Conditions: Squamous Cell Carcinoma of Skin Carcinoma, Squamous Cell
Keywords: metastatic cutaneous skin cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if the combination of two established anti-cancer therapies are beneficial in patients with squamous cell carcinoma of the skin. Specifically, investigators want to determine if the combination of 5-FU/Capecitabine (oral pills) and Interferon alpha-2b (injection) can help people with advanced cases of squamous cell carcinoma of the skin. For participants that are not approved for oral capecitabine, treating physicians will use continuous infusion 5-FU. Both 5-FU/Capecitabine and Interferon alpha-2b have been used separately to treat squamous cell carcinoma of the skin and are FDA approved in other cancer types.

Detailed description:

Arms:
arm 1: Participants will start the Capecitabine pills on day 1 thru day 14 and be off for 7 days (day 15-day 21).

Participants will receive 5-FU days 1-4 of each 21 day cycle.

Participants will receive the Interferon alpha-2b injection weekly every week. The three week period is referred to as one cycle.

After three cycles, new imaging studies will be performed that will measure how the disease is responding to treatment. Participants whose disease is stable or improved will undergo an additional 3 cycles of therapy and the imaging studies will be repeated. Again, participants whose disease is stable or improved will undergo a final 3 cycles of treatment (a total 27 weeks of treatment).

Interventions: intervention 1: Pegylated Interferon alpha-2b intervention 2: Capecitabine intervention 3: 5-FU
Intervention descriptions: intervention 1: Drug administration will occur on an outpatient basis at the infusion center at Moffitt Cancer Center. Dose will be weight-based. Starting treatment doses of 3 mcg/kg will be given subcutaneously (SC) injection in the thigh, abdominal wall, or upper arm every week for a total of 27 weeks as tolerated. intervention 2: Drug administration will be on an outpatient basis. Capecitabine will be administered at an initial dose of 800 mg/m\^2 by mouth twice daily on days 1-14 of a 21 day cycle with days 15-21 off. This cycle will be repeated every 21 days during the study for a maximum of 9 cycles as tolerated. Administration via feeding tube in patients unable to swallow is permitted. intervention 3: If participants are not able to acquire oral capecitabine, then treating physicians will start participants on infusional 5-FU which can be delivered via standard of care. Participants will need to have a port placed for continuous infusion treatments. 5-FU pumps will be activated in the infusion center at Moffitt Cancer Center with a starting dose of 800 mg/m\^2 days 1-4, with pump removal on day 5 at the infusion center. 5-FU pumps will be attached every 21 days (1 cycle) for a maximum of 9 cycles.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
TITLE: A Phase 2 Study of Capecitabine or 5-FU with Pegylated Interferon alpha-
2b in Unresectable/Metastatic Cutaneous Squamous Cell Carcinoma 
 
NCT02218164 
 
 
Version 6.0 
June 15, 2017 




2 
Protocol Version Date:   v6.0 – 06/15/2017 
 
 
SCHEMA 
 
Progressive 
Disease 
Progressive 
Disease 
1) Patients with Unresectable or Metastatic Cutaneous Squamous Cell 
Carcinoma not treatable by surgical intervention or radiotherapy treatments 
2) Confirm eligibility by pathology, RECIST evaluable lesions, organ function 
studies, and review at Moffitt Cutaneous Oncology Tumor Board; 
3) Request punch biopsy (optional) 
One Cycle of Treatment: 
1) Capecitabine 800 mg/m2 PO BID 
d1-14 on/7 days off q 21 days 
OR 
5-FU 800 mg/m2 IV d1-4 (Continuous Infusion) q21 days 
AND 
2) Peg-Interferon 3 mcg/kg SC q week x3 
 
Treat for 3 cycles (9 weeks); assess 
for disease response by imaging 
(RECIST) 
Off Study 
- Follow up q3 months for 1 year 
 
Treatment for 3 additional cycles 
 (9 weeks);Assess for disease 
response by imaging (RECIST) 
Treatment for 3 additional cycles 
 (9 weeks); Assess for disease 
response by imaging (RECIST) 
Off Study 
- Follow up q3 months for 1 year 
 
Assess Outcomes: 
 
1) Primary Endpoint:  
- Response Rate 
 
2) Secondary Endpoints:  
- Progression Free Survival at 1 year 
- Overall Survival at 1 year 
- Adverse Events 
 
Off Study; 
Request additional punch biopsy (optional) 
 
- Follow up q3 months for 1 year 


3 
Protocol Version Date:   v6.0 – 06/15/2017 
 
TABLE OF CONTENTS 
 
 
Page 
SCHEMA 
......................................................................................................................................... 2 
 
1. OBJECTIVES ........................................................................................................................... 5 
 
2. BACKGROUND 
........................................................................................................................ 5 
2.1  Study Disease 
............................................................................................................... 5 
2.2  PEG Interferon alpha-2b 
............................................................................................... 5 
2.3   5-FU/Capecitabine 
........................................................................................................ 6 
2.4  Rationale 
....................................................................................................................... 7 
 
3. PATIENT SELECTION ............................................................................................................. 8 
3.1  Inclusion Criteria  
.......................................................................................................... 8 
3.2  Exclusion Criteria 
........................................................................................................ 10 
3.3  Inclusion of Women and Minorities ............................................................................ 10 
3.4   Patient Registration .................................................................................................... 10 
3.5       Removal of patients from study  ................................................................................. 10 
 
4. TREATMENT PLAN ............................................................................................................... 11 
4.1      Capecitabine Administration 
........................................................................................ 11 
  
4.1.1   Supportive Care Guidelines ............................................................................ 11 
4.2   5-FU Adminstration 
  
4.2.1   Supportive Care Guidelines  ........................................................................... 11 
4.3      Interferon alpha-2b Administration............................................................................... 11 
  
4.3.1   Supportive Care Guidelines ............................................................................ 11 
4.4      Duration of Therapy ..................................................................................................... 12 
4.5      Duration of Follow Up .................................................................................................. 12 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
......................................................................... 12 
 
6. PHARMACEUTICAL INFORMATION 
.................................................................................... 14 
 
7. ADVERSE EVENTS and REGULATORY REPORTING 
....................................................... 15 
 
8. STUDY CALENDAR 
............................................................................................................... 17 
 
9. MEASUREMENT OF EFFECT 
............................................................................................... 18 
9.1  Definitions 
................................................................................................................... 18 
9.2  Guidelines for Evaluation of Measurable Disease 
..................................................... 19 
9.3  Response Criteria 
....................................................................................................... 19 
9.4  Confirmatory Measurement/Duration of Response 
.................................................... 20 
9.5  Progression-Free Survival 
.......................................................................................... 21 
 
10. REPORTING REQUIREMENTS 
............................................................................................. 21 
10.1  Expedited Adverse Event Reporting .......................................................................... 21 
10.2  Data Reporting 
............................................................................................................ 21 
10.2.1 Institutional Review Board .................................................................................... 21 
10.2.2 Data reporting ....................................................................................................... 21 
10.2.3 Informed Consent ................................................................................................. 22 
10.2.4 Hospital/Clinical Records 
...................................................................................... 22 


4 
Protocol Version Date:   v6.0 – 06/15/2017 
 
10.2.5  Investigator Study Files 
......................................................................................... 22 
10.3  Reporting and Exclusions ........................................................................................... 22 
 
11. STATISTICAL CONSIDERATIONS ....................................................................................... 22 
 
12. Correlative Studies  
…………………………………………………………………………………23 
 
13. REFERENCES ....................................................................................................................... 25 
 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria 
............................................................................................. A-1 
 
 
APPENDIX B 
Informed Consent 
............................................................................................................. B-1 
 
 


5 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
1. OBJECTIVES 
1.1 Primary Objective(s) 
To establish the objective response rate, using RECIST criteria, to the combination  
Treatment of Interferon alpha-2b and 5-FU/Capecitabine in patients with unresectable and/or 
metastatic cutaneous squamous cell carcinoma of the skin 
 
1.2 Secondary Objective(s) 
To establish the progression free and overall survival at one year, adverse events,  
and safety profile of the combination treatment of Interferon alpha-2b and  
5-FU/Capecitabine in patients with unresectable and/or metastatic cutaneous squamous  
cell carcinoma of the skin 
 
2. BACKGROUND 
2.1 Study Disease 
While squamous cell carcinoma of the skin is a very common cancer, the true number of 
cutaneous squamous cell carcinoma (CSCC) cases are difficult to determine, as the national 
SEER database does not capture non-melanomatous skin cancers (NMSC)1. However, it has 
been estimated that there are over 1.5 million cases of NMSC (75% Basal cell carcinoma and 
25% Squamous cell carcinoma) diagnosed annually in the US2. Besides the known risk factor of 
UV exposure, an increase in cutaneous squamous cell carcinoma (CSCC) has been noted as a 
result of rising rates of transplants (BMT and solid organ) and the widespread use of 
immunosuppressive agents. 
 
The majority of CSCCs are local in origin and are therefore treated with focal therapies including 
surgery, cryotherapy, topical chemotherapy (imiquimod, topical 5-FU), photodynamic therapy, 
and radiation therapy.  Local control with these therapies typically exceeds 90% and even in 
patients with recurrent local disease, local control rates remain quite high3. 
 
Seventy-five percent of recurrences occur in the first two years and typically recur locally or in 
regional lymph nodes placing patients at high risk for developing distant metastasis
4. While 
metastatic squamous cell cancer of the skin is rare, its’ consequences are profound.  In one 
study, 34 of 695 cases of cutaneous squamous cell carcinoma developed metastases for a 
metastatic rate of approximately 5%.  The overall mortality of all patients was 3.4%; however, the 
mortality rate in the metastatic group exceeded 70%5. Similarly, in CSCC patients with distant 
metastasis, Alam et al. described a 5-yr survival rate of less than 10%6. 
 
Thus, while many patients are cured with local therapy, those with unresectable locoregional 
disease or known sites of distant metastasis have an increased mortality rate. Presently there is 
no standard accepted treatment for unresectable or metastatic disease. 
 
2.2 PEG Interferon alpha-2b 
PEG Interferon (IFN) alpha-2b was approved in 2001 by the FDA for the adjuvant treatment of 
melanoma for those patients with residual microscopic or gross disease. Currently, IFN alpha-2b 
is also approved for use in patients with hepatitis C and used frequently in patients with renal cell 
carcinoma. The non-PEG formulation has been tested in a variety of tumor types including 
cutaneous squamous cell carcinoma. 
 
The pegy
lated formulation of IFN alpha-2b was designed to protect IFN from proteolytic 
breakdown and extend the half-life of the protein. IFN alpha-2b is a protein produced by 
recombinant DNA techniques from a strain of E. Coli bearing a engineered plasmid containing 


6 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
the interferon gene from human leukocytes. The drug comes in a lyophilized power in a single-
use vial and reconstituted with 0.7 mL sterile water. Peg-IFN alpha-2b is given SQ on a weekly 
basis from doses of 3 mcg/kg (maintenance) to 6 mcg/kg (induction therapy) in the setting of 
melanoma and doses of 1-1.5 mcg/kg in hepatitis C patients. Treatment periods range from 24-
48 weeks for hepatitis C and 1-5 years for melanoma. Of note, IFN alpha-2a and -2b are related 
protein products, but PEG IFN alpha-2b was selected as it is dosed by body weight, has a more 
rapid absorption, and a wider distribution within the body. 
 
The mechanism(s) of action had not been fully identified; however, it is considered an 
immunomodulatory cytokine that enhances the phagocytic and cytotoxic activity of macrophages 
and leukocytes.  
 
The drug has a half-life of approximately 40 hours with a peak plasma time of 15-44 hours. It is 
excreted renally and dose reductions of 25-50% are recommended for moderate to severe renal 
impairment (Cr Cl <50 or <29 ml/min respectively). The drug is contraindicated for patients with a 
known hypersensitivity to IFN, patients with autoimmune hepatitis, or hepatic decompensation. 
 
Common adverse events include: headache, fatigue, injection site reactions, depression, 
emotional liability, suicidal ideation, insomnia, alopecia, fever, transaminitis, anorexia, GI 
irritation (abdominal pain, nausea, diarrhea), arthralgias, myalgias, chills, and rash. Severe 
adverse reactions include: neuropsychiatric reactions, arrhythmia, cardiovascular 
decompensation, retinopathy resulting in blindness, hepatic failure, and can result in new or 
worsening of endocrinopathies. 
 
Currently there are no known drug interactions, however, data suggest possible impairment of 
CYP2C9 (increased activity) and CYP2D6 (decreased activity). When combined with drugs with 
narrow therapeutic windows, it is recommend to monitor those drug levels frequently. 
 
2.3 5-FU/Capecitabine 
 
5-FU is an antineoplastic antimetabolite that blocks the methy
lation reaction of deoxyuridy
lic acid 
to thymidy
lic acid, and in consequence, interferes with the synthesis of DNA and to a lesser 
extent RNA. Given the essential nature of DNA and RNA for cell growth, the generation of a 
thymine deficiency can result in cell death, most pronounced on rapidly growing cells, as found 
commonly in a variety of cancers7. 
 
In the US, 5-FU is given as a continuous infusion IV where it is partial excreted by the kidneys 
(20%) and the remainder is metabolized by the liver. Half-life is approximately 20 minutes and it 
can cross the blood-brain barrier. 5-FU is formally FDA approved in colorectal cancer, breast, 
stomach, and pancreatic cancers, but is widely used off label in a variety of cancers including 
mucosal squamous head and neck cancers and cutaneous squamous cell carcinomas.  
 
Adverse events associated with 5-FU includes: stomatitis, nausea, diarrhea, neutropenia, 
neurotixicity, hand-foot syndrome, as well as risk of a hypersensitivity reaction in patients with a 
dipyrimidine dehydrogenase deficiency. 5-FU is teratogenic in lab animals and rated pregnancy 
class D. 
 
Capecitabine,an oral pre-drug of 5-FU, was first approved for use in the United States by the 
FDA in 1988.  It is presently approved for use in patients with metastatic breast cancer, both as 
monotherapy and in combination with docetaxel.  It is also approved for both metastatic 


7 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
colorectal cancer and as an adjuvant followers and resection of Dukes’ Stage C colon cancer.  
Despite this rather limited FDA labeling, it is widely used both as a single agent and in 
combination for a multiplicity of other tumors including gastric, pancreatic, and squamous cell 
cancers of the head and neck.  
 
While the standard FDA approved dose as listed in the package insert is 1250 mg per meter 
squared twice daily for two weeks followed by seven-day rest period, most clinicians have found 
this dose to be intolerable on a chronic basis.  Therefore, it has become conventional to initiate 
dosing at 1000 mg per meter squared twice daily instead. The drug is presently available as 
Xeloda in two pill sizes, 150 mg and 500 mg.  When the patent expires on Xeloda in 2013 is 
unclear when or if generic equivalents will become available and in what doses the pills will be 
manufactured.  Should a generic version become available while this trial is open and accruing 
patients, the protocol will be modified accordingly. 
 
The mechanism of action of capecitabine is conversion to 5-fluorouracil in vivo, occurring mostly 
in the liver.  Cells subsequently metabolize 5- fluorouracil to FdUMP and FUTP.  FdUMP inhibits 
thymidy
late synthase, thereby decreasing pools of thymidine triphosphate available for DNA 
synthesis. FUTP can substitute for UTP during RNA synthesis, thereby disrupting protein 
synthesis from the abnormal RNA. Capecitabine is absorbed rapidly and conversion into 5-FU is 
rapid with peak levels reached within two hours post ingestion.  Concomitant food consumption 
with capecitabine lowers both peak concentration and area under the curve concentration of 
capecitabine substantially.  The elimination half-life of capecitabine and its metabolites is quite 
fast, on the order of approximately one hour.  However, the cellular consequences of thymidy
late 
synthase and RNA synthesis disruption are much more prolonged as they are dependent on 
regeneration of normal pools of the enzymes and RNA precursors. 
 
Metabolism and bioactivation of capecitabine is hepatic, while excretion of capecitabine and its 
metabolites is predominantly accomplished by the kidneys with minimal fecal excretion.  
Therefore, dose adjustments for both renal insufficiency and hepatic insufficiency are warranted. 
 In the case of mild renal impairment with a creatinine clearance greater than 50 mL/min, no 
dose adjustment is recommended.  With moderate renal impairment (creatinine clearance 30-49 
mL/min), a 20% dose reduction is recommended.  While there is no defined dose adjustment for 
patients with hepatic dysfunction, caution should be used in administering capecitabine to 
patients with markedly abnormal hepatic function.  Additional details on warnings and dose 
modifications for hepatic and renal dysfunction are available in the capecitabine package insert. 
 
Common adverse events associated with capecitabine include diarrhea (stomatitis from 
gastrointestinal toxicity), coagulopathy, cardiotoxicity, fetal harm, hand-foot syndrome, 
hyperbilirubinemia, and bone marrow suppression, resulting in anemia, thrombocytopenia, and 
neutropenia. 
 
There are known drug-drug interactions between 5-FU/capecitabine and coumadin 
anticoagulants, as well as 5-FU/capecitabine and phenytoin.  While co-administration of these 
agents is not prohibited, frequent monitoring of prothrombin time and phenytoin levels in patients 
on concurrent 5-FU/capecitabine is warranted. 
 
2.3 Rationale 
There are no drugs presently approved by the US Food and Drug Administration for treatment of 
metastatic squamous cell carcinoma of the skin.  However, several drugs are used off-label, 
based on a limited number of investigations in the medical literature.  Prior case reports or case 


8 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
studies have reported objective responses using cisplatin in combination with bleomycin, 
methotrexate, or doxorubicin8-10. Phase II data using retinoic acid and interferon-alpha alone or 
in combination with cisplatin demonstrated response rates of 34% and 43%, respectively
11,12.  
A Phase I trial attempted to combine cis-retinoic acid, IFN alpha-2a, cisplatin, and 5-
FU/Leucovorin; however, cytopenic toxicities limited the full administration of this regimen13. A 
more recent adjuvant Phase III trial in post-surgical patients with CSCC used cis-retinoic acid 
and interferon alpha versus observation, but failed to reduce the risk of recurrence14.  
 
Capecitabine has also been used against CSCC with modest response rates, but the data is 
reported as two case series
15,16. In virtually every disease studied in which 5- fluorouracil is 
clinically active, capecitabine has demonstrated similar activity. Previously, we have treated a 
number of skin squamous cell carcinoma patients with capecitabine off-label and have noted 
dramatic and prolonged antitumor effects in a number of these patients. Additionally, we found 
that with the ease of titrating the oral doses of capecitabine, we could reduce drug toxicity, and 
patients were able to tolerate therapy for an extended period of time. Furthermore, the use of an 
oral agent may be favored by patients rather than an IV infusion. 
 
Unfortunately, the studies discussed above suffer from small patient numbers, combined 
squamous and basal cell cohorts, and the demonstration of chemotherapy-induced toxicity. 
While no standard therapy exists for CSCC, we propose that a cytotoxic drug with documented 
response rates in CSCC combined with an immunomodulatory agent, also known to have 
benefit in this patient group, may result in overall improved response rates. 
 
Therefore, we intend to conduct a phase II, single arm trial of interferon alpha-2b and 5-
FU/capecitabine in patients with advanced or recurrent squamous cell carcinoma of the skin for 
which local regional treatment would not be expected to be curative.  Because there is no known 
first line standard of care treatment for these patients and because of the known activity of 5- 
fluorouracil analogues and interferon-alpha in this disease, our intention is to allow patients to be 
treated in the first line with the combination of interferon alpha-2b and 5-FU/capecitabine without 
regard to prior chemotherapy, other than prior systemic treatment with 5-fluorouracil analogues. 
 
It is our intention to use commercially available PEG interferon alpha-2b and 5-FU/capecitabine 
for this trial.  Based on prior experience, a high percentage of these patients are able to attain 
these drugs for off-label use in this situation.  However, we have found in some cases, insurance 
companies have been reticent to approve coverage for capecitabine.  We believe that by 
generating data showing that capecitabine in combination with interferon alpha-2b is safe and 
effective in this group of patients, its use will become more widely accepted based on this 
proposed clinical trial as well as to provide continued support of the benefit of immunotherapy in 
this disease. For patients that are not approved for oral capecitabine, we will use continuous 
infusion 5-FU as described above. 
 
3. PATIENT SELECTION 
 
3.1 Inclusion Criteria 
3.1.1 Patients must have histologically or cytologically confirmed squamous cell 
carcinoma of the skin. Patients who present with “squamous cell carcinoma of 
unknown primary lesions” at the time of diagnosis will be eligible if patients 
have a plausible primary skin site removed in the past. Similarly, patients with 
neck, parotid, or facial lymph nodes positive for squamous cell carcinoma with 
no identifiable mucosal primary would also be eligible. 


9 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
 
3.1.2 Patients must have measurable disease, defined by RECIST v1.1 as at least 
one lesion that can be accurately measured in at least one dimension of >10 
mm by CT, MRI, or calipers. See section 9.2 for the evaluation of measurable 
disease.  
 
3.1.3  There is no limitation to prior treatments with local, regional, topical or  
        systemic agents, except for prior systemic treatment with 5-  
       fluorouracil or prodrugs thereof.  Prior topical treatment with 5-  
           fluorouracil is permitted. Patients who are on chronic daily doses of  
           prednisone of greater than 10 mg are excluded. There is no restriction  
           on timing of last treatments as long as patients have recovered from  
           all expected toxicities and at least 21 days have passed since last  
           administration. 
 
3.1.4 Age >=18 years. Because no dosing or adverse event data are currently 
available on the use of 5-FU/Capecitabine or IFN alpha-2b in patients <18 
years of age, children are excluded from this study. 
 
3.1.5 Life expectancy of greater than 3 months. 
 
3.1.6 ECOG performance status <=2 (Karnofsky >=60%; see Appendix A). 
 
3.1.7 Patients must have normal organ and marrow function as defined  
            below: 
 
Absolute neutrophil count  
>=1,500/mcL 
 
Platelets 
>=75,000/mcL 
 
Total Bilirubin 
< ULN 
       
or up to 2x ULN if patient has clinically    
                                                     documented Gilbert’s syndrome  
       
(elevated unconjugated bilirubin from  
       
decreased UGT1A1 activity) 
 
AST(SGOT)/ALT(SGPT)  
≤2.5x institutional upper limit of 
                         
normal or up to 5x ULN if known to  
                         
be caused by liver metastasis 
 
Creatinine Clearance  
>=50 mL/min by either Cockcroft-Gault 
formula or 24 hr urine collection analysis. 
 
3.1.8 Patients must not be candidates for curative locoregional treatments.  
     Patients with recurrent locoregional disease following surgery and/or  
     radiation for who a resection is unacceptably morbid and unlikely to be  
     curative are eligible. Patients must be reviewed at the Moffitt Cutaneous  
     Tumor Board prior to enrolling on trial to verify unresectability. 
 
3.1.9 The effects of 5-FU/Capecitabine and IFN alpha-2b on the developing  


10 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
     human fetus at the recommended therapeutic dose are unknown.  For  
     this reason and because anti-metabolites are known to be teratogenic,  
     women of child-bearing potential and men must agree to use adequate  
     contraception (barrier method of birth control; abstinence)  
     prior to study entry and for the duration of study participation.  Should  
     a woman become pregnant or suspect she is pregnant while  
     participating in this study, she should inform her treating physician  
     immediately. 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2   Exclusion Criteria 
3.2.1 Patients who have had chemotherapy or radiotherapy within 21 days (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or those 
who have not recovered from adverse events due to agents administered 
more than 3 weeks earlier. 
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
3.2.3 Patients with known brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to either 5-FU/Capecitabine or Interferon. 
 
3.2.5  Uncontrolled, ongoing illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, 
myocardial infarction <30 days, CVA/TIA <30 days, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements.  
 
3.2.6  Pregnant women are excluded from this study because 5-FU/Capecitabine is 
an anti-metabolite agent with the potential for teratogenic or abortifacient 
effects. Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with 5-FU/Capecitabine, 
breastfeeding should be discontinued if the mother is treated with 5-
FU/Capecitabine. Pregnancy testing will be completed on all female 
participants of child-bearing potential by urine analysis.  
 
3.2.8    Any heart or lung transplant patient on immunosuppressive agents. Renal 
transplant patients are allowed if patient is willing to reduce 
immunosuppressive agents and understand risk of rejection and possible 
need to return to dialysis. Patients with CLL or other hematologic 
malignancies are allowed as long as they meet other criteria listed above. 
 
3.3 
Inclusion of Women and Minorities 


11 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
Both men and women and members of all races and ethnic groups are eligible for 
this trial.   
 
3.4   Patient Registration 
Once clinical eligibility is confirmed, patients must sign an informed consent prior to 
registration indicating awareness of the investigation nature of the study and its 
inherent risks in keeping with the policies of the hospital and Federal regulations 
(Code of Federal Regulations Part 1X, Subpart B, Sections 50.20-50.27).   
 
3.5  Removal of Patients From Study 
  Patients may be removed from the study for any of the following reasons: 
o Progression of disease 
o Significant protocol violation 
o Patient non-compliance: defined as any deviation from the protocol 
without prior agreement of the principal investigator 
o Investigator non-compliance: defined as any significant medical or 
non-medical deviation from the protocol without agreement of the 
sponsor 
o Patient’s request to withdraw from the study or refusal of further 
therapy 
o Unacceptable toxicity.  A patient may be removed from the study for 
any complication of treatment that the investigator feels is life 
threatening. 
o If patient does not meet eligibility criteria  
 
4. TREATMENT PLAN 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy. Interferon alpha-2b and 5-
FU/Capecitabine are available commercially and a commercial supply will be used for this study. 
 
4.1 Capecitabine Administration 
        Drug administration will be on an outpatient basis. Capecitabine will be  
        administered at an initial dose of 800 mg/m2 by mouth twice daily on days  
         1-14 of a 21 day cycle with days 15-21 off. This cycle will be repeated every 21 days  
        during the study for a maximum of 9 cycles as tolerated. Administration via feeding  
        tube in patients unable to swallow is permitted. For severe side effects, dose  
        reductions are listed in Table 5. Reported adverse events and potential risks are  
        described in Section 6.   
 
        Capecitabine tablets should be swallowed with water within 30 min after a  
        meal. The calculated dose by body surface area (BSA) will be rounded down  
        to allow as close to as total daily dose of 1600 mg/m2 divided as closely as  
        possible into AM and PM doses of 800 mg/m2 using a combination of 150  
        mg and 500 mg tablets. There will be no modification of BSA calculation  
        based on idealized body weight or other corrective factor. 
 
  4.1.1 Storage: Capecitabine tablets should be kept a room temperature 
 
  4.1.2 Pill Diary: The patient will be requested to maintain a medication diary for  
        review at the end of each cycle of treatment and reconciled with a pill count.  


12 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
        If the patient is clinically stable after 3 cycles, then a diary review and pill  
        counts may be discontinued. 
 
 
4.1.3 Supportive Care Guidelines 
        Capecitabine has a low emetogenic potential. Routine anti-emetics are not  
        recommended but may be used at the treating physician’s discretion.  
        Standard use of anti-diarrheal agents is permitted. 
 
  4.2       5-FU Administration 
        If patients are not able to acquire oral capecitabine, then we will start patients on 
infusional 5-FU which can be delivered via standard of care. Patients will need to have a port 
placed for continuous infusion treatments. 5-FU pumps will be activated in the infusion center at 
Moffitt Cancer Center with a starting dose of 800 mg/m2 days 1-4, with pump removal on day 5 
at the infusion center. 5-FU pumps will be attached every 21 days (1 cycle) for a maximum of 9 
cycles. For severe side effects, dose reductions are listed in Table 5. Reported adverse events 
and potential risks are described in Section 6.   
 
 
  4.2.1  Storage 
        Drug stored in pharmacy per manufacturer’s instructions. 
 
  4.2.2  Supportive Care Guidelines 
         5-FU has a low-medium emetogenic potential. Routine anti-emetics may be used at 
the treating physician’s discretion. Standard use of anti-diarrheal agents is permitted. 
 
    4.3 Interferon Administration 
       Drug administration will occur on an outpatient basis at the infusion center at  
        Moffitt Cancer Center. Dose will be weight-based. Starting treatment doses of  
        3 mcg/kg will be given SC injection in the thigh, abdominal wall, or upper arm every  
        week for a total of 27 weeks as tolerated. Patients will be premedicated with 650 mg 
          of acetaminophen or 400 mg of ibuprofen as tolerated. For severe side effects, dose 
          reductions are allowed as discussed in Section 5. Reported adverse events and  
        potential risks are described in Section 6.   
 
  4.3.1 Storage: Drug stored in pharmacy per manufacturer’s instructions. 
 
  4.3.2 Supportive Care Guidelines 
Anti-pyrectics such as ibuprofen and acetaminophen can be used as directed to 
manage low grade fevers and muscle/joint pains. Anti-nausea and anti-diarrheal 
agents can be used at the treating physician’s discretion.  
 
4.4 Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue 
for 9 cycles or until one of the following criteria applies: 
 
Χ Disease progression, 
Χ Concurrent illness that prevents further administration of treatment, 
Χ Unacceptable adverse event(s), 
Χ Patient decides to withdraw from the study, or 


13 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
Χ General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
  4.5   Duration of follow up 
           Patients will be followed for up to one year after removal from study or  
           until death. Patients removed from the study for unacceptable adverse  
           event(s) will be followed until resolution or stabilization of the adverse  
           event. 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
5.1 5-FU/Capecitabine 
A dose reduction will be instituted upon any grade 3 or 4 toxicity that is attributable to 5-
FU/capecitabine.  For  all  grade  3  or  4  
toxicities  related  
to 5-FU/capecitabine,  
the  study 
treatment will be withheld for up to 3 weeks until the toxicity has resolved to CTCAE grade 1 
or better (or back to baseline), and then treatment may be restarted.  Dose reduction/re-
challenge for each toxicity criterion will be managed as discussed 
in the sections 
that 
follow. 
 Patients will be withdrawn from the study 
if toxicity does not resolve to ≤ CTCAE grade 1 (or 
to baseline) within 3 weeks.   
Myelosuppression 
On Day 1 of each cycle, if the neutrophil count is < 1000/mm3, or the platelet count is < 
75,000/mm3, then treatment with 5-FU/capecitabine will be held until 
the neutrophil count 
is ≥ 
1000/mm3, and platelet count 
is ≥ 75,000/mm3.  Once restarted, 5-FU/Capecitabine will be 
dose reduced per Table 1. If treatment is required to be held for ≥ 3 weeks, then study 
treatment will be discontinued.   
 
GI Toxicity 
Nausea, vomiting, or both may be controlled with antiemetic therapy.  Diarrhea should be 
treated with standard medications to avoid dose modification or interruption, if possible.  
Electrolyte  supplementation  with  regular  laboratory  monitoring  should  be  used,  when 
appropriate, to maintain electrolytes within normal limits. 
Dose modifications for diarrhea will be as follows: 
If  ≥ grade 3 diarrhea refractory to oral anti-diarrheal medication occurs, treatment will be 
held  until  
the  
toxicity  
is  <  grade  2,  
then  
the 5-FU/capecitabine  dosage  will  be  
reduced 
according to Table 2 shown below. If treatment must be withheld for more than 3 weeks for 
resolution of diarrhea, the patient will not restart treatment and the patient will be withdrawn 
from the study.   
 
Mucositis or Hand/Foot Syndrome (HFS) 
If ≥ grade 3 mucositis or HFS occurs, 5-FU/capecitabine will be 
interrupted 
for a minimum of 
1 week. If the toxicity has not improved to < grade 2, the treatments will be held for up to 2 
additional weeks. Once restarted, the dose of capecitabine will be reduced according to 
Table  2.  
If  
treatment  
is  
required  
to  be  held  
for  ≥  3  weeks,  
then  study  
treatment  will  be 
discontinued.   
 
Other toxicities 
If ≥ grade 3 toxicities directly attributable to 5-FU/capecitabine other than those discussed 
above occur (except fatigue, alopecia, or nausea/emesis in the absence of anti-emetics), 
therapy will be discontinued until the toxicity is < grade 2. If there is no evidence of tumor 


14 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
progression, therapy may resume with a dose reduction according to Table 1. If 
treatment 
is 
required to be held for ≥ 3 weeks, then study treatment will be discontinued.   
 
TABLE 1: Capecitabine dose levels 
Dose Level 
5-FU/Capecitabine  Dose  
-2 
400 mg/m2 per 21 day cycle   
-1 
600 mg/m2  
0 ( starting dose) 
800 mg/m2  
 
5.2 Interferon Alpha-2b 
     A dose reduction will be instituted upon any grade 3 or 4 toxicity that is attributable to  
     Interferon alpha-2b. For all grade 3 or 4 toxicities related to IFN, the study treatment will  
     be withheld for up to 3 weeks until the toxicity has resolved to CTCAE grade 1 or better,  
     and then treatment may be restarted.  Dose reduction/re-challenge for each toxicity  
     criterion will be managed as discussed in the sections that follow.  Patients will be  
     withdrawn from the study if toxicity does not resolve to ≤ CTCAE grade 1 within 3  
     weeks. 
 
     Fatigue 
     If patient complains of severe fatigue (>gr3), IFN will be held for the remained for the  
     cycle. Upon starting the next cycle, patient will be placed in the dose ”-1” group and  
     managed according to table 2. If patient is unable to receive IFN for greater than 3  
     weeks, they will be withdrawn from the study. 
 
     Arthralgias/Myaglias 
     Pain management will initially be done with acetaminophen or ibuprofen as tolerated, or  
     opiates as indicated. For severe toxicity, IFN will be held for 3 weeks and dose reduced 
     according to Table 2. If not resolved to CTCAE grade 1 or better, patient will be  
     removed from the study. 
 
     Weightloss 
     If patient weightloss occurs >10% of initial body weight, then IFN alpha will be held for  
     3 weeks. Weight gaining medications such as megace, marinol, and mirtazapine are  
     acceptable. Patients will be dose reduced according to Table 2. If weight does not  
     stabilize or start to recover within 3 weeks, patients will be withdrawn from the study 
 
     Depression 
     For moderate depression grade 1 or 2, patients may be started on SSRI therapy as  
     necessary. Any acute grade 3 or 4 reaction (psychosis, mania, suicidal ideation), IFN 
     alpha will be stopped for 3 weeks. Patients can be restarted at reduced doses according  
     to Table 2. If toxicities do not resolve to CTCAE grade 1 or better within 3 weeks, patients  
     will be withdrawn from the study. Referral for acute hospitalization or psychiatric  
     consultation will be placed for any life-threatening events. 
 
GI Toxicity 
Nausea, vomiting, or both may be controlled with antiemetic therapy.  Diarrhea should be 
treated with standard medications to avoid dose modification or interruption, if possible.  
Electrolyte  supplementation  with  regular  laboratory  monitoring  should  be  used,  when 
appropriate,  to  maintain  electrolytes  within  normal  
limits. For  persistent  Gr3/4  adverse 
events, pt will be dose reduced according to Table 2.   


15 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
 
TABLE 2: IFN alpha-2b dose levels 
 
Dose Level 
IFN alpha-2b 
-2 
1 mcg/kg SQ q week per 21 day cycle   
-1 
2 mcg/kg SQ q week per 21 day cycle   
0 ( starting dose) 
3 mcg/kg SQ q week per 21 day cycle   
 
6. PHARMACEUTICAL INFORMATION 
 
   5-FU/Capecitabine and IFN are commercially available and will be used from commercial 
suppliers. 
 
 6.1 Expected potential toxicities of 5-FU/Capecitabine: 
   Hematologic: anemia, neutropenia, thrombocytopenia 
  Constitutional: fatigue, pyrexia, edema, pain, chest pain 
  Dermatologic: hand-foot syndrome, dermatitis, skin discoloration, alopecia, nail  
   disorders 
  Gastrointestinal:  diarrhea, nausea, vomiting, stomatitis, abdominal pain, gastrointestinal  
  motility disorder, constipation, oral discomfort, upper GI inflammatory disorders,  
   gastrointestinal hemorrhage, ileus 
  Hepatic:  hyperbilirubinemia 
  Infections:  bacterial or viral 
  Metabolic: appetite decreased, dehydration 
  Musculoskeletal:  back pain, arthralgia 
  Neurologic:  peripheral sensory neuropathy, headache, dizziness, insomnia, taste  
   disturbance 
  Ocular:  eye irritation, vision abnormal 
   Psychiatric:  mood alteration, depression 
  Pulmonary:  dyspnea, cough, pharyngeal disorder, epistaxis, sore throat 
   Vascular:  venous thrombosis 
  Cardiac: myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure,  
  sudden death, electrocardiographic changes, and cardiomyopathy.  
  Dihydropyrimidine Dehydrogenase Deficiency: Rarely, unexpected, severe toxicity  
   (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has  
  been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. 
 
 6.2 Expected potential toxicities of IFN alpha-2b: 
  General: "Influenza-like" symptoms (mainly fever, headache, chills, myalgia, and  
  fatigue)  
  Gastrointestinal: anorexia, nausea, diarrhea, vomiting, altered taste, abdominal pain,  
  constipation, gingivitis, loose stools, dyspepsia 
  Hepatic: elevated SGOT, right upper quadrant pain 
  Psychiatric: depression, anxiety, nervousness 
  Dermatologic: alopecia, rash, pruritus, dry skin, dermatitis, hair discoloration 
  Respiratory: dyspnea, coughing, pharyngitis, sinusitis, nonproductive cough, nasal  
  congestion, and bronchitis  
  Nervous system: headache, somnolence, dizziness, irritability, paresthesia, impaired  
  concentration, amnesia, confusion, insomnia, hypoesthesia, vertigo, and decreased  
  libido 


16 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
  Musculoskeletal: myalgia, musculoskeletal pain, and arthralgia 
  Immunologic: nonspecific infection, viral infection, and herpes simplex 
  Hematologic: neutropenia, anemia, thrombocytopenia, bleeding, and purpura  
  Genitourinary: Amenorrhea, polyuria 
  Cardiovascular: hypertension. Angina, arrhythmia, atrial fibrillation,  
  bradycardia, cardiac failure, cardiomegaly, cardiomyopathy, coronary artery  
  disorder, extrasystoles, heart valve disorder, hematoma, hypotension, palpitations,  
  phlebitis, postural hypotension, pulmonary embolism, Raynaud
's disease,  
  tachycardia, thrombosis, and varicose vein have been reported in less than 5% of  
  patients. 
  Endocrine: aggravation of diabetes mellitus, goiter, hyperthyroidism, and  
  hypothyroidism in less than 5% of patients.  
  Metabolic: Hypertriglyceridemia, dehydration, hypercalcemia, hyperglycemia, and  
  Ocular: Ocular side effects have included abnormal vision, blurred vision, diplopia,  
  dry eyes, eye pain, lacrimal gland disorder, lacrimation, nystagmus, and  
  photophobia in less than 5% of patients.  
  Renal: increased BUN and renal insufficiency in less than 5% of patients.  
  Hypersensitivity: Hypersensitivity side effects have included allergic reaction 
  Local: injection site inflammation 
 
 
7.  ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse Event: Any untoward medical occurrence in a patient of clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with treatment. An adverse event (AE) can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
 
Adverse Event Characteristics: 
CTCAE term (AE description) and grade:  The descriptions and grading scales found  
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version  
4.0 will be utilized for AE reporting. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Hematologic and metabolic toxicities of Grade 1 and 2 will not be reported. 
 
Expedited Serious Adverse Event (SAE) Reporting: 
A SAE is any sign, symptom or medical condition that emerges during treatment or 
during a post-treatment follow-up period that (1) was not present at the start of treatment 
and it is not a chronic condition that is part of the patient’s medical history, OR (2) was 
present at the start of treatment or as part of the patient’s medical history but worsened 
in severity and/or frequency during therapy, AND that meets any of the following 
regulatory serious criteria: 
•  Results in death  
•  Is life-threatening  
•  Requires or prolongs inpatient hospitalization  
•  Is disabling  




18 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
ECOG/Performance 
status 
X  
X      X      X  
   
X 
CBC w/diff 
X  
X      X      X     
X 
Serum chemistryb  
X  
X      X      X     
X 
EKG (as indicated)  
X  
            
  
   
 
Adverse event 
evaluation 
  
X---------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements and imaging are repeated 
every nine weeks.  Documentation must be 
provided for patients removed from study for 
progressive disease. If treatment is held for 
adverse event recovery thereby extending cycle 
length, then imaging and tumor measurement 
intervals may be correspondingly altered so that 
the patient is imaged every third cycle. 
 
Radiologic 
evaluation 
X 
a= Blood Pressure, Heart Rate (Pulse), Temperature,  
b= Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, , potassium, total protein, SGOT[AST], SGPT[ALT], sodium 
c= Off-study evaluation to be conducted within 30 days of last dose (+/- 7 days).   
d= patients will be on either 5-FU infusion treatments or capecitabine, not both 
 
9. MEASUREMENT OF EFFECT 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every nine weeks. 
If treatment is held for adverse event recovery thereby extending cycle length, then imaging and 
tumor measurement intervals may be correspondingly altered so that the patient is imaged every 
third cycle. 
 
9.1  Definitions 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Committee [JNCI 92(3):205-216, 2000].  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note:  Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy. 
 
9.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as > 10 mm with 
conventional techniques (CT, MRI, x-ray). All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 


19 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
9.1.2 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT 
scan), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis,, 
inflammatory breast disease, abdominal masses (not followed by CT or MRI), 
and cystic lesions are all non-measurable. 
 
9.1.3 Target lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 
lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their size (lesions with the longest 
diameter) 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. 
 
9.1.4 Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Non-target lesions include 
measurable lesions that exceed the maximum numbers per organ or total of 
all involved organs as well as non-measurable lesions.  Measurements of 
these lesions are not required, but the presence or absence of each should 
be noted throughout follow-up.  
9.2 
  Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, 
documentation by calipers or color photography ( including a ruler to estimate the 
size of the lesion) is recommended.  
 
Conventional CT and MRI.  These techniques should be performed with cuts of 10 
mm or less in slice thickness contiguously.  Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen, and pelvis.  Head and neck tumors and those of extremities usually require 


20 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
specific protocols. 
 
9.3 
  Response Criteria 
 
9.3.1  Evaluation of target lesions 
Complete Response (CR):  Disappearance of all target lesions 
 
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 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest 
sum LD recorded since the treatment started 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 
 
 
9.3.2  Evaluation of non-target lesions 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Incomplete Response/  
Persistence of one or more non-target lesion(s) 
Stable Disease (SD):    
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 
 
Although a clear progression of “non-target” lesions only is exceptional, in 
such circumstances the opinion of the treating physician should prevail, and 
the progression status should be confirmed at a later time by the review panel 
(or study chair). 
9.3.3  Evaluation of best overall response 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient
's best response assignment will depend on the 
achievement of both measurement and confirmation criteria (see section 
9.3.1). 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
 
 
 


21 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
CR 
Incomplete 
response/SD 
No 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: 
1) Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.”   
 
2) In some circumstances, it may be difficult to distinguish residual disease from normal tissue.   
When the evaluation of complete response depends on this determination, it is recommended  
that the residual lesion be investigated (fine needle aspirate/biopsy) before confirming the  
complete response status. 
 
9.4 
  Confirmatory Measurement/Duration of Response 
 
9.4.1  Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must 
be confirmed by repeat assessments that should be performed 4 weeks after 
the criteria for response are first met.  In the case of SD, follow-up 
measurements must have met the SD criteria at least once after study entry at 
a minimum interval of 9 weeks (see section 9.3.3). 
 
9.4.2  Duration of overall response 
The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since 
the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively 
documented. 
 
9.4.3  Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements 
recorded since the treatment started.  
 
9.5 
  Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of  
treatment to time of progression or death, whichever occurs first. 


22 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
 
 
10. REGULATORY AND REPORTING REQUIREMENTS 
 
10.1  Expedited Adverse Event Reporting 
     The PI of this study has primary responsibility for the overall study, including patient  
     welfare, data integrity, and monitoring of adverse events.dverse event lists,  
     guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse  
     Events: List and Reporting Requirements). 
 
10.2  Data Reporting 
10.2.1  Institutional Review Board 
  The protocol, the proposed informed consent, and all forms of participant information  
  related to the study (e.g. advertisements used to recruit participants) will be reviewed  
  and approved by the IRB and Moffitt Cancer Centers’ Scientific Review Committee  
  (SRC).  Any changes made to the protocol will be submitted as a modification and  
  will be approved by the IRB prior to implementation.  The Protocol Director will  
  disseminate the protocol amendment information to all participating investigators.  
  No subject is to be enrolled on this protocol until the Center’s Institution  
     Review Board has approved it. 
 
 
10.2.2  
 Data Reporting 
 
Moffitt Cancer Center’s Data and Safety Monitoring Committee (DSMC) will  
 
be the monitoring entity for this study. The DSMC will audit study-related  
 
activities to determine whether the study has been conducted in accordance  
 
with the protocol, local standard operating procedures, FDA regulations, and  
 
Good Clinical Practice (GCP).  In addition, the DSMC will regularly review  
 
serious adverse events and protocol deviations associated with the research  
 
to ensure the protection of human subjects.  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 needed 
 
 
Data will be captured in Oncore, Moffitt’s Clinical Trials Database. Regulatory  
documents and case report forms will be monitored internally according to Moffitt  
Cancer Center Monitoring Policies. Monitoring will be performed regularly to verify 
data is accurate, complete, and verifiable from source documents; and the conduct of 
the trial is in compliance with the currently approved protocol/amendments, Good  
Clinical Practice (GCP), and applicable regulatory requirements. 
 
10.2.3 Informed Consent 
The investigator is responsible for patient care and for obtaining consent by the 
patient.  Written informed consent must be obtained prior to entry of any patient. 
 
        10.2.4 Hospital/Clinic Records 
Hospital records for patients on this study are the responsibility of the investigator.  
They will be available for review by the sponsors of the trial, health care personnel 
involved in this study, the IRB, DHHS, and the FDA. 
 
10.2.5 Investigator Study Files 


23 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
The Principal Investigator is responsible for maintaining study files 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.  The following documents should be kept in the 
study files: 
 
A completed, signed FDA Form 1572 (Statement of Investigator) and copies of all 
current curricula vitae of all sub investigators listed on the Statement of the 
Investigator. 
  The original protocol and all amendments 
  Final IRB approval, annual renewals and all IRB correspondence 
  Blank Case Report Forms 
  Copy of all IRB approved Informed Consent forms with applicable version 
date 
  Updated laboratory certification and laboratory values (covering entire time of 
study) 
  Copy of all patient’s signed informed consent forms 
  The final completed case report form for all patients 
 
     10.2.6 Data Management Plan 
      Electronic case report forms for specified protocol related information on each trial  
      patient, using the Oncore system, will be created.  Electronic data will be kept secure  
      within the Oncore password protected system. Paper copies of the documentation  
      from the medical record which support the data entered into Oncore will be kept in  
      patient specific binders in a secure, locked, and HIPPA compliant environment. 
 
10.3 Reporting and Exclusions 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 5-
FU/capecitabine and IFN alpha-2b. Adverse events that occur during screening will not 
be captured. Adverse events will only be captured until 30 days after the last dose of any 
investigational drug. 
    
11. STATISTICAL CONSIDERATIONS 
 
11.1  Study Endpoints 
       11.1.1 Primary Objective 
        To establish the objective response rate to IFN alpha-2b and 5-FU/capecitabine  
        using RECIST criteria in patients with unresectable/metastatic CSCC after 3  
        cycles of treatment (9 weeks). 
 
11.1.2 Secondary Objective 
To establish the progression free survival (PFS), overall survival (OS), and safety 
profile (AEs) of the combination of IFN alpha-2b and 5-FU/capecitabine in this patient 
population at 6 months and 1 year. 
 
  11.2   Statistical Design 
        This is a single arm, Phase II trial using a Simon’s two-stage design to evaluate the  
        RECIST response rate to 5-FU/capecitabine and interferon alpha-2b in patients with  








27 
Protocol Version Date:  v4.0 – 04/06/16 
Amendment:        
 # 1 
 
of clinical oncology : official journal of the American Society of Clinical Oncology. 
1990;8(2):342-346. 
10.  Denic S. Preoperative treatment of advanced skin carcinoma with cisplatin and 
bleomycin. American journal of clinical oncology. 1999;22(1):32-34. 
11.   Lippman SM, Parkinson DR, Itri LM, et al. 13-cis-retinoic acid and interferon alpha-2a: 
effective combination therapy for advanced squamous cell carcinoma of the skin. Journal 
of the National Cancer Institute. 1992;84(4):235-241. 
12.   Shin DM, Glisson BS, Khuri FR, et al. Phase II and biologic study of interferon alfa, 
retinoic acid, and cisplatin in advanced squamous skin cancer. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2002;20(2):364-
370. 
13.   Fleming GF, O
'Brien SM, Hoffman PC, et al. Phase I study of treatment with oral 13-cis-
retinoic acid, subcutaneous interferon alfa-2a, cisplatin, and 24-hour infusion 5-
fluorouracil/leucovorin. Cancer chemotherapy and pharmacology. 1997;39(3):227-232. 
14.   Brewster AM, Lee JJ, Clayman GL, et al. Randomized trial of adjuvant 13-cis-retinoic 
acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2007;25(15):1974-1978. 
15.  Cartei G, Cartei F, Interlandi G, et al. Oral 5-fluorouracil in squamous cell carcinoma of 
the skin in the aged. American journal of clinical oncology. 2000;23(2):181-184. 
16.   Wollina U, Hansel G, Koch A, Kostler E. Oral capecitabine plus subcutaneous interferon 
alpha in advanced squamous cell carcinoma of the skin. Journal of cancer research and 
clinical oncology. 2005;131(5):300-304. 
17.  Seymour L, Ivy SP, Sargent D, et al. The design of phase II clinical trials testing cancer 
therapeutics: consensus recommendations from the clinical trial design task force of the 
national cancer institute investigational drug steering committee. Clinical cancer 
research : an official journal of the American Association for Cancer Research. 
2010;16(6):1764-1769. 
18.  Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. 
1989;10(1):1-10.