocol/project does not include children because the number of children is limited and 
because the majority are already accessed by a nationwide pediatric cancer research 
network. This statement is based on exclusion 4b of the NIH Policy and Guidelines on the 
Inclusion of Children as Participants in Research Involving Human Subjects. 
 
17.2 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The 
IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the 
SAE Office at sae@mskcc.orgcontaining the following information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
 
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• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
17.3 Risks, Benefits, Toxicities/side effects 
Potential risks to human subjects include drug related toxicity, pain and discomfort 
associated with ribavrin side effects (Section 5 and Section 11), phlebotomy, and possible 
psychological discomfort from the stresses associated with obtaining imaging studies. There 
also is a small potential risk associated with low-level radiation exposure from the research 
FDG PET-CT scan in this study.  All efforts will be made to avoid any complication by 
completely reviewing patients’ symptoms, providing appropriate management, and 
monitoring blood tests. 
 
For patients who undergo research biopsy, this may be associated with discomfort at the 
biopsy site and minor bleeding or infection at the biopsy site. 
 
If an adverse medical event occurs, the patient will first contact the primary oncologist or the 
Principal Investigator.  At nights and on weekends, there is an oncology physician on call at 
all times.  Patients may either call or come directly to the urgent care center at Memorial 
Hospital (or to their local emergency room) to be seen. Patients suffering serious adverse 
reactions must be carefully followed and all follow-up information also recorded. 
 
17.4 Alternatives/options 
Participation in this trial is voluntary.  Patients may opt not to participate in this study prior to 
the planned surgery. 
 
 
17.5 Financial Costs/Burdens 
The patient will be responsible for all costs related to treatment and complications of 
treatment. Costs to the patient (third party insurer) will include the costs routine blood tests 
and diagnostic studies, office visits, baseline EKG, doctor’s fees, and any hospitalizations. 
Patients will not be charged for any research tests performed on research specimens. 
Ribavirin is purchased with Head and Neck DMT research funds and with not billable to 
research participants.  Post-treatment FDG PET-CT scan, if obtained, is paid for Head and 
Neck DMT research funds and is not billable to research participants. 
 
 
18.1 INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 


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Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 


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20.0 
APPENDICES 
 
Appendix A   - Pill Diary