Clinical trial NCT00504023
Conditions: Vulvar Cancer
Keywords: Paget disease of the vulva recurrent vulvar cancer stage 0 vulvar cancer stage I vulvar cancer stage II vulvar cancer stage III vulvar cancer imiquimod 07-029
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2007-04-01; Completion date: 2018-01-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Biological therapies, such as imiquimod, may stimulate the immune system in different ways and stop tumor cells from growing. Applying topical imiquimod to the vulva may be an effective treatment for recurrent Paget's disease.

PURPOSE: This clinical trial is studying how well topical imiquimod works in treating patients with recurrent Paget's disease of the vulva.

Detailed description:
OBJECTIVES:

* To assess the clinical and histologic effects of topical imiquimod therapy on recurrent extramammary Paget's disease.

OUTLINE: This is a pilot, prospective, multicenter study.

Patients apply topical imiquimod cream to a target vulvar lesion 3 times weekly. Treatment continues for up to 12 weeks in the absence of disease progression or unacceptable toxicity. If the lesion is still present after completion of 12 weeks of imiquimod therapy, the patient undergoes surgical excision of the target lesion (and any other progressive lesions suspicious for evolving adenocarcinoma) at week 16.

Patients undergo punch biopsy and photographic assessment of a target vulvar lesion at baseline and again at 12 weeks.

After completion of imiquimod therapy or after surgical excision, patients are followed at 6 weeks and then every 3 months for at least 2 years.

Arms: arm 1: This is a pilot study of the use of a topical immunomodulatory agent, imiquimod, for the treatment of recurrent Extramammary Paget's disease (EMPD).
Interventions: intervention 1: imiquimod intervention 2: biopsy intervention 3: therapeutic conventional surgery
Intervention descriptions: intervention 1: The patient will be seen in clinic every six weeks during treatment for examination. Imiquimod cream is to be applied 3 times per week for 12 weeks. intervention 2: Punch biopsy and photography will be performed at the baseline and 12 week time points. intervention 3: If the lesion is still present after 12 weeks of therapy, the treating physician will recommend excision of the lesion four weeks after completion of therapy (week 16).

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-029A(6) 
Amended:  3/5/14 
 
 
 
 
 
 
 
A Pilot study of Topical Imiquimod Therapy for the Treatment of Recurrent Extramammary 
Paget’s Disease 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
Principal Investigator/Department: 
Dennis Chi, MD 
Department of Surgery, Division of 
Gynecologic Oncology 
 
Co-Principal 
Investigator(s)/Department: 
 
Investigator(s)/Department: 
Robert Soslow, MD 
 
 
 
Kay Park, MD 
Department of Pathology 
 
 
 
Department of Pathology 
 
Consenting 
Professional(s)/Department: 
Nadeem Abu-Rustum, MD 
Richard Barakat, MD 
Carol Brown, MD 
Dennis Chi, MD 
Douglas Levine, MD 
Yukio Sonoda, MD 
Mario Leitao, MD 
Elizabeth Jewell, MD 
Ginger Gardner, MD 
Department of Surgery, Division of 
Gynecologic Oncology 
 
 
 
 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human Subjects 
Education and Certification Program. 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 


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Collaborating Institutions: 
Ohio State University College of Medicine 
PI: David O’Malley, MD 
Ohio State University College of Medicine 
M210 Starling-Loving 
320 West 10th Ave. 
Columbus, OH 43210 
Phone: 614-293-7642 
Email:david.o'malley@osumc.edu 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#:07-029A(6) 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL .............................................................. 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA................................................................ 1 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.......................................................................... 2 
3.0 
BACKGROUND AND RATIONALE............................................................................... 2 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .................................................... 3 
4.1 
DESIGN .................................................................................................................. 3 
4.2 
INTERVENTION ................................................................................................... 4 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ....................................................................... 4 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ....................................................................... 5 
6.1 
SUBJECT INCLUSION CRITERIA...................................................................... 5 
6.2 
SUBJECT EXCLUSION CRITERIA..................................................................... 6 
7.0 
RECRUITMENT PLAN (WITH LIMITED WAIVER OF AUTHORIZATION) ............ 6 
8.0 
PRETREATMENT EVALUATION .................................................................................. 7 
9.0 
TREATMENT/INTERVENTION PLAN .......................................................................... 7 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .......................................... 7 
11.0 
TOXICITIES/SIDE EFFECTS ........................................................................................... 8 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT............... 11 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ................................................................ 12 
14.0 
BIOSTATISTICS ............................................................................................................. 12 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES............................................................................................................................. 12 
16.0 
DATA MANAGEMENT REQUIREMENTS FOR PARTICIPATING SITES .............. 14 
17.0 
PROTECTION OF HUMAN SUBJECTS ....................................................................... 19 
18.0 
INFORMED CONSENT PROCEDURES ....................................................................... 21 
18.1 FOR PARTICIPATING CENTERS..................................................................................... 22 
20.0 
APPENDICES…………………………………………………………………………...19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amended:  3/5/14 


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IRB Protocol 
IRB#: 07-029A(6) 
Amended:  3/5/14 
- 1 - 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Study Population 
Patients with Recurrent Extramammary Paget’s Disease 
(EMPD) 
Study Design 
Pilot, prospective cohort study 
Therapy 
Imiquimod 5% Cream applied T.I.W. 
Duration of Therapy 
12 weeks 
Assessment of Response 
a. Clinical assessment of before and after photographs by an 
independent reviewer 
b. Non-blinded histologic assessment of baseline biopsies and 
post therapy excisional biopsies 4 weeks after end of treatment 
Number of evaluable 
subjects required 
20 
Target sample size 
Assuming a 15% dropout rate, target sample size is 17 
 
 
This is a pilot study of the use of a topical immunomodulatory agent, imiquimod, for the 
treatment of recurrent Extramammary Paget’s disease (EMPD). In this protocol we will assess 
the clinical and histologic effects of topical imiquimod on recurrent EMPD. 
 
Imiquimod 5% cream (Aldara, 3M Pharmaceuticals, St Paul, Minnesota) is an FDA approved 
safe and effective treatment of anogenital warts, superficial basal cell carcinoma, and actinic 
keratosis.i 
 
Imiquimod has been demonstrated to induce cytokines that promote a TH1 immune response 
following both systemic and topical administration.ii The induced cytokines include alpha 
interferon, gamma interferon, and interleukin 12.  The specific mechanism of action by which 
imiquimod eliminates warts, basal cell carcinoma, and actinic skin cancers is unknown. 
 
Several published case reports suggest the potential efficacy of topical 5% imiquimod cream 
in the treatment of EMPD after median treatment duration of 7.5 weeks (range 6-16). 
iii, iv, v, vi 
In  addition,  a  recent  abstract  presented  at  the  annual  Society  of  Gynecologic  Oncology 
meeting reported complete response of recurrent EMPD in five of six (83%) patients treated 
with imiquimod for a median duration of 12 weeks (range 6-48).xxi    In this study we will 
recruit  individuals  with  biopsy-proven  recurrent  EMPD.    Imiquimod  5%  cream  will  be 
applied by the patient 3 times per week for 12 weeks.  The patient will be seen in clinic every 
six weeks during treatment for examination, teaching, and to assess compliance.   Punch 
biopsy and photography will be performed at the baseline and 12 week time points.  Biopsies 
will be performed using the 3mm punch biopsy instrument.  The location will be at the 
periphery of the lesion as determined by the physician with an attempt made to incorporate 
some normal tissue.  Biopsy or biopsies will be obtained of the most suspicious area.  If the 
lesion  is  still  present  after  12  weeks  of  therapy,  the  treating  physician  will  recommend 
excision of the lesion four weeks after completion of therapy (week 16).  The patient will have 
a follow-up exam 6 weeks after excision and then every 3 months for at least 2 years. If no 


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IRB Protocol 
IRB#: 07-029A(6) 
Amended:  3/5/14 
- 2 - 
 
 
 
lesion is present or the patient refuses surgical excision at week 16, the patient will return for 
follow-up exams every 3 months for at least 2 years. The treating physician will continue to 
offer surgical excision at any later point during follow-up if the lesion is still present. 
 
We will evaluate the clinical and histologic response of recurrent EMPD to treatment. Clinical 
response will be assessed by a pathologist (non-blinded) and an independent reviewer who 
will compare clinical photographs obtained at study completion to those obtained at baseline. 
Lesions will be evaluated based on size as having undergone complete response, partial 
response, no change, or progression.  Histologic evaluation will entail quantifying the number 
of residual Paget cells following treatment.  Side effects and toxicities of therapy will be 
monitored and recorded. 
 
Presented below is the treatment schema for this prospective cohort. 
 
 
Baseline 
assessment with 
exam, biopsy, and 
photography 
 
 
 
 
Imiquimod 5% 3x week for 12 
weeks. Repeat assessment with 
exam, biopsy, and photography 
 
 
 
NED 
DISEASE 
 
 
 
No excision 
 
Surgical excision 
at 16 weeks 
 
 
Clinic visits: 
Q3-4 months 
x 2 years 
 
 
NED 
 
 
Clinic visit: 6 
weeks post 
excision 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
To assess the clinical and histologic effects of topical imiquimod therapy on recurrent 
extramammary Paget’s disease (EMPD). 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1   Topical chemotherapy for the treatment of recurrent EMPD 


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Amended:  3/5/14 
- 3 - 
 
 
 
 
EMPD  represents  1%  to  5%  of  all  vulvar  neoplasia.  The  diagnosis  is  confirmed  by  the 
histological identification of unique intraepithelial neoplastic cells showing glandular 
differentiation.vii   Surgery is accepted to be the standard modality of treatment; however, this is 
associated with significant disfigurement and high local recurrence rate with many patients 
requiring multiple excisions.   In a review of 100 patients treated surgically for vulvar Paget’s 
disease, there was a recurrence rate of 34% after a median follow-up of 3 years (range, 0.6-15 
years).viii    Topical chemotherapeutic agents including 5-fluorouracil (5-FU), bleomycin and 
imiquimod have been used to treat EMPD.  Unfortunately, 5-FU and Bleomycin were associated 
with poor response rates and toxic side effects.ix  x  Case reports of imiquimod therapy in 5 
patients with EMPD demonstrate a complete clinical response after a median follow-up of 6 
months (range, 0.5-14 months).iii,iv,v,vi There are no prospective clinical trials evaluating EMPD 
and imiquimod therapy.   Although the incidence of EMPD is small, MSKCC treats 
approximately 5 patients a year and therefore has a unique opportunity to perform a pilot study 
evaluating the effects of imiquimod on recurrent EMPD. 
 
3.2       The therapeutic agent 
 
Imiquimod is an immune response modifier that has been demonstrated to induce cytokines that 
promote a TH1 response following both systemic and topical administration. The cytokines 
induced include alpha and gamma interferon and interleukin 12.   In humans, imiquimod 5% 
cream (Aldara, 3M Pharmaceuticals, St Paul, MN) is an FDA approved safe and effective 
treatment of anogenital warts, actinic keratosis, and superficial basal cell carcinoma. As noted 
above, isolated cases have been reported of the eradication of EMPD with topical 5% imiquimod 
therapy. 
 
 
4.0       OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1       Design 
 
This is a pilot study of the use of a topical immunomodulatory agent, imiquimod, for the 
treatment of recurrent Extramammary Paget’s disease (EMPD). In this protocol, we will assess 
the clinical and histologic effects of topical imiquimod on recurrent EMPD. 
 
Imiquimod 5% cream is an FDA approved safe and effective treatment of anogenital warts, 
superficial basal cell carcinoma, and actinic keratosis.xi 
 
Imiquimod has been demonstrated to induce cytokines that promote a TH1 immune response 
following both systemic and topical administration.xii The induced cytokines include alpha 
interferon, gamma interferon, and interleukin 12.  The specific mechanism of action by which 
imiquimod eliminates warts, basal cell carcinoma, and actinic skin cancers is unknown. 
 
Several  case  reports  suggest  the  potential  efficacy  of  topical  5%  imiquimod  cream  in  the 
treatment of EMPD after median treatment duration of 7.5 weeks (range 6-16). 
xiii, xiv, xv, xvi   In this 
study, we will recruit a total of 20 individuals with biopsy-proven recurrent EMPD.  Imiquimod 


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IRB Protocol 
IRB#: 07-029A(6) 
Amended:  3/5/14 
- 4 - 
 
 
 
5% cream will be applied by the patient 3 times per week for 12 weeks.  The patient will be seen 
in clinic every six weeks during treatment for examination, teaching, and to assess compliance. 
Compliance with therapy will be monitored with a patient diary (see Appendix) with 
quantification of residual medication at study completion.  Punch biopsy and photography will 
be performed at the baseline and 12 week time points.  If the lesion is still present after 12 weeks 
of therapy, the treating physician will recommend excision of the lesion four weeks after 
completion of therapy (week 16).  The patient will have a follow-up exam 6 weeks after excision 
and then every 3 months for at least 2 years. If no lesion is present or the patient refuses surgical 
excision at week 16, the patient will return for follow-up exams every 3 months for at least 2 
years. The treating physician will continue to offer surgical excision at any later point during 
follow-up if the lesion is still present. 
 
 
 
4.2       Intervention 
 
The patient will be seen in clinic every six weeks during treatment for examination.  Imiquimod 
cream is to be applied 3 times per week for 12 weeks.  Several case reports suggest the potential 
efficacy of topical 5% imiquimod cream in the treatment of EMPD after median treatment 
duration of 7.5 weeks (range 6-16).   The technique for proper dose administration should be 
demonstrated by the prescriber to maximize the benefit of imiquimod therapy. It should be 
applied prior to normal sleeping hours, and left on the skin for 6-10 hours.  Following the 
treatment period cream should be removed by washing the treated area with mild soap and water. 
Examples of 3 times per week application schedules are: Monday, Wednesday, Friday; or 
Tuesday, Thursday, Saturday application prior to sleeping hours.  The technique for proper dose 
administration should be demonstrated by the prescriber to maximize the benefit of imiquimod 
therapy. Handwashing is recommended before and after applying imiquimod 5% cream. 
 
Punch biopsy and photography will be performed at the baseline and 12 week time points.  If the 
lesion is still present after 12 weeks of therapy, the treating physician will recommend excision 
of the lesion four weeks after completion of therapy (week 16).  The patient will have a follow- 
up exam 6 weeks after excision and then every 3 months for at least 2 years. If no lesion is 
present or the patient refuses surgical excision at week 16, the patient will return for follow-up 
exams every 3 months for at least 2 years. The treating physician will continue to offer surgical 
excision at any later point during follow-up if the lesion is still present. 
 
 
5.0       THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Aldara™  (imiquimod)  Cream,  5%  is  the  brand  name  for  imiquimod  which  is  an  immune 
response modifier.xvii   Each gram of the 5% cream contains 50 mg of imiquimod in an off-white 
oil-in-water vanishing cream base consisting of isosteric acid, cetyl alcohol, stearyl alcohol, 
white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, 
benzyl alcohol, methylparaben, and propylparaben. Chemically, 
imiquimod 
is 1-(2- 
methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine. Imiquimod has a molecular formula of 
C14H16N4 and a molecular weight of 240.3.xviii 


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Pharmacodynamics 
The mechanism of action of imiquimod in treating genital/perianal warts, superficial basal cell 
carcinoma, and actinic keratosis is unknown. Imiquimod has no direct antiviral activity in cell 
culture. Mouse skin studies suggest that imiquimod induces cytokines including interferon-α. 
However, the clinical relevance of these findings is unknown.xviii 
 
Pharmacokinetics 
Percutaneous  absorption  of  [14C]  imiquimod  was  minimal  in  a  study  involving  6  healthy 
subjects treated with a single topical application (5 mg) of [14C] imiquimod cream formulation. 
No radioactivity was detected in the serum (lower limit of quantitation: 1 ng/mL) and <0.9% of 
the radiolabelled dose was excreted in the urine and feces following topical application.xviii 
 
Administration of topical imiquimod 
Imiquimod cream is to be applied 3 times per week, prior to normal sleeping hours, and left on 
the skin for 6-10 hours. Following the treatment period cream should be removed by washing the 
treated area with mild soap and water. Examples of 3 times per week application schedules are: 
Monday,  Wednesday,  Friday;  or  Tuesday,  Thursday,  Saturday  application  prior  to  sleeping 
hours. Local skin reactions (erythema) at the treatment site are common.  Local anesthetic cream 
or non-occlusive dressings such as cotton gauze or cotton underwear may be used in the 
management  of  skin  reactions.      Treatment  may  resume  once  the  reaction  subsides.  The 
technique for proper dose administration should be demonstrated by the prescriber to maximize 
the benefit of imiquimod therapy. Handwashing before and after cream application is 
recommended. Imiquimod 5% cream is packaged in single-use packets which contain sufficient 
cream to cover an area of up to 20 cm2; use of excessive amounts of cream should be avoided. A 
thin layer is applied to the skin and rubbed in until the cream is no longer visible. The application 
site is not to be occluded. 
 
Aldara (imiquimod) cream, 5%, is supplied in single-use packets which contain 250 mg of the 
cream. Available as: box of 12 packets NDC 0089-0610-12. Store below 25°C (77°F). Avoid 
freezing. 13 
 
 
6.0       CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1       Subject Inclusion Criteria 
 
All patients presenting to the Gynecology outpatient service at a participating institution who 
meet eligibility requirements may be included in this clinical trial. The eligibility requirements 
are as follows: 
 
1.  Age ≥18. 
2.  Ability to give informed consent. 
3.  Patients must have biopsy proven recurrent extramammary Paget’s disease confirmed at the 
participating site. 


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6.2       Subject Exclusion Criteria 
 
1. Patients with known hypersensitivity to imiquimod. 
2. Pregnant and nursing women are not eligible 
3. Patients with underlying adenocarcinoma on biopsy of lesion confirmed at the participating 
site. 
 
7.0       RECRUITMENT PLAN (WITH LIMITED WAIVER OF AUTHORIZATION) 
 
As a multi-center trial, participants will be recruited from MSKCC as well as the participating 
site  OSUMC.  Potential  research  subjects  will  be  identified  by  a  member  of  the  patient’s 
treatment team, the protocol investigator, or the research team at each respective institution. 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. 
 
The principal investigator may also screen the medical records of patients with whom they do 
not have a treatment relationship for the limited purpose of identifying patients who would be 
eligible to enroll in the study and to record appropriate contact information in order to approach 
these patients regarding the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/research staff and the patient; the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process.  The investigator/research staff may also review portions of their medical 
records in order to further assess eligibility.   They will use the information provided by the 
patient and/or medical record to confirm that the patient is eligible and to contact the patient 
regarding study enrollment.  If the patient turns out to be ineligible for the research study, the 
research staff will destroy all information collected on the patient during the initial conversation 
and medical records review, except for any information that must be maintained for screening 
log purposes.  If the woman agrees to study participation, a consenting individual (listed below 
in section 15.1) will obtain informed consent from the patient until a goal of 20 eligible patients 
are entered into the study. 
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team.  The recruitment process outlined presents no more than minimal risk to the privacy of the 
patients who are screened and minimal PHI will be maintained as part of a screening log.  For 
these  reasons,  we  seek  a  (partial)  limited  waiver  of  authorization  for  the  purposes  of  (1) 
reviewing medical records to identify potential research subjects and obtain information relevant 
to  the  enrollment  process;  (2)  conversing  with  patients  regarding  possible  enrollment;  (3) 
handling of PHI contained within those records and provided by the potential subjects; and (4) 
maintaining information in a screening log of patients approached (if applicable). 


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IRB Protocol 
IRB#: 07-029A(6) 
during follow-up if the lesion is still present. 
Amended:  3/5/14 
- 7 - 
 
 
 
8.0       PRETREATMENT EVALUATION 
 
The pre-therapy evaluation will include: 
• Histologic confirmation of recurrent EMPD 
• A history and physical examination as per standard clinical work-up for a vulvar lesion at 
the participating site 
• Photography of lesion 
 
 
 
9.0       TREATMENT/INTERVENTION PLAN 
 
The patient will be seen in clinic every six weeks during treatment for examination, teaching, 
and to assess compliance.  Imiquimod cream is to be applied 3 times per week for 12 weeks.  It 
should be applied prior to normal sleeping hours, and left on the skin for 6-10 hours.  Following 
the treatment period cream should be removed by washing the treated area with mild soap and 
water. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday; or 
Tuesday, Thursday, Saturday application prior to sleeping hours.  The technique for proper dose 
administration should be demonstrated by the prescriber to maximize the benefit of imiquimod 
therapy. Handwashing is recommended before and after applying imiquimod 5% cream. 
 
Punch biopsy and photography will be performed at the baseline and 12 week time points.  If the 
lesion is still present after 12 weeks of therapy, the treating physician will recommend excision 
of the lesion four weeks after completion of therapy(week 16). If no lesion is present or the 
patient refuses surgical excision at week 16, the patient will return for follow-up exams every 3 
months for at least 2 years. The treating physician will continue to offer surgical excision at any 
later point during follow-up if the lesion is still present. 
 
 
 
10.0     EVALUATION DURING TREATMENT/INTERVENTION 
The patient will be seen in clinic at approximately six week intervals during treatment for 
examination (e.g. week 6 visit will be completed between 35-49 days, week 12 visit between 77- 
91 days, and week 16 visit between 105-119 days after baseline). Punch biopsy and photography 
will be performed at the baseline and 12 week visit.  The lesion will be assessed after the initial 
12 weeks of therapy by visual inspection by the treating physician.  Photodocumentation of the 
area will also be performed at this time.  If the lesion is still present, repeat punch biopsy with 
histologic assessment will be performed (week 12).  If the lesion is still present after the initial 
12 weeks of therapy, the treating physician will recommend excision of the lesion four weeks 
following completion of therapy (week 16) to permit resolution of treatment associated 
inflammation.  During this four week time period, the patient will not use imiquimod 5% cream. 
Any lesion progressing to a clinical appearance suspicious for evolving adenocarcinoma will be 
excised prior to study completion.   The patient will have a follow-up exam 6 weeks after 
excision and then every 3 months for at least 2 years. If no lesion is present or the patient refuses 
surgical excision at week 16, the patient will return for follow-up exams every 3 months for at 
least 2 years. The treating physician will continue to offer surgical excision at any later point 


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Soreness 
Amended:  3/5/14 
3% 
0% 
0% 
1% 
- 8 - 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Week 
6 
Week 12 
Week 16 
Week 22 
(if lesion 
was 
excised) 
Every 3 months 
for 2 years 
Clinical 
Assessment 






Photography 


Biopsy 
Punch 
biopsy of 
lesion 
Repeat 
Punch 
biopsy of 
lesion 
Excision of 
lesion if still 
present 
(recommended) 
11.0     TOXICITIES/SIDE EFFECTS 
Topical imiquimod therapy has been generally well tolerated although both local and systemic 
side effects have been observed. Local skin reactions such as erythema, erosion, 
excoriation/flaking, and edema are common. Should severe local skin reaction occur, the cream 
should be removed by washing the treatment area with mild soap and water.   Treatment with 
imiquimod cream can be resumed after the skin reaction has subsided. Overall, in reported 
studies of patients treated with imiquimod™ three times weekly, 1.2% (4/327) of the patients 
discontinued due to local skin/application site reactions.xix  The incidence and severity of local 
skin reactions during controlled clinical trials are shown in the following table. xix 
 
3X/WEEK APPLICATION 
FEMALES 
MALES 
Imiquimod 
Vehicle 
Imiquimod 
Vehicle 
(n=117) 
(n=103) 
(n=156) 
(n=158) 
 
 
 
APPLICATION SITE REACTIONS 
Itching 
32% 
20% 
22% 
10% 
Burning 
26% 
12% 
9% 
5% 
Pain 
8% 
2% 
2% 
1% 


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Amended:  3/5/14 
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FUNGAL INFECTION* 
11% 
3% 
2% 
1% 
SYSTEMIC REACTIONS: 
Headache 
4% 
3% 
5% 
2% 
Influenza-like symptoms 
3% 
2% 
1% 
0% 
Myalgia 
1% 
0% 
1% 
1% 
 
*Incidences reported without regard to causality with imiquimod 
 
 
 
 
 
 
Remote site skin reactions were also reported in patients treated three times weekly with 
imiquimod 5% cream. The severe remote site skin reactions reported for females were erythema 
(3%), ulceration (2%), and edema (1%); and for males, erosion (2%), and erythema, edema, 
induration, and excoriation/flaking (each 1%). 
 
Adverse events judged to be possibly or probably related to imiquimod and reported by more 
than 1% of patients include: Application Site Disorders: Burning, hypopigmentation, irritation, 
itching, pain, rash, sensitivity, soreness, stinging, tenderness); Remote Site Reactions (bleeding, 
burning, itching, pain, tenderness, tinea cruris); Body as a Whole: fatigue, fever, influenza-like 
symptoms;  Central  and  Peripheral  Nervous  System  Disorders:  headache;  Gastro-Intestinal 
System Disorders: diarrhea; Musculo-Skeletal System Disorders: myalgia. 
 
Carcinogenicity, Mutagenesis, and Impairment of Fertility 
In a 52 week dermal photo-carcinogenicity study, the median time to onset of skin tumor 
formation was decreased in hairless mice following chronic topical dosing (3X/week; 40 weeks 
of treatment followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 
days  per  week)  with  imiquimod  Cream  vehicle  alone.     No  additional  effect  on  tumor 
development beyond the vehicle effect was noted with the addition of the active ingredient, 
imiquimod, to the vehicle cream. 
 
Imiquimod was without effect in a series of eight different mutagenicity assays including Ames, 
mouse lymphoma, CHO chromosome aberration, human lymphocyte chromosome aberration, 
SHE cell transformation, rat and hamster bone marrow cytogenetics, and mouse dominant lethal 
test. Daily oral administration of imiquimod to rats, at doses up to 8 times the recommended 
human dose on a mg/m2 basis throughout mating, gestation, parturition and lactation, 
demonstrated no impairment of reproduction. 
 
While there is no data to suggest the carcinogenicity of topical imiquimod in the setting in which 
it is being employed in this study, the possibility of progression of EMPD to invasive carcinoma 
cannot be ruled out. 
 
Pregnancy 
Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. 
Imiquimod should only be used during pregnancy only if the potential benefit justifies the 


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potential risk to the fetus.   Systemic embryofetal development studies were conducted on rats 
and rabbits.   Oral doses of 1, 5 and 20 mg/kg/day imiquimod were administered during the 
period of organogenesis (gestational days 6 – 15) to pregnant female rats.   In the presence of 
maternal toxicity, fetal effects noted at 20 mg/kg/day [8X Maximum recommended human dose] 
included increased resorptions, decreased fetal body weights, delay in skeletal ossification, bent 
limb  bones,  and  two  fetuses  in  one  litter  (2  of  1567  fetuses  demonstrated  exencephaly, 
protruding tongues and low-set ears.  No treatment related effects on embryofetal toxicity or 
teratogenicity were noted at 5 mg/kg/day. 
 
Nursing Mothers 
It is not known whether topically applied imiquimod is excreted in breast milk. 
Postmarketing experience 
Individuals who used Imiquimod Cream after it was approved by the Food and Drug 
Administration have reported the following adverse reactions.  It is not possible to reliably 
estimate their frequency or to establish a causal relationship to drug exposure.  These events 
include the following: 
• Angioedema - swelling, similar to hives, but the swelling is beneath the skin rather than 
on the surface 
• Capillary leak syndrome - is a rare medical condition where the number and size of the 
pores in the capillaries are increased which leads to a leakage of fluid from them 
• Cardiac Failure - the inability of the heart to fill with or eject blood due to any structural 
or functional cardiac conditions. 
• Cardiomyopathy - serious disease in which the heart muscle becomes inflamed and 
doesn't work as well as it should. 
• Arrhythmias - disorder of the heart rate (pulse) or heart rhythm, such as beating too fast 
(tachycardia), too slow (bradycardia), or irregularly. 
• Chest pain - discomfort or pain in the chest that may be a key warning symptom of a 
heart attack 
• Ischemia - a condition in which the blood flow (and thus oxygen) is restricted to a part of 
the body 
• Myocardial infarction - commonly known as a heart attack, is the interruption of blood 
supply to a part of the heart 
• Syncope - temporary loss of consciousness and posture, described as "fainting" or 
"passing out." 
• Thyroiditis - inflammation of the thyroid gland 
• Decrease in white blood count 
• Decrease in red blood count 
• Decrease in platelet count 
• Abnormal liver function 
• Agitation - Emotional state of excitement or restlessness 
• Cerebrovascular accident – this is also known as a “stroke,” which is the loss of brain 
function(s) due to disturbance in the blood supply to the brain 
• Convulsions - when a person's body shakes rapidly and uncontrollably 


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• Depression - mental disorder characterized by an low mood accompanied by low self- 
esteem, and by loss of interest or pleasure in normally enjoyable activities 
• Insomnia – when a person is unable to fall asleep or remain asleep for an adequate length 
of time 
• Multiple Sclerosis aggravation – worsening of the symptoms of Multiple Sclerosis 
• Paresis - partial loss of movement, or impaired movement 
• Suicide - the act of a human being intentionally causing his or her own death 
• Dyspnea - difficulty in breathing 
• Proteinuria - the presence of an excess of proteins in the urine 
• Exfoliative dermatitis - widespread scaling of the skin, often with itching, skin redness, 
and hair loss 
 
12.0     CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
The biopsied lesion will be the focus of the histologic assessment.  All biopsies will be routinely 
sectioned and stained (H&E).   Photographs will be obtained by the treating physician. 
Standardized 1:1 fixed distance photography will be performed with a contact camera with a 
built in light source to ensure standardized images.  Millimeter scales will be included in each 
image to ensure spacial standardization. 
 
 
 
Clinical response will be assessed by comparison of pairs of clinical photographs obtained at study 
completion and baseline. Pairs of photographs will be graded as: 
 
Complete response = reversion to clinically normal appearing skin. 
Partial response = 50% or greater reduction in diameter of affected skin. 
Progression = 50% or greater increase in diameter of affected skin. 
 
Primary histologic evaluation will entail quantification of the number of involved areas /mm2 that 
have Paget’s cells. Histologic response will be graded as: 
 
Complete response = No evidence of Paget’s cells 
Partial response = ratio of involved areas/mm2 in post-treatment biopsy specimen/ pre- 
treatment biopsy specimen < 50% 
Progression = ratio of involved areas/mm2 in post-treatment biopsy specimen/ pre- 
treatment biopsy specimen >150% 
 
 
We recognize the subjective nature of determining “significant” changes in appearance of the skin 
lesion.  This problem, common to many dermatology studies, has defied a standardized technologic 
solution to date.  We will use the method that is similar to that employed by a recently published 
study evaluating the effects of imiquimod on dysplastic nevi.xx    In this study, Junctional lesional 
cells were counted in multiple high power fields and reported as lesional cells/mm2 and lesional cell 


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counts were compared between treated and untreated nevi. Complete response was defined as 
reversion to clinically normal appearing skin. Partial response was defined as a 50% or greater 
reduction in diameter and progression was defined as a 50% or greater increase in diameter. 
 
 
13.0     CRITERIA FOR REMOVAL FROM STUDY 
 
In the event that the treated lesion changes in a clinically worrisome fashion with correlating 
histology demonstrating invasive carcinoma during the study, the patient will be removed from 
the study.     Patients who have unacceptable toxicities will be removed from the study. 
Unacceptable toxicities consist of headache, influenza-like symptoms, and myalgia, 
 
If, at any time, the patient withdraws consent to participate in the study, he/she will be removed 
from the study. In such event the investigator will carefully consider whether the patient’s 
withdrawal of consent is due to an adverse event, and if so, record the adverse event as the 
reason for withdrawal. 
 
 
14.0     BIOSTATISTICS 
 
The purpose of this pilot study is to assess the clinical and histologic effects of a topical 
immunomodulatory  agent,  imiquimod,  on  extramammary  Paget’s  disease  (EMPD).   This  is 
a multicenter study in which the patient and the pathologist will not be blinded to treatment 
status. Photographs obtained before and after treatment will be evaluated by an independent 
reviewer.   The institutions involved in this study include: Memorial Sloan-Kettering Cancer 
Center  in  New  York  City, NY  (MSKCC),  and  Ohio  State  University  College  of  Medicine 
(OSUMC) in Columbus, Ohio. 
 
Twenty patients will be accrued onto this study. It is unknown how patients will respond to this 
topical treatment and 20 patients is the maximum number of patients that can be accrued in a 
reasonable time period. Assuming a drop out rate of 15% our target sample size is 17. At the end 
of this study, we hope to estimate a response rate with a 95% confidence interval ± 24 % based 
on  17  patients.   Approximately  7  patients  are  diagnosed  a  year with  EMPD  at MSKCCand 
approximately 1-2 patients a year from OSU. From this we expect to accrue 5-8 patients per year 
until  20  patients  are  accrued  on  study  (approximately 3  years).   At  the  end  of  the  study, 
descriptive statistics will be performed to evaluate the effectiveness of imiquimod therapy on 
extramammary Paget’s disease patients. 
 
 
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. 


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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. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 
15.2 
For Participating Sites: 
 
Central registration for this study will take place at Memorial Sloan Kettering Cancer 
Center. 
 
To complete registration and enroll a participant from another institution, the study staff 
at that site must contact the designated research staff at MSKCC to notify him/her of the 
participant registration. The site staff then needs to fax registration/eligibility documents 
to the Department of Surgery, Gynecology Service at MSKCC at 212.557.2434. 
 
The following documents must be sent for each enrollment within 24 hours of the 
informed consent form being signed: 
• The completed MSKCC eligibility checklist 
• The signed informed consent and signed HIPAA Authorization form (Research 
Authorization) 
• Supporting source documentation for eligibility questions (pathology reports, MD 
notes, physical exam sheets, medical history, prior treatment records). 
 
Upon receipt, the research staff at Memorial Sloan Kettering Cancer Center will conduct 
an interim review to confirm all documents are received to complete registration. 
 
If the participant meets all criteria, all source documentation is received, the participating 
site local IRB has granted approval for the protocol, and the site is in good standing with 
MSKCC, the MSK RSA will send the completed registration documents to the MSKCC 
Protocol Participant Registration (PPR) Office to be enrolled as stated in section 15.1. 
The participant will be registered. 
 
15.3 
Protocol Participant Number at Participating sites 
 
Once eligibility has been established and the participant is registered, the participant will 
be assigned an MSKCC clinical research database (CRDB) number (protocol participant 


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number).  This number is unique to the participant and must be written on all data and 
correspondence for the participant. This protocol participant number will be relayed back 
to study staff at the registering site via e-mail and will serve as the enrollment 
confirmation. 
 
 
16.0     DATA MANAGEMENT REQUIREMENTS FOR PARTICIPATING SITES 
 
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. 
 
 
16.1.0  Data and Source Documentation 
 
Data 
Standardized Case Report Forms (CRFs), directions for use and sign off requirements have 
been generated for this study. Blank case report forms will be sent to the study staff at each 
participating site for use. The participating Site PI is responsible for ensuring these forms are 
completed accurately, legibly and in a timely manner. 
 
Source Documentation 
 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data into CRFs. Relevant source documentation 
to be submitted throughout the study includes: 
o MD office visit notes 
o Pathology reports 
o Photographs 
o Clinical assessment forms 
o Grade 3-5 toxicities/adverse events not previously submitted with SAE Reports 
 
16.1.1  Data and Source Documentation Submission 
Participating sites should fax the CRFs to MSKCC to the contact provided below. 
Submissions should include a cover page listing all CRFs enclosed per participant. 
 
FAX: 212.557.2434 to the attention of Protocol 07-029 RSA 
 
16.1.2   Data and Source Documentation Submission Timelines 
 
• CRFs and source documentation to support data in the CRFs should be submitted 
according to chart below. 


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• Participating sites should respond to data queries within 14 days of receipt. 
 
 
 
16.2     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://mskweb2.mskcc.org/irb/index.htm 
 
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 
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 will be assessed for its 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. 
 
 
16.3     Regulatory Documentation 
 
Prior to implementing this protocol at MSKCC, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSKCC IRB/PB. Prior to implementing this protocol at the participating centers, approval 
must be obtained from the participating center’s Local IRB of Record. 
The following documents must be provided to MSKCC before the participating site can be 
initiated and begin enrolling participants: 
• Participating site IRB of approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
• Participating site IRB approved consent form 
• Participating site IRB’s membership list 
• Participating site IRB’s of Record’s Federal Wide Assurance number and OHRP 
Registration number 
• Curriculum vitae and medical license for each investigator and consenting professional 


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• Documentation of Human Subject Research Certification and HIPAA training for 
investigators and key staff members 
 
16.3.1  Amendments 
 
Each change to the protocol must be organized and documented by MSKCC and first 
approved by the MSKCC IRB/PB. After approval at the lead institution, MSKCC will 
distribute the non-expedited amendments to the participating centers, for approval by their 
local IRBs. 
 
Participating sites must obtain approval for all non-expedited amendments from their local 
IRB of record within 90 calendar days of receipt from the MSKCC. If the amendment is the 
result of a safety issue or makes eligibility criteria more restrictive, sites will not be permitted 
to continuing enrolling new participants until local IRB approval has been granted. 
 
The following documents must be provided to MSKCC for each amendment within the stated 
timelines: 
• Participating site IRB approval 
• Participating site IRB approved, revised documents including the protocol, informed 
consent form and HIPAA  authorization 
 
16.3.2  Additional IRB Correspondence 
 
 
Annual re-approval or Continuing Review Approval 
Annual re-approval from the participating center’s Local IRB of Record and the most current 
approved version of the consent form should be submitted to MSKCC within 7 days of 
expiration. Failure to submit the re-approval will result in suspension of accrual privileges. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration in 
their study plan. If a deviation from the protocol is proposed for a potential or existing 
participant at a participating site, approval from the MSKCC IRB/PB is required prior to the 
action. Participating sites should contact the MSKCC PI who will in turn seek approval from 
the MSKCC IRB/PB 
 
A protocol violation is anything that occurs with a participant, which deviated from the 
protocol without prior approval from the MSKCC IRB/PB. For protocol violations that are 
reported after they occur, the participating site should report to MSKCC as soon as possible. 
The MSKCC PI will in turn report the violation to the MSKCC IRB/PB. 
 
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as possible per local guidelines. Approvals/acknowledgments from the Local IRB of Record 
for protocol deviations and violations should be submitted to MSKCC as received. 
 
Other correspondence 
Participating sites should submit other correspondence to their local IRB of Record according 
to local guidelines, and submit copies of that correspondence to MSKCC. 
 
16.3.3  Document maintenance 
 
The MKSCC PI and the Participating Site PI will maintain adequate and accurate records to 
enable the implementation of the protocol to be fully documented and the data to be 
subsequently verified. 
 
The participating sites will ensure that all local IRB correspondence (IRB approval letters 
referencing protocol version date and amendment number, IRB approved protocol, 
appendices, consent forms, deviations, violations, and approval of annual reviews) is sent to 
MSKCC and maintained in the regulatory binder on site. 
 
A regulatory binder for each site will also be maintained at MSKCC; this binder may be paper 
or electronic. 
 
After study closure, the investigator will maintain all source documents, study related 
documents and CRFs for 3 years. 
 
 
 
16.4   Quality Assurance 
 
Study personnel will generate monthly registration reports to monitor patient accrual and 
completeness  of  registration  data.  Routine  data  quality  reports  will  be  generated  to  assess 
missing data and inconsistencies. Accrual rates, 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. 
 
Data quality and protocol compliance audits will be conducted by the study team on a regular 
basis throughout the study period. 
 
 
16.4.1 Quality Assurance for Participating sites 
 
Each site participating in the accrual of participants to this protocol will be audited by the staff of 
the MSKCC study team for protocol and regulatory compliance, data verification and source 
documentation.   Audits may be accomplished in one of two ways: (1) selected participant 
records can be audited on-site at participating sites or (2) source documents for selected 
participants will be sent to MSKCC for audit. Audits will usually be determined by participant 


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accrual numbers and rate of accrual, but can also be prompted by reported SAEs or request of 
MSKCC PI. 
 
Audits will be conducted at least once shortly after initiation of participant recruitment at a site, 
during the study (if the trial lasts 3 or more years) and at the end or closeout of the trial at a site. 
At a minimum, audits will be conducted once a year or more frequently, if indicated. The 
number of participants audited will be determined by available time and the complexity of the 
protocol. 
 
The audit will include a review of source documentation to evaluate compliance for: 
 
• Informed Consent documents and procedures 
• Adherence to eligibility criteria 
• Protocol defined treatment 
• Required baseline, on study and follow-up protocol testing 
• IRB documents (submitted amendments, annual continuing review reports, SAEs) 
• Required specimen submission 
• Pharmacy review, if applicable 
• Case Report Form submissions to MSKCC: timing and accuracy 
 
A wrap-up session will be conducted at the outside site and preliminary findings will be 
discussed with the outside site PI and research team. The preliminary results will be sent to the 
MSKCC PI. 
 
 
 
Each audit will be summarized and a final report will be sent to the PI at the audited participating 
institution within 30 days of the audit. The report will include a summary of findings, participant 
by participant case review, specific recommendations on any performance and/or shortcomings 
and request for corrective action, when necessary. When corrective action is required, the 
participating institution must reply within 45 days of receipt of audit report with their corrective 
action plan. 
 
A copy of the audit report and corrective action plan (if applicable) submitted by the outside site 
must be sent to the MSKCC IRB, CRQA and maintained in the department’s protocol regulatory 
binder. 
 
 
 
16.4.2 Response Review 
 
Since therapeutic efficacy is a stated primary objective, all sites participant’s responses are 
subject to review by MSKCC’s Therapeutic Response Review Committee (TRRC).  Radiology, 
additional lab reports and possibly bone marrow biopsies and/or aspirates will need to be 


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obtained from the outside sites for MSKCC TRRC review and confirmation of response 
assessment. These materials must be sent to MSKCC within sixty days of request to the site. 
 
16.5   Noncompliance 
 
If a participating site is noncompliant with the data and regulatory requirements set forth in 
protocol document, accrual privileges may be suspended and/or contract payments maybe 
withheld (if applicable), until the outstanding issues have been resolved. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Risks:  It is unlikely that significant risks will be associated with the limited topical use of 
imiquimod planned in this study. 
 
Benefits:  Patients with a good clinical response to imiquimod may benefit from future broader 
application of this therapy. 
 
Possible Toxicities and Side Effects:  Local application site reactions can be anticipated. 
Previously reported toxicities/side effects of topical imiquimod are elaborated in section 11.0 of 
this protocol. While there is no data to suggest the carcinogenicity of topical imiquimod in this 
setting, the possibility of progression of a lesion to cancer cannot be ruled out. 
 
Consent Process:  Participation in this protocol is voluntary. All patients will be required to sign 
a statement of informed consent, which must conform to MSKCC IRB guidelines. 
 
Costs:  Patients will not be charged for protocol related costs. 
 
Alternatives:  There are no proven nonsurgical treatments for EMPD. All study patients will be 
offered surgical treatment for EMPD. 
 
17.1 
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. 
 
 
 
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.org.  The report should contain 
the following information:Fields populated from the CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 


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• 
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 
• 
The intervention 
• 
Detailed text that includes the following information: 
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. 
 
17.2.1 Serious Adverse Event (SAE) Reporting for Participating Sites 
 
Responsibility of participating sites: 
 
• 
Participating sites are responsible for reporting all SAEs to the MSKCC PI via fax or e-mail 
within 3 calendar days of learning of the event. 
• 
Participating sites should notify the MSKCC PI of any grade 5 events immediately. 
• 
Participating sites should use the SAE Report Template (appendix #2) to report SAEs to 
MSKCC. 
 
SAE contact information for the Coordinating Center is listed below: 
 
Dennis Chi, M.D., Principal Investigator 
Department of Surgery, Division of Gynecologic Oncology 
Memorial Sloan-Kettering Cancer Center 
New York, NY 10021 
(212) 639-5016 
 
Gina Gualtiere, RSA 
Department of Surgery, Division of Gynecology Oncology 
Memorian Sloan-Kettering Cancer Center 
New York, NY 10021 
(646) 227-2232 


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• 
The MSKCC RSA is responsible for submitting all SAEs to the MSKCC IRB as 
specified in 17.2 . 
 
• The MSKCC PI is responsible for informing all participating sites about unexpected 
SAEs within 30 days of receiving the stamped SAE from the MSKCC IRB/PB. 
• Any report pertaining to a grade 5 event will be distributed to the participating sites as 
soon as possible. 
 
 
17.3 Safety Reports 
 
• MSKCC will distribute outside safety reports to the participating sites immediately upon 
receipt. 
• MSKCC must submit outside safety reports to the MSKCC IRB/PB according to 
institutional guidelines. 
• Participating sites must submit safety reports to their institution’s IRBs within 30 days of 
receipt from MSKCC or per participating site guidelines. 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent form indicating 
their consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. The consent form 
will include the following: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 


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Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
 
18.1 For Participating Centers 
 
The investigators listed on the cover page and their qualified designees at each participating 
institution may obtain consent and care for the participants according to good clinical practice 
and protocol guidelines. 
 
Duplicate originals or copies of the signed informed consent should be distributed as follows: 
One copy will be given to the participant to be retained for their personal records. One copy will 
be maintained on file at the MSKCC. The third copy will be confidentially maintained by the 
participating institution. 
 
A note will be placed in the medical record documenting that informed consent was obtained for 
this study, and that the participant acknowledges the risk of participation. 
 
19.0 reference(s) 
 
i Beutner, KR, Geisse, JK, Helman D, Fox TL, Ginkel A, Owens ML. Therapeutic response of 
basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad 
Dermatol 41:1002-7, 1999 
 
ii Testerman TL, Gerster JF, Imbertson LM et al. Cytokine induction by the immunomodulators 
imiquimod and S-27609. J Leukocyte Biol  58:365-372, 1995 
 
iiiZampogna JC, Flowers FP, Roth WI, Hassenein, A. Treatment of primary limited cutaneous 
extramammary Paget’s disease with topical imiquimod monotherapy.  Two case reports.  J Am 
Acad Dermatol 47:229-35, 2002 
 
iv Wang LC, Blanchard A, Judge DE, Lorincz AA, Medenica MM, Busbey S. Successful 
treatment of recurrent extramammary Paget's disease of the vulva with topical imiquimod 5% 
cream. J Am Acad Dermatol. 49(4):769-72, 2003 
 
v Qian Z, Zeitoun N, Shieh S et al. Successful treatment of extramammary Paget’s Disease with 
Imiquimod. J Drugs Dermatol 2:73-76, 2003 
 
vi Berman B, Spencer J et al.  Successful treatment of extramammary Paget’s disease of the 
scrotum with Imiquimod 5% cream.  At: the European Academy of Dermatology Meeting, Oct 
2002, Prague, Czech Republic 


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vii Jones RE, Austin C, Ackerman AB, Extramammary Paget’s Disease: A critical 
reexamination.  Am J. Dermatopathol  1:101-102, 1979 
 
viii Fanning J, Lamber L et al.   Paget’s disease of the vulva:  Prevalence of associated underlying 
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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 07-029A(6) 
Amended:  3/5/14 
- 24 - 
 
 
 
 
xx Dusza S, Delgado R, Busam K, Marghoob A, Halpern A.  Treatment of Dysplastic Nevi with 
5% Imiquimod Cream, A Pilot Study.  J Drugs Dermatol 5:56-62, 2006 
 
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20.0 
APPENDICES 
Appendix 1. Patient calendar