Pilot Study to Test the Safety and Efficacy of the Combination of Imiquimod and Pembrolizumab for the Treatment of Metastatic Melanoma
Phase: EARLY_PHASE1
Conditions: Metastatic Melanoma, Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7, Stage IV Cutaneous Melanoma AJCC v6 and v7
Sponsor: Mayo Clinic

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Mayo Clinic Cancer Center 
 
Pilot study to test the safety and efficacy of the combination of imiquimod and pembrolizumab for 
the treatment of metastatic melanoma. 
 
 
Study Chair:  
   
 
 
 
 
 
 
 
 
 
Statistician: 
  
  
 
 
 
 
 
 
√Study contributor(s) not responsible for patient care. 
 
Drug Availability  
 
Commercial Agents: Imiquimod 
Drug Company Supplied: Pembrolizumab  
 
 
Document History 
 
Activation 
12/20/2017 
Amendment 1 
3/15/2019 
Amendment 2 
7/27/2022 
 
 
 
 
 
 
 

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Protocol Version Date: 13May2022 
Protocol Resources 
 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
 
Drug administration, infusion pumps,  
nursing guidelines 
 
 
 
Forms completion and submission 
 
 
 
Protocol document, consent form, 
regulatory issues 
  
 
 
Serious Adverse Events  
 
 
  
*No waivers of eligibility per NCI  
 

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Table of Contents 
Pilot study to test the safety and efficacy of the combination of imiquimod and pembrolizumab for the treatment of 
metastatic melanoma. .................................................................................................................................................... 1 
Protocol Resources ........................................................................................................................................................ 2 
Table of Contents........................................................................................................................................................... 3 
Schema .......................................................................................................................................................................... 4 
1.0 
Background .................................................................................................................................................. 5 
2.0 
Goals ............................................................................................................................................................ 9 
3.0 
Patient Eligibility ......................................................................................................................................... 9 
4.0  
Test Schedule ............................................................................................................................................. 13 
5.0 
Stratification Factors OR Grouping Factor: ............................................................................................... 15 
6.0  
Registration/Randomization Procedures .................................................................................................... 15 
7.0 
Protocol Treatment .................................................................................................................................... 17 
8.0 
Dosage Modification Based on Adverse Events ........................................................................................ 18 
9.0 
Ancillary Treatment/Supportive Care ........................................................................................................ 20 
10.0 
Adverse Event (AE) Reporting and Monitoring ........................................................................................ 23 
11.0 
Treatment Evaluation Using RECIST Guideline ....................................................................................... 32 
12.0 
Descriptive Factors .................................................................................................................................... 38 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ........................................................................... 39 
14.0 
Body Fluid Specimens ............................................................................................................................... 40 
15.0 
Drug Information ....................................................................................................................................... 40 
16.0  
Statistical Considerations and Methodology.............................................................................................. 44 
17.0  
Pathology Considerations/Tissue Biospecimens ....................................................................................... 47 
18.0 
Records and Data Collection Procedures ................................................................................................... 49 
19.0  
Budget ........................................................................................................................................................ 50 
20.0 
References ................................................................................................................................................. 51 
Appendix I 
ECOG Performance Status .............................................................................................................. 52 
 

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Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Generic name: Pembrolizumab 
Brand name(s): Keytruda 
Mayo Abbreviation: MK-3475 
Availability: Investigational 
Generic name: Imiquimod 
Brand name(s): Aldara 
Mayo Abbreviation: IMQ 
Availability: Commercial 
Registration 
Pembrolizumab + Imiquimod 
Completed 2 years 
of study treatment 
Disease progression, 
Treatment intolerability 
Or patient refusal to 
continue treatment 
Observation 
Event Monitoring 
Event Monitoring 

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1.0 
Background  
 
1.1 
Melanoma is the fifth most common cancer in men and sixth most common in women in 
the United States with an estimated ten thousand deaths a year. Recent advances in 
systemic therapy for metastatic melanoma have dramatically improved outcomes; 
however, the majority of patients ultimately die from their disease.  
 
1.2 
One of the major breakthroughs for the treatment of metastatic melanoma is the 
immunotherapy pembrolizumab (MK-3475). Pembrolizumab has demonstrated dramatic 
clinical activity in patients with metastatic melanoma inducing response rates in ~20-40% 
of patients. In addition, the majority of these responses are durable which will likely 
result in significant improvement in long-term survival for patients. Despite the success 
of pembrolizumab in a large minority of patients, the majority of patients ultimately go 
on to progress and require additional therapy. 
 
1.3 
Approximately 20-30% of patients with metastatic melanoma have metastatic cutaneous 
lesions that are amenable to treatment with the combination of systemic therapy with 
topical or injectable therapy. 
 
1.4 
Pharmaceutical and Therapeutic Background on Pembrolizumab 
 
1.41  
The importance of intact immune surveillance in controlling outgrowth of 
neoplastic transformation has been known for decades.  Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer 
tissue and favorable prognosis in various malignancies.  In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
 
1.42 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control.  The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions.  PD-
1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and 
CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD L2).  The structure of murine 
PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell 
stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the 
CD3 T-cell signaling cascade.  The mechanism by which PD-1 down modulates 
T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-
cells, B-cells, T regs and Natural Killer cells.  Expression has also been shown 

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during thymic development on CD4-CD8- (double negative) T-cells as well as 
subsets of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and 
PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors. Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in 
the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor 
immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
 
1.43 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) 
has recently been approved in the United States for the treatment of patients with 
unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
1.5 
Pharmaceutical and Therapeutic Background on Imiquimod 
 
1.51 
Imiquimod is a toll-like receptor seven (TLR7) agonist that activates the innate 
arm of the immune system. Imiquimod stimulates immune cells to secrete pro-
inflammatory cytokines such as interferon-α (IFN-α), interleukin-6 (IL-6), and 
tumor necrosis factor-α (TNF-α). Cells activated by imiquimod include natural 
killer cells, macrophages and B-lymphocytes.  Overall imiquimod acts on several 
levels, which appear to synergistically underlie the profound antitumoral activity 
of the compound. (1) 
 
1.6 Preclinical and clinical Trial Data 
 
1.61 
The clinical trial data for pembrolizumab for the treatment of patients with 
metastatic melanoma has been previously published in detail. In summary, 
pembrolizumab induces durable remissions in a sizable minority of patients with 
metastatic melanoma (20-40%) with an acceptable safety profile of less than 10% 
grade 3 or 4 adverse events.  
 
1.62 
Imiquimod is a toll-like receptor 7 (TLR7) agonist approved for the treatment of 
basal cell carcinoma and genital warts. Imiquimod was tested in a randomized 
phase three study of patients with superficial basal cell carcinoma. (2) In this 
study, imiquimod induced histologic clearance in 80% of patients compared with 
3% in the control arm with less than 10% of patients experiencing a severe (grade 
3 or 4) adverse event. In the setting of genital warts, imiquimod 5% cleared 72-

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84% of warts with a complete remission rate of 40-70% with few recurrences (5-
19%). (3) 
 
1.63  
There are several reports demonstrating the clinical activity of imiquimod in 
treating cutaneous melanoma. In 2000, imiquimod 5% induced a complete 
remission in one patient with lentigo maligna melanoma. [1] In 2002, topical 
imiquimod 5% induced a complete remission in a patient with invasive 
melanoma however the patient did eventually develop lymph node metastases. 
[2] Also in 2002, Bong et al reported 3 patients with cutaneous metastases treated 
topical imiquimod with excellent responses in 2/3 of patients with the third 
patient achieving a response when combining imiquimod with intra-lesional 
interleukin-2. [3] Taken together, topical imiquimod is effective at controlling 
some patients with cutaneous melanoma but not at preventing distant metastases. 
 
1.64 
Topical imiquimod certainly has clinical activity in cutaneous melanoma 
metastases, however, often times additional immune modulation is necessary to 
achieve a complete response or prevent distant spread. With this in mind, Green 
et al performed a phase 1/2 study combining imiquimod with intralesional 
interleukin-2 in 13 patients demonstrating an overall response rate of 50% and 
complete response rate of 40%. [4] In a separate study, the combination of 
imiquimod 5% with BCG demonstrated complete remissions in 2 out of 3 
patients. [5] In another case series of 11 patients with in-transit melanoma, 100% 
of patients responded to a combination of intra-lesional IL-2, imiquimod, and a 
topical retinoid. [6] Taken together, there is ample evidence that imiquimod is an 
effective at treating local cutaneous melanoma metastases however there are high 
rates of distant failure providing the rational for combining imiquimod with 
systemic therapy. 
 
1.7 Rationale 
 
 
1.71 
Approximately 20% of patients with metastatic melanoma are burdened with 
surgically unresectable cutaneous disease. The standard of care for these patients 
is systemic therapy as there are no FDA approved agents to apply directly to the 
skin. While systemic therapy can sometimes generate response in patients’ 
cutaneous lesions, a topical therapy that could assist the systemic therapy would 
be highly desirable.  
 
1.72 
Multiple topical agents have been utilized to treat cutaneous melanoma with 
variable success. Imiquimod is a topical immune modulator thought to activate 
the toll-like receptor (TLR) pathway and help the body produce interferon locally 
to increase the activity of the immune system. Imiquimod is approved for the use 
of variety of skin disorders including basal cell carcinoma, actinic keratosis, and 
genital warts. Several studies have explored the efficacy of imiquimod to treat 
cutaneous melanoma and have demonstrated activity. There are no studies 
combining the use of imiquimod with pembrolizumab.  
 
1.73 
A case series reports successfully treated two patients with the combination of 
ipilimumab and imiquimod[7]. In both patients, cutaneous tumors substantially 
grew while on ipilimumab only to regress after the addition of imiquimod. Both 
patients tolerated the combination well and both patients have a durable 
remission of 9-12 months. 
 

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1.8 Rationale for Trial and Selected Subject Population 
 
1.81 
Despite recent improvement in the treatment of metastatic melanoma, the 
majority of patients still die from their disease providing a clear need to improve 
upon current treatments.  
 
1.82 
More specifically anti-PD1 agents such as pembrolizumab are capable of 
stimulating the patient’s immune system by inhibiting the PD1/PDL1 axis. Given 
the ability of pembrolizumab to stimulate the patient’s immune system, 
combining pembrolizumab with additional immune stimulation has the potential 
to provide additive or synergistic benefit when compared to single agent 
pembrolizumab. 
   
1.83 
Patients with metastatic melanoma and cutaneous metastases provide a unique 
opportunity to combing both topical and systemic therapy. We have previously 
demonstrated that the combination of imiquimod and ipilimumab is both safe and 
effective in two patients (under review). 
 
1.84 
The potential benefit of the combination of imiquimod and pembrolizumab 
remains to be tested in controlled studies. 
 
1.9a 
Rationale for Fixed Dose of Pembrolizumab 
 
1.9a1 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed 
dosing is based on simulations performed using the population PK model of 
pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will 
provide exposures that 1) are optimally consistent with those obtained with the 2 
mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the 
exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe. 
 
1.9a2 
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors.  A fixed dosing scheme will 
also reduce complexity in the logistical chain at treatment facilities and reduce 
wastage. 
 
1.9b 
Rationale for dose of Imiquimod 
 
 
The dose of imiquimod 5% applied Monday-Friday was selected on the basis of 
previous clinical studies demonstrating acceptable toxicity and efficacy profile in 
other skin conditions. 
 
1.9c 
Rationale for Clinical Endpoints 
 
1.9c1 
As mentioned above, this is a pilot study to test both the safety and efficacy of 
the combination of pembrolizumab and imiquimod. Both safety and efficacy will 
be assessed individually. 
 

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1.9c11 Clinical Efficacy Endpoint- The expected single agent response rate of 
pembrolizumab is ~40% in the front line setting and ~25% when given 
after progression on ipilimumab.  Given the small number of patients to 
be enrolled onto this trial, we will construct a 90% confidence interval 
for the proportion of patients who have a CR or PR on two consecutive 
evaluations at least 6 weeks among all the patients enrolled on this trial.   
 
1.9c12 Clinical Safety Endpoint - Given the non-overlapping toxicities of 
pembrolizumab and imiquimod, we expect serious toxicities to occur at a 
rate similar to each drug individually. For example, pembrolizumab 
induces serious adverse events in ~10% of patient and imiquimod 
induces serious adverse events in 1-3% of patients. Therefore we expect 
~10-13% of patient to experience a serious adverse event.   
 
 
1.9d 
Biomarker Research 
 
 
One of the largest unmet needs in improving the therapeutic potential of 
pembrolizumab is identifying reliable predictive biomarkers. In this study, the 
biomarker research will be exploratory in nature and will include assessing total 
tumor RNA through RNA seq and PDL1 expression through the use of 
immunohistochemistry.  Attempts will then be made to associate molecular 
markers with clinical outcomes. 
 
2.0 
Goals  
 
2.1 
Primary 
 
 
To gain preliminary data of the anti-tumor activity and safety profile of the 
combination of imiquimod and pembrolizumab in patients with unresectable 
cutaneous melanoma.    
 
2.3 
Correlative Research 
 
 
To compare and contrast (in a hypothesis generating manner) the biomarker 
profiles of patients who have a confirmed CR or PR by RECIST criteria with 
patients who do not. Immunologic markers to be assessed include tumor-
infiltrating lymphocytes (TIL), tumor expression of programmed death ligand 
one (PDL1), and toll-like receptor 7. 
 
3.0 
Patient Eligibility    
 
3.1 
Registration – Inclusion Criteria  
 
3.11 
Age ≥18 years. 
 
3.12 
Histological confirmation of Stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c that is 
not suitable for surgical resection.  
 
3.13 
Patients must not have received prior pembrolizumab or other anti-PD1/PDL1 
therapies for their metastatic disease.  
 

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3.14 
At least one cutaneous lesion that is amenable to treatment with topical 
imiquimod. 
 
3.15 
Measurable disease by RECIST as defined in Section 11.0.   
  
3.16 
ECOG Performance Status (PS) of 0 or 1 (Appendix I). 
 
3.17 
The following laboratory values obtained ≤14 days prior to registration.  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin >9.0 g/dL or ≥5.6 mmol/L without transfusion or EPO 
dependency (within 7 days of assessment). 
• 
Serum total bilirubin ≤ 1.5 X ULN or Direct bilirubin ≤ (ULN) for subjects 
with total bilirubin levels > 1.5 ULN 
• 
Aspartate transaminase (AST) ≤2.5 x ULN or ≤ 5 x ULN for subjects with 
liver metastases. 
• 
Albumin ≥2.5mg/dL 
• 
Creatinine ≤1.5 X upper limit of normal (ULN) 
NOTE: Measured or calculated (per institutional standard) creatinine 
clearance is acceptable ≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN. Calculated creatinine clearance can be used in place of 
creatinine or CrCl and must be ≥45 ml/min using the Cockcroft-Gault 
formula below: 
 
 
 
3.18 
Negative urine or serum pregnancy test done ≤72 hours prior to first treatment, 
for women of childbearing potential only. 
 
 If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
 
 
 
3.19a 
Provide informed written consent. 
 
3.19b Willing to return to enrolling institution for follow-up. 
 
3.19c 
Willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumor lesion in appropriate low risk cutaneous lesions. 
 
NOTE:  If the tissue biopsy is deemed to be of increased risk for the patient, the 
biopsy should not be performed and is optional. 
 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
(140 - age)(weight in kg) 
  
 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
(140 - age)(weight in kg)(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 

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NOTE: Newly-obtained is defined as a specimen obtained up to 42 days prior to 
registration where no anti-cancer therapy after the specimen was obtained and 
registration.  
 
 
3.2 
Registration – Exclusion Criteria  
 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown:  
 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception 
 
 
 
NOTE: Female subjects of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication 
(Reference Section 5.7.2).  Subjects of childbearing potential are those who have 
not been surgically sterilized or have not been free from menses for > 1 year. 
Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy. Abstain from heterosexual activity is also acceptable method of 
contraception for males. 
 
3.22 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
 
3.23 
Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 
 
3.24 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
3.25 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm or used an investigational device ≤ 4 weeks 
from registration. 
 
3.26 
History of myocardial infarction ≤6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
 
3.27 
Known history of active TB (Bacillus Tuberculosis) 
 
3.28 
Hypersensitivity to pembrolizumab or any of its excipients. 
 
3.29a 
Prior anti-cancer monoclonal antibody (mAb) ≤ 4 weeks prior to registration or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks prior to registration 

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3.29b Prior chemotherapy, targeted small molecule therapy, or radiation therapy ≤ 2 
weeks prior to registration or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.  
 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
 
 
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  
 
3.29c 
Known secondary malignancy that has progressed within the last 3 years or 
requires active treatment. Exceptions include basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially curative 
therapy or in situ cervical cancer. 
 
3.29d Known central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
 
3.29e 
Active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
 
3.29f 
History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
3.29g Active infection requiring systemic therapy. 
 
3.29h History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s 
participation for the full duration of the trial, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator. 
 
3.29i 
Known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
3.29j 
Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
3.29k Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).  
 
3.29l 
Received a live vaccine ≤30 days prior to registration. 
 
 
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 

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 4.0  
Test Schedule 
Tests and Procedures 
≤28 Days 
prior to 
Registration 
Day 1 (+/-3 
days) of 
each cycle  
End of 
Treatment 
Observation 
 
 
Every 12 (+/-
2) weeks for 
months 24 
thru 36 post 
registration 
at progression 
History and Physical 
Examination, wt, PS 
X 
X 
X 
X 
X 
Height  
X 
 
 
 
 
Adverse Events 
Assessment 
X 
X 
X 
X 
X 
Pregnancy Test – Urine or 
Serum –HCG1 
 
X6 
 
 
 
 
 
 
 
 
 
CBC w/diff 
X2 
X 
X 
X 
X 
Renal Profile: Sodium, 
Potassium, Chloride, 
Bicarbonate, Creatinine, 
Bun, Glucose 
X2 
X 
X 
X 
X 
Albumin, bilirubin total 
and direct, alkaline 
phosphatase, total protein, 
AST, and ALT 
X2 
X 
 
 
 
FT4 and TSH 
X 
X 
X 
 
 
Disease Evaluation3 
X 
X4 
X 
X 
X 
Research  Tissue 
CollectionR 
 
X5 
 
 
 
Photograph of lesions 
X 
X 
X 
X 
X 
1. For women of childbearing potential only. Must be done ≤72 hours prior to registration. 
2. ≤14 Days prior to Registration 
3. Radiographic tumor imaging assessments must include CT scan, PET/CT, or MRI of the chest, 
abdomen, and pelvis. CT scan or MRI of the brain with contrast will only be performed if symptoms or 
signs of CNS metastasis are present.  Use same imaging throughout the study. 
4. At the completion of cycle 4 (approximately week 12) and then at completion of every 4th cycle 
(approximately every 12 weeks) thereafter  (±7days) until PD.  
5. Tissue specimens must be collected and submitted after registration but prior to the start of treatment, 
at completion of cycles 2 and 4 (approximately weeks 6 and 12). 
6. For women of childbearing potential only. Must be done ≤ 72 hours prior to start of treatment. Must be 
repeated if pre-registration test is ˃ 72 hours prior to the start of treatment. 
R Research funded (see Section 19.0) 
 
 
 
 
 
 
 

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4.1 
Event Monitoring/Survival Follow-up 
 
 
 
Event Monitoring Phase1 
q. 6 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. 
If a patient is still alive 3 years after registration, no further follow-up is required. 
 
 
 

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5.0 
Stratification Factors OR Grouping Factor:  
None 
6.0  
Registration/Randomization Procedures 
6.1 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
 
The instructions for the registration/randomization application are available on the 
MCCC web page 
and detail the process for 
completing and confirming patient registration.  Prior to initiation of protocol treatment, 
this process must be completed in its entirety and a MCCC subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent.  Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
  If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.2 
Correlative Research. 
 
A mandatory correlative research component is part of this study, the patient will be 
automatically registered onto this component (see Sections 3.19c and 17.1). 
 
6.3 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 
  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
 
6.4 
Prior to accepting the registration, registration application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  

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6.5 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research of melanoma at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
 
6.6 
Treatment cannot begin prior to registration and must begin ≤ 14 days after registration. 
 
6.7 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
 
6.8 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
 
6.9a 
Treatment on this protocol must commence at Mayo Clinic Florida under the supervision 
of a medical oncologist.  
 
6.9b 
Study drug is available on site.  
 
 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule - Use actual weight or estimated dry weight if fluid retention 
 
Agent 
Dose 
Route 
Day 
ReRx 
Pembrolizumab 
200 mg 
IV 
Day 1  
every 21 (+/- 
3) days for a 
maximum of 2 
years 
(approximately 
35 cycles) 
Imiquimod 
5% 
Cutaneous 
M-Fa,b  
a  Regardless of what day of the week the cycle starts,  imiquimod is to be administered 
daily for the remaining weekdays up to and including Friday.    
b. At the completion of cycle 2 and cycle 4, a biopsy of the treated lesion will be 
performed (and if appropriate, a biopsy of an untreated lesion).  Imiquimod is not to be 
administered the day of the biopsy or for six days following the biopsy.  If the biopsy is 
performed on Monday, Imiquimod treatment should be given the following M-F.  If the 
biopsy is performed on Tuesday, Imiquimod treatment should be given the next Tuesday-
Friday and then M-F for the remainder of the cycle.  If the biopsy is performed on 
Wednesday, Imiquimod treatment should be given the next Wednesday-Friday and then 
M-F for the remainder of the cycle. If the biopsy is performed on Thursday, Imiquimod 
treatment should be given the next Thursday-Friday and then M-F for the remainder of 
the cycle.  If the biopsy is performed on Friday, Imiquimod treatment should be given the 
next Friday and then M-F for the remainder of the cycle.   
 
 
7.2 
Patients can be instructed in administration techniques of imiquimod and granted 
treatment independence.This training must be documented in  medical record. Imiquimod 
is a commercial product dispensed from the pharmacy  and is the same drug that would 
be prescribed to any other patient not on trial.  
 
7.3 
Imiquimod will be held for one week after biopsy to allow for proper wound healing. 
 
7.4 
If more than 1 cutaneous lesion is present, at least one lesion will not be treated with 
imiquimod to serve as a control for the effect of just pembrolizumab. The untreated 
lesion must be at least 2 cm from the treated lesion to account for possible treatment 
effect from the imiquimod on the primary. 
 
 
 
7.5 
Treatment by a local medical doctor (LMD) is not allowed. 
 
 

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8.0 
Dosage Modification Based on Adverse Events  
 
8.1 Dose-Modification Guidelines for Drug Related Adverse Events for Pembrolizumab 
 
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE 
EVENT 
 
Hold 
Treatment 
for Grade 
 
Timing for Restarting 
Treatment  
Discontinue Subject 
Gastrointestinal 
disorders 
Diarrhea/Colitis 
2-3 
AE resolves to Grade 0-
1 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Investigations 
AST, ALT, or 
Blood bilirubin 
2 
AE resolves to Grade 0-
1 
AE does not resolve 
within 12 weeks of last 
dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Metabolism and 
nutrition disorders 
Glucose 
intolerance (Type 
1 diabetes 
mellitus [if new 
onset] or 
Hyperglycemia 
Type 1 
diabetes 
mellitus or 
3-4 
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 
hyperglycemia 
associated with evidence 
of beta cell failure. 
Resume pembrolizumab 
when patients are 
clinically and 
metabolically stable. 
Endocrine disorders 
Hypophysitis 
2-3 
AE resolves to Grade 0-
1 
AE does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10mg or 
less of prednisone or 
equivalent per day within 
12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Endocrine disorders 
Hyperthyroidism 
3 
AE resolves to Grade 0-
1 
AE does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 

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CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE 
EVENT 
 
Hold 
Treatment 
for Grade 
 
Timing for Restarting 
Treatment  
Discontinue Subject 
Endocrine disorders 
Hypothyroidism 
2-4 
Therapy with 
pembrolizumab can be 
continued while 
treatment for the thyroid 
disorder is instituted 
Therapy with 
pembrolizumab can be 
continued while treatment 
for the thyroid disorder is 
instituted. 
General disorders and 
administration site 
conditions 
Infusion reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Respiratory, thoracic 
and mediastinal 
disorders 
Pneumonitis 
2 
AE resolves to Grade 0-
1 
AE does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal and urinary 
disorder 
Acute kidney 
injury or Chronic 
kidney disease 
(e.g. Renal 
failure or 
Nephritis) 
2 
AE resolves to Grade 0-
1 
AE does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
 
All Other Drug 
Related Adverse 
Events2 
2  
AE resolves to Grade 0-
1 
AE does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks 
3-4
Permanently discontinue
Permanently discontinue 
* 
Located at 
 
 
NOTE:  Permanently discontinue Treatment for any severe or Grade 3 drug-related AE that 
recurs or any life-threatening event. 
 
aFor patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
bPatients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. 
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with treatment with 
study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.  
 
 
 
 
 

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8.2 Dose-Modification Guidelines for Drug Related Adverse Events for Imiquimod 
 
CTCAE 
System/Organ/Class 
(SOC) 
ADVERSE EVENT 
Hold 
Treatment 
for Grade 
ACTION 
General Disorders and 
administration site 
conditions 
Local skin reaction 
3 
Temporarily interrupt treatment for up to 
several days for severe or intolerable 
reactions; may consider resuming therapy 
once reaction subsides. 
Flu-like symptoms 
3 
Temporary disruption of therapy 
 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Full supportive care  
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
 
9.2 
Hypersensitivity reactions 
Patients do not require premedication prior to pembrolizumab treatment, as 
hypersensitivity reactions is not expected. In the unlikely event of a hypersensitivity 
reaction, treatment with antihistamines, H2 blockers, and corticosteroids is 
recommended. Patients should be pre-medicated with the typical regimen for subsequent 
cycles.  
 
9.3 
Patients may not enroll in a different clinical study, including Cancer Control studies, 
in which investigational procedures or agents are being used, while participating in 
this study.  
 
9.4 
Patients must terminate study treatment if they are to receive radiation therapy for 
palliative reasons as it impacts upon assessing response. 
 
9.5 
General patient monitoring and supportive care guidelines 
 
9.51 
Patients should be carefully monitored during the treatment phase and then 
followed appropriately.  Decisions for retreatment or dose 
modifications/interruption should follow the guidelines in Sections 8.2. 
 
9.52 
Patients who have an ongoing study agent-related serious adverse event upon 
study completion or at discontinuation from the study will be contacted by the 
treating physician or his/her designee at least every 2 weeks until the event is 
resolved or determined to be irreversible. 
 

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9.6 
Side effect management for PEMBROLIZUMAB toxicities- these are to be regarded 
as guidelines for managing toxicity that occurs with pembrolizumab therapy and 
should not replace clinical judgement (i.e. - patients with grade 1 rash may require 
systemic steroids). 
 
9.61 
Diarrhea 
 
9.611 Grade 1- without abdominal pain/or blood in stool and symptoms, may 
be caused either by pembrolizumab. Infectious etiologies should be ruled 
out.  Patients may be managed symptomatically, including the use of 
loperamide.Instruct patients to report any increase in stools.  
 
9.612  Grade 2- without abdominal pain/or blood in stool and symptoms < 1 
week, and resolve to grade 0 or 1- continue to monitor. Infectious 
etiologies should be ruled out.  
 
9.613  Grade 2- symptoms >1 week, should be started on systemic steroid 
therapy. Infectious etiologies should be ruled out.  
 
9.614  Grade 3 or greater- who have other etiologies ruled out should be 
started on systemic steroids Assess for dehydration. Patients may require 
hospitalization for IV steroids followed by oral steroids.   
 
** Once patients have improvement of symptoms to grade 0 or 1 taper of steroids 
should occur over at least 1 month- if patients have been started on budesonide in 
addition to systemic steroids, start tapering the prednisone FIRST.  
 
Do NOT administer loperamide in patients with ≥ Grade 2 diarrhea as this 
may cause toxic megacolon and/or perforation.  
 
If at any time patients experience diarrhea with the following symptoms: 
fever or abdominal pain patients should have a CT scan of the abdomen to 
rule out perforation. Emergent surgical evaluation should be performed if 
perforation is found. If a patient has bloody diarrhea, a Gastroenterology 
consult should be obtained. A Gastroenterology consult should be obtained 
if provider is considering infliximab for treatment of colitis.  
 
For all patients- assess hydration status and monitor electrolytes, including 
magnesium. 
 
9.62 
Rash 
 
9.621  Grade 2- Initiate therapy with topical or systemic steroids at 0.5-
1mg/kg/day of prednisone or equivalent. 
 
9.622  Grade 3 or greater. Initiate systemic steroid therapy at 1-2 mg/kg/day 
of prednisone or equivalent. 
 
 
 
 

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9.63 
Hyperthyroidism 
 
9.631  Grade 3- Initiate systemic steroid treatment at 1-2 mg/kg/day of 
prednisone or equivalent. 
 
9.632  Grade 4 - Initiate systemic steroid therapy at 1-2 mg/kg/day of 
prednisone or equivalent. 
 
9.64 
Immune-Mediated Hypophysitis 
 
9.641  Grade 2 and 3 – Initiate systemic steroid at 0.5-1mg/kg/day of 
prednisone or equivalent and physiologic replacement dose.  
 
9.642  Grade 4 – Initiate systemic steroid at 1-2 mg/kg/day of prednisone or 
equivalent and physiologic replacement dose. 
 
9.65 
Pneumonitis 
 
9.651  Grade 1- No change in treatment  
 
9.652  Grade 2- Initiate steroids at 0.5-1mg/kg/day of prednisone or 
equivalent. 
 
9.653  Grade 3 or greater- Consider hospitalization, and initiate systemic 
steroids 
 
9.66 
Liver Dysfunction (AST or ALT) 
 
9.661 AST or ALT ≤ 3 ULN- No change in treatment  
 
9.662 AST or ALT >3 but <5 ULN or Grade 2- Consider initiating systemic 
steroids at 0.5-1mg/kg/day of prednisone or equivalent.  
 
9.663 AST or ALT ≥ Grade 3- Discontinue pembrolizumab. Initiate 
systemic steroid therapy.  
 
9.67 
Liver Dysfunction (Bilirubin) 
 
9.671 Grade 1- No change in treatment  
 
9.672 Grade 2- Consider initiating systemic steroids at 0.5-1mg/kg/day of 
prednisone or equivalent. 
 
9.673 Grade 3 or greater- Monitor levels until resolved to ≤ Grade 1. Initiate 
therapy with steroids at 1-2 mg/kg/day of prednisone or equivalent. 
 
 

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10.0 
Adverse Event (AE) Reporting and Monitoring 
 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure.  
 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating investigators in a 
written safety report of any of the following:  
 
• 
Any suspected adverse reaction that is both serious and unexpected.  
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity.  
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug.  
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB).  
• 
Any outcomes related to pregnancy while on study. 
• 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
Non Mayo sites – complete and 
forward to 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
 
Will automatically be sent to 
 
 
Definitions 
 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the 
adverse event. 
 

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Protocol Version Date: 13May2022 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming 
aware of the event. 
 
Routine Reporting 
Events reported to sponsor via case report forms 
 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, 
but that for a specific protocol are being reported via expedited means in order to 
facilitate the review of safety data (may be requested by the FDA or the sponsor).  
 
Unanticipated Adverse Device Event (UADE) 
Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects  
 
 
10.1 
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.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site:  
(
    
 
a. Identify the grade and severity of the event using the CTCAE version 4.0.  
b. Determine whether the event is expected or unexpected (see Section 10.2).  
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 

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Protocol Version Date: 13May2022 
investigational plan).  
 
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent.  Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required.   
 
 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME (Combination) Arm 
 
NOTE:  When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for investigational agents/interventions.  
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent require 
an expedited report, unless hospitalization is required.  Refer to Section 10.4 for 
specific AE reporting requirements or exceptions. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent.  Therefore, if an expected AE (for the commercial agent) 

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occurs with a higher degree of severity or specificity, expedited reporting is 
required.   
• An increased incidence of an expected adverse event (AE) is based on the 
patients treated for this study at their site.  A list of known/expected AEs is 
reported in the package insert or the literature, including AEs resulting from a 
drug overdose. 
• Commercial agent expedited reports must be submitted to the FDA via MedWatch 
3500A for Health Professionals (complete all three pages of the form). 
 
Instructions for completing the MedWatch 3500A: 
 
 
10.32 EXPECTED Serious Adverse Events:  Protocol Specific Exceptions to 
Expedited Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6). * 
 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
 
 
System Organ Class 
(SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the event 
will not be expeditedly reported.1 
General disorders and 
administration site 
conditions 
Fatigue  
<Grade 3 
Malaise 
<Grade 3 
Cutaneous irritation from 
imiquimod 
<Grade 3 
1These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  

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Specific protocol exceptions to expedited reporting should be reported expeditiously be 
investigators ONLY if they exceed the expected grade of the event. 
 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on 
this trial 
● Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the 
cancer.] 
 
 
10.4 
Expedited Reporting Requirements for IND/IDE Agents  
10.41 Phase 1 and Early Phase 2 Studies:  Expedited Reporting 
Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below.  
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization 
≥24 hrs 
7 Calendar Days 
24-Hour 3 Calendar 
Days 
Not resulting in 
Hospitalization 
≥24 hrs 
Not required 

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Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 
10.42 General reporting instructions 
Use Mayo Expedited Event Report form 
for investigational agents or 
commercial/investigational agents on the same arm.  
Submit to: 
  
For commercial agents:  
Submit form 
 
 
 
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 
10.5 
Other Required Reporting 
 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 

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Protocol Version Date: 13May2022 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the Reportable Event coversheet and appropriate 
documentation to 
 The Mayo Regulatory 
Affairs Office will review and process the submission to the Mayo Clinic IRB. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
Any death occurring greater than 30 days with an attribution of possible, 
probable, or definite to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including cysts and 

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Protocol Version Date: 13May2022 
polyps) – Other (Progressive Disease)” under the system organ class 
(SOC) of the same name. Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND/IDE will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 

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NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
10.541 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.542 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.543 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
 
10.6 
Required Routine Reporting  
 
10.61 Baseline and Adverse Events Evaluations 
 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation per CTCAE v4.0 grading unless otherwise stated in 
the table below: 
 
System Organ Class 
(SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
Febrile Neutropenia 
 
X 
Cardiac Disorders 
Myocardial infarction 
 
X 
Gastrointestinal disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
Abdominal pain 
X 
X 
Baseline # of stools 
X 
 

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Diarrhea 
 
X 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
Fever 
 
X 
Immune system disorders Allergic reaction 
 
X 
Anaphylaxis 
 
X 
Investigations 
Neutrophil count decreased 
 
X 
Platelet count decreased 
 
X 
White blood cell decreased 
 
X 
Aspartate aminotransferase 
increased 
X 
X 
Alkaline phosphatase increased 
X 
X 
Blood bilirubin increased 
X 
X 
Musculoskeletal and 
connective tissue 
disorders 
Arthralgia 
X 
X 
Myalgia 
X 
X 
Nervous system disorders Peripheral sensory neuropathy 
X 
X 
 
10.62 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.623 Grade 5 AEs (Deaths) 
 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.6232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.7 
Late Occurring Adverse Events 
 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
11.0 Treatment Evaluation Using RECIST 1.1 Guideline 
 
11.1 
The first scan after treatment initiation will be performed after the completion of cycle 4 
(approximately week 12) and will be then performed every 12 weeks until disease 
progression is confirmed  

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Disease progression for this protocol is defined as meeting the RECIST criteria for 
disease progression on two consecutive evaluations at least 6 weeks apart (see Section 
13.2). 
 
11.2 
Definitions of Measurable and Non-Measurable Disease 
 
11.21   Measurable Disease 
 
11.211  A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥2.0 cm with chest x-ray, or as ≥1.0 cm with CT 
scan, CT component of a PET/CT, or MRI. 
 
11.212  A malignant lymph node is considered measurable if its short axis 
 
is >1.5 cm when assessed by CT scan (CT scan slice thickness 
 
recommended to be no greater than 5 mm).   
 
NOTE:  Tumor lesions in a previously irradiated area are not considered 
measurable disease.   
 
11.22 Non-Measurable Disease 
 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥1.0 to <1.5 cm).  Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable as well. 
 
 NOTE:  ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described 
above.  However, if non-cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.  
 
Lymph nodes that have a short axis <1.0 cm are considered non-  pathological 
(i.e., normal) and should not be recorded or followed. 
 
11.3 
Guidelines for Evaluation of Measurable Disease 
 
11.31 Measurement Methods:   
 
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. 
 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-
up. For patients having only lesions measuring at least 1 cm to less than 2 cm 
must use CT imaging for both pre- and post-treatment tumor assessments.   
 
 
 

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11.32 Acceptable Modalities for Measurable Disease:       
 
• 
Conventional CT and MRI:  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm 
or less. If CT scans have slice thickness greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.     
 
• 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type 
and site of disease.  The lesions should be measured on the same pulse 
sequence.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
• 
PET-CT:  If the site can document that the CT performed as part of a PET-CT 
is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.   
 
• 
Chest X-ray:  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, CT 
scans are preferable. 
 
• 
FDG-PET:  FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease.  
A ‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid 
with an update greater than twice that of the surrounding tissue on the 
attenuation corrected image; otherwise, an FDG-PET scanned lesion is 
considered ‘negative.’  New lesions on the basis of FDG-PET imaging can be 
identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
 
b.   No FDG-PET at baseline and a positive FDG-PET at follow-up:   
 
i. 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD.   
 
ii. If the positive FDG-PET at follow-up is not confirmed as a new site 
of disease on CT at the same evaluation, additional follow-up CT 
scans (i.e., additional follow-up scans at least 4 weeks later) are 
needed to determine if there is truly progression occurring at that site. 
In this situation, the date of PD will be the date of the initial abnormal 
PDG-PET scan.   
 
iii If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the 
anatomic images, it is not classified as PD. 

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11.33 Measurement at Follow-up Evaluation:   
 
• 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate between 
response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
 
• 
Cytologic and histologic techniques can be used to differentiate between PR 
and CR in rare cases (e.g., residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain.) 
 
11.4 
Measurement of Effect 
 
11.41 Target Lesions & Target Lymph Nodes 
 
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 5 
lesions, representative of all involved organs, should be identified as “Target 
Lesions” and recorded and measured at baseline.  These lesions can be non-
nodal or nodal (as defined in 11.21), where no more than 2 lesions are from 
the same organ and no more than 2 malignant nodal lesions are selected.  
 
Note: If fewer than 5 target lesions and target lymph nodes are identified (as 
there often will be), there is no reason to perform additional studies beyond 
those specified in the protocol to discover new lesions.   
 
• 
Target lesions and target lymph nodes should be selected on the basis of their 
size, be representative of all involved sites of disease, but in addition should 
be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion (or malignant lymph node) 
does not lend itself to reproducible measurements in which circumstance the 
next largest lesion (or malignant lymph node) which can be measured 
reproducibly should be selected.   
 
• 
Baseline Sum of Dimensions (BSD):  A sum of the longest diameter for all 
target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the baseline sum of dimensions (BSD).  The 
BSD will be used as reference to further characterize any objective tumor 
response in the measurable dimension of the disease.   
 
• 
Post-Baseline Sum of the Dimensions (PBSD):  A sum of the longest diameter 
for all target lesions plus the sum of the short axis of all the target lymph 
nodes will be calculated and reported as the post-baseline sum of dimensions 
(PBSD).  If the radiologist is able to provide an actual measure for the target 
lesion (or target lymph node), that should be recorded, even if it is below 0.5 
cm.  If the target lesion (or target lymph node) is believed to be present and is 
faintly seen but too small to measure, a default value of 0.5 cm should be 
assigned.  If it is the opinion of the radiologist that the target lesion or target 

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Protocol Version Date: 13May2022 
lymph node has likely disappeared, the measurement should be recorded as 0 
cm. 
 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and 
the PBSD. 
 
 
11.42  Non-Target Lesions & Non-Target Lymph Nodes 
 
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions or non-target lymph nodes and should also be recorded at baseline.  These 
lesions and lymph nodes should be followed in accord with 11.433. 
 
11.43 Response Criteria 
 
11.431 All target lesions and target lymph nodes followed by 
 
CT/MRI/PET-CT/Chest X-ray/physical examination must be measured 
on re-evaluation at evaluation times specified in Section 11.1.  
Specifically, a change in objective status to either a PR or CR cannot be 
done without re-measuring target lesions and target lymph nodes.  
 
Note: Non-target lesions and non-target lymph nodes should be 
evaluated at each assessment, especially in the case of first response or 
confirmation of response.  In selected circumstances, certain non-target 
organs may be evaluated less frequently.  For example, bone scans may 
need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
 
11.432 Evaluation of Target Lesions 
 
• Complete Response (CR): All of the following must be true: 
 
a. Disappearance of all target lesions. 
 
b. Each target lymph node must have 
reduction in short axis to <1.0 cm. 
 
• Partial Response (PR): 
At least a 30% decrease in PBSD (sum of 
the longest diameter for all target lesions 
plus the sum of the short axis of all the 
target lymph nodes at current evaluation) 
taking as reference the BSD (see Section 
11.41). 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant lesion, 
which also includes any lymph node 
that was normal at baseline (< 1.0 cm 
short axis) and increased to ≥ 1.0 cm 
short axis during follow-up.  
 

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b. At least a 20% increase in PBSD (sum 
of the longest diameter for all target 
lesions plus the sum of the short axis 
of all the target lymph nodes at current 
evaluation) taking as reference the 
MSD (Section 11.41).  In addition, the 
PBSD must also demonstrate an 
absolute increase of at least 0.5 cm 
from the MSD.  
 
c. See Section 11.32 for details in 
regards to the requirements for PD via 
FDG-PET imaging. 
  
• Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR, nor sufficient increase to qualify for 
PD taking as reference the MSD. 
 
11.433 Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
 
• Complete Response (CR): 
All of the following must be true: 
 
a. Disappearance of all non-target 
lesions.  
 
b. Each non-target lymph node must 
have a reduction in short axis to <1.0 
cm. 
 
• Non-CR/Non-PD: 
Persistence of one or more non-target 
lesions or non-target lymph nodes. 
 
• Progression (PD): 
At least one of the following must be true: 
 
a. At least one new malignant  lesion, 
which also includes any lymph node that 
was  normal at baseline (< 1.0 cm 
 
short axis) and increased to ≥ 
 
1.0 cm short axis during follow-up.   
 
b. Unequivocal progression of existing 
non-target lesions and non-target 
lymph nodes.  (NOTE:  Unequivocal 
progression should not normally 
trump target lesion and target lymph 
node status.  It must be representative 
of overall disease status change.)  
   
c. See Section 11.32 for details in 
regards to the requirements for PD 
via FDG-PET imaging. 

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11.44 Overall Objective Status 
 
 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, target lymph nodes, non-target lesions, non-target 
lymph nodes, and new disease as defined in the following tables:  
 
 
Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR** 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
*See Section 11.431 
 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status 
requiring discontinuation of treatment without objective evidence of disease 
progression at that time, and not either related to study treatment or other medical 
conditions, should be reported as PD due to “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after 
discontinuation of treatment due to symptomatic deterioration.  A patient is 
classified as having PD due to “symptomatic deterioration” if any of the 
following occur that are not either related to study treatment or other medical 
conditions: 
• Weight loss >10% of body weight. 
• Worsening of tumor-related symptoms. 
• Decline in performance status of >1 level on ECOG scale. 
 
12.0 
Descriptive Factors  
None 
 
 

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13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who have not had disease progression and have experienced acceptable toxicity 
are to continue treatment per protocol or a maximum of 2 years (approximately 35cycles) 
or until confirmed PD, unacceptable toxicity or refusal.   
 
13.2      The first instance in which a patient’s disease status meets the RECIST criteria for PD 
will continue for two additional cycles of treatment per protocol (approximately 6 weeks) 
and then undergo a disease evaluation.If the initial documented progression is not 
confirmed by this scan, patients will continue treatment per protocol.If the initial 
documented progression is confirmed by this scan, patients will go to the event-
monitoring phase until death or a maximum of years post-registration. 
 
 
 
Exception:  Patients who develop PD in the CNS only should discontinue study 
 
treatment and go to Event Monitoring.  
 
13.3     Criteria for discontinuation of protocol therapy include: 
 
• 
Disease progression where disease progression is:  the development of a new metastatic 
lesion or an objective status of disease progression (as defined by RECIST criteria) on 
two consecutive evaluations at least 6 weeks apart (section 13.2). Exception:  Patients 
who develop PD in the CNS only should discontinue study  treatment and go to Event 
Monitoring.  
 
• 
Request by patient to discontinue study treatment 
• 
Unacceptable toxicity 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments 
of clinical status to a significant degree or require discontinuation of drug 
• 
Administration of radiotherapy, non-protocol chemotherapy, immunotherapy, 
biological agents, or an experimental drug during the trial 
• 
Development of new primary cancer 
• 
Ineligibility 
 
Patients who discontinue treatment due to intolerability, patient request, physician 
decision, or inter-current illness preventing further administration of protocol treatment 
will proceed to event monitoring phase of the trial where patient and disease status until 
death or a maximum of 3 years post-registration 
 
13.4      Patients who complete 2 years of protocol treatment (approximately 35 cycles) without  
(confirmed) disease progression will proceed to the Observation phase until confirmed 
disease progression or a maximum of 3 years post registration.   If the patient has a 
documented confirmed disease progression during observation, the patient will continue 
on to the event monitoring phase for a maximum of 3 years post registration. 
 
13.5 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.   
 
• 
If the patient received any protocol treatment, all data (except biospecimens) up until 
the point of confirmation of ineligibility must be submitted.  Event monitoring will 
be required per Section 18.0 of the protocol.  

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Protocol Version Date: 13May2022 
 
• 
If the patient never received any protocol treatment, on-study material (except 
biospecimens) and the End of Active Treatment/Cancel Notification Form must be 
submitted. No further No further data submission is necessary. 
 
13.6 
A patient who withdraws consent before any study treatment is given.  On-study material 
(except biospecimens) and the End of Active Treatment/Cancel Notification Form must 
be submitted.  No further data submission is necessary. 
 
14.0 
Body Fluid Specimens 
 
 
None 
 
15.0 
Drug Information 
 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background: Pembrolizumab is a potent humanized IgG4 monoclonal antibody 
with high specificity of binding to the PD-1 receptor, thus inhibiting its 
interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation  
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial.  
15.13 Preparation and storage:  
Vials should be stored in the refrigerator at temperatures between 2-8°C.  
Drug concentrate is further diluted with normal saline (or 5% dextrose in 
the concentration range of 1 to 10 mg/mL) in IV containers made of 
polyvinyl chloride (PVC) or non-PVC material. The infusion solution in 
the IV bag should be immediately administered. Pembrolizumab solutions 
may be stored at room temperature for a cumulative period of up to 4 
hours. This includes room temperature storage of reconstituted solution in 
vials, room temperature storage of infusion solution in the IV bag and the 
duration of infusion. 
In addition,IV bags may be stored at 2-8 °C for up to a cumulative time of 
20 hours. If refrigerated, the vials and/or IV bags should be allowed to 
equilibrate to room temperature prior to subsequent use. 
15.14 Administration: Pembrolizumab is administered by intravenous infusion over 
30 minutes via a 0.22 micron in-line filter. The final infusion volume must be 
between 1 and 10 mg/mL. Maximum rate of infusion should not exceed 6.7 
mL/minute through a peripheral or indwelling catheter. Flush the line with 0.9% 
NaCL following the completion of the infusion. 
15.15 Pharmacokinetic information: 
a) Absorption – during repeated dosing of MK-3475 every two weeks, 
steady state conditions were reached within 16 weeks of treatment. Steady 
state trough concentrations obtained at 24, 36 and 48-weeks of treatment 

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Protocol Version Date: 13May2022 
with 10 mg/kg Q2W were on average 20% percent higher compared to 10 
mg/kg Q3W treatment. 
b) Distribution – pembrolizumab has a limited volume of distribution.  
c) Excretion – mean estimated t1/2 values from the 28-day single dose 
profiles ranged from 14.1 to 21.6 days. Clearance is nonlinear and 
saturable. 
15.16 Potential Drug Interactions: There are no known significant drug 
interactions. 
15.17 Known potential toxicities:  
Common known potential toxicities, >10%: 
Cardiovascular: Peripheral edema 
Central nervous system: Fatigue, headache, chills, insomnia, dizziness 
Dermatologic: Pruritus, skin rash, vitiligo 
Endocrine & metabolic: Hyperglycemia, hyponatremia, hypoalbuminemia, 
hypertriglyceridemia, hypocalcemia 
Gastrointestinal: Nausea, decreased appetite, constipation, diarrhea, 
vomiting, abdominal pain 
Hematologic & oncologic: Anemia 
Hepatic: Increased serum AST 
Neuromuscular & skeletal: Arthralgia, limb pain, myalgia, back pain 
Respiratory: Cough, dyspnea, upper respiratory tract infection 
Miscellaneous: Fever 
 
Less common known potential toxicities, 1% - 10%: 
Dermatologic: Cellulitis 
Endocrine & metabolic: Hypothyroidism, hyperthyroidism 
Gastrointestinal: Colitis 
Infection: Sepsis 
Renal: Renal Failure 
Respiratory:  Pneumonitis, pneumonia 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening): 
Adrenocortical insufficiency (immune-mediated), arthritis (immune-
mediated), exfoliative dermatitis (immune-mediated), hemolytic anemia 
(immune-mediated), hepatitis (including autoimmune hepatitis; grade 4: 
<1%), hypophysitis (grade 2: <1%; grade 4: <1%), interstitial nephritis 
(with renal failure; grade 3: <1%; grade 4: <1%), Lambert-Eaton 
syndrome (immune-mediated), myositis (immune-mediated), nephritis 
(grade 2 autoimmune: <1%), optic neuritis (immune-mediated), 
pancreatitis (immune-mediated), partial epilepsy (immune-mediated; in a 
patient with inflammatory foci in brain parenchyma), rhabdomyolysis 
(immune-mediated), uveitis (immune-mediated) 
15.18 Drug procurement: Pembrolizumab will be provided free of charge to study 
participants by Merck. 
15.19 Nursing Guidelines: 
15.191 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 

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Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.192 
Diarrhea can be seen however, is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the 
study team. Treat per Section 9.0 and monitor for effectiveness.  
15.194 
Monitor LFT’s closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysistis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well.” Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD. 
15.197 
Patients who are started on steroid therapy for any side effects of 
pembrolizimab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper.  
15.198 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
 
15.199 
Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines. 
 
15.200 
Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and venoocclusive disease, if they have previously been treated with 
pembrolizumab. 
 

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15.201 
Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
 
15.202 
Autoimmune hematologic disorders including ITP and hemolytic 
anemia have been reported. Monitor blood counts closely and report 
any abnormalities to the study team. 
 
15.203 
Rare neurologic disorders including Guillian-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, parasthesias, or numbness, 
tingling to the study team immediately. 
 
15.2 
Imiquimod 
 
 
 
15.21 Preparation and Storage: 
 
Single-use, 0.25 gm packets, containing 5% imiquimod. This is a 
commercial product that will be dispensed from the pharmacy.  One or 
two packets will be used for each application. 
 
 
 
15.22 Known Potential Toxicities: 
 
 
 
 
Local Reactions: 
 
 
Local skin reactions have been reported with imiquimod as used for 
genital warts.  Erythema, excoriation/flaking, and edema are described as 
“common” in the package insert.  Itching, burning, pain, and soreness 
occur at the treatment site.  Remote skin reactions can occur in less than 
5% of patients.  Ulceration, scabbing, and vesicles occur in 3 to 5%.  
Fungal infections are reported in 11% of women using imiquimod.  The 
vaginal and cervical tissues are likely to be at least as sensitive to the 
inflammatory effects as the vulvar tissues.  Examination prior to each 
application will be the primary means of protecting patients from 
cumulative local toxicities.   
 
 
 
 
Systemic Reactions: 
 
 
 
Systemic reactions have not been a major problem with topical use of 
imiquimod.  When systemic symptoms are reported, they are suggestive of 
a viral syndrome.  Headaches, myalgias, and flu-like symptoms have been 
reported.  The frequency of these symptoms with vulvar application 
appears to be elevated no more than 1% over the frequency in the placebo 
group.  The frequency of systemic symptoms with repeated application 
will be monitored in this trial.   
 

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15.23 Nursing guidelines: 
 
 
 
15.231 Patients should wear gloves (if possible) while applying 
imiquimod. Instruct patient to wash hands carefully when done.  
 
 
 
15.232 Avoid contact with eyes and mucous membranes. 
 
 
 
15.233 A certain amount of redness, irritation, and/or burning is expected 
at the site of administration.  Patients experiencing large areas of 
erythema or significant pain with administration should be 
instructed to call the study team immediately. 
 
 
 
15.234 Rarely if patients are applying to large surface areas, they can 
experience mild flu-like symptoms (i.e myalgias, fatigue, etc). 
Instruct patient to report these to the study team. Treat 
symptomatically and monitor for effectiveness. 
 
 
 
 
 
15.24 Drug Procurement 
 
 
The research base pharmacy will obtain the drug from  
 
3M Pharmaceuticals.  Each institution will order the drug from the 
research base pharmacy.  Submit the drug order form to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
This pilot study will enroll 10 patients to gain preliminary data on the anti-tumor activity 
and safety profile of the combination of imiquimod and pembrolizumab in patients with 
unresectable cutaneous melanoma.    
 
If there are no tumor responses documented among these 10 patients, then upper bound of 
a one-sided 95% confidence interval for the tumor response rate would be 25.9%.   
 
 
All patients meeting the eligibility criteria who have signed a consent form and have begun 
treatment will be evaluable for assessment of all of the clinical endpoints.  
 
16.2  
Tumor response rate and duration of response 
 

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16.21 Tumor response rate is defined as percentage of patients whose objective disease 
status meets the criteria for RECIST criteria for partial or complete response on 
two consecutive disease evaluations at least 12 weeks apart. 
 
16.22 For those patients who disease had a partial or complete response to treatment on 
two consecutive disease evaluations at least 12 weeks apart, the duration of 
treatment response is defined as the time from registration to disease progression. 
 
16.3  
Safety Profile 
 
16.31 Adverse events will be graded and attribution assigned using CTC CAE version 
4.0.  For each type of toxicity reported, the proportion of patients experiencing a 
severe level of that toxicity will be determined.  
 
16.4  
Progression-free and overall survival  
 
16.41 Progression-free survival time is defined as the time from registration to 
documentation of first disease progression or death due to any cause.  Survival 
time is defined as the time from registration to death due to any cause.  
 
16.42 The duration of response and the distributions of OS times and PFS times will be 
estimated using the Kaplan-Meier method.   
 
16.5   Biomarker changes during treatment 
 
16.51  Biomarkers will be assessed prior to treatment and 6 and 12 weeks following the 
start of treatment.  For each patient and each biomarker, a times-series plot of 
biomarker value will be constructed.  These graphs will be visually examined for 
trends within and between the group of patients whose tumor responded to 
treatment and the group of patients whose tumor did not respond to treatment.  
 
16.52 Plots of the percent change in biomarker level at 6 weeks versus response (yes vs. 
no) to visually assess whether the percent change in biomarker level at 6 weeks 
tends to be greater for one group versus the other.  This will be repeated for the 
value of the biomarker at 6 weeks to gain insight into whether it is the amount of 
the change or where the biomarker lands after 6 weeks of treatment that separates 
the two groups.     
 
16.6 
Monitoring of the trial 
 
This clinical trial will be monitored by the Mayo Clinic Cancer Center Data and Safety 
Monitoring Board (MCCC DSMB).   The study statistician will prepare a report 
containing accrual and adverse event that will be submitted to MCCC DSMB every 6 
months.  
 
16.61 Safety Stopping rules 
 
After every 5th  patient has been enrolled, the tolerability of the regimen will be 
examined.   If  2 out of the first 5 patients enrolled or  more than 25% of the 
patients thereafter develop a grade 4 adverse event anything during the course of 
treatment that is considered possibly, probably, or definitely related to treatment, 

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enrollment will temporarily close.  The study team will review all adverse event 
data.  A trial recommendation will be formulated and presented to the MCCC 
DSMB – the study may permanently close or may re-open to accrual after 
MCCC DSMB review and IRB approval of protocol/consent form modifications.  
 
 
16.7 
Inclusion of Women and Minorities 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
0 
0 
Not Hispanic or Latino 
4 
6 
10 
Ethnic Category: Total of all subjects* 
 
 
 
Racial Category 
American Indian or Alaskan Native 
 
 
 
Asian 
 
 
 
Black or African American 
 
 
 
Native Hawaiian or other Pacific Islander 
 
 
 
White 
4 
6 
10 
Racial Category: Total of all subjects* 
4 
6 
10 
 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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17.0  
Pathology Considerations/Tissue Biospecimens  
Core tissue biopsies will be performed at baseline, 6 weeks, and 12 weeks. Core biopsies with 16 gauge needles will be taken from at least 
one lesion treated with imiquimod and if present one untreated. Cores will be formalin fixed paraffin embedded and stored until the end of 
the study when correlative research will be performed. 
 
17.1  
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, 
Slides, Core, 
etc. (# of 
each to 
submit) 
Visit 1 
(Baseline)  
Visit 2 
(6 
weeks) 
Visit 3 
(12 
weeks) 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
IHC PDL1 
Mandatory 
FFPE 
1 slide 
X 
X 
X 
Yes 
Ambient 
IHC PD1 
Mandatory 
FFPE 
1 slide 
X 
X 
X 
Yes 
Ambient 
IHC CD3 
Mandatory 
FFPE 
1 slide 
X 
X 
X 
Yes 
Ambient 
IHC CD4 
Mandatory 
FFPE 
1 slide 
X 
X 
X 
Yes 
Ambient 
IHC CD8 
Mandatory 
FFPE 
1 slide 
X 
X 
X 
Yes 
Ambient 
RNA expression 
Nanostring immune 
panel 
Mandatory 
FFPE 
5 slides 
X 
X 
X 
Yes 
Ambient 

48 
 
 
17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
 
Hematoxylin and eosin stain, S100, and HMB-45 will be performed by 
dermatopathologist, 
 
 
Along with original diagnostic slides, include pathology reporting form, surgical 
pathology report and operative report. 
 
17.3 
Correlative Tissue Collection  
 
17.31 FFPE tumor tissue blocks/slides (10 unstained slides) will be collected in order to 
assess correlation of tumor bound PD-L1 expression and level of tumor 
infiltrating T-cells (CD3, CD4, and CD8) in response to treatment.  Both 
measurements will be semi-quantitatively assessed by established 
immunohistochemistry (IHC) methodology in our laboratory. 
 
17.32 Definitive immunohistochemical analysis using tumor biopsies will be performed 
at the completion of the study, comparing pre-treatment measurements with 
changes at time of tumor progression on therapy. 
 
17.33 RNA expression analysis of an immune panel from Nanostring of tumor biopsies 
will be performed at the completion of the study, comparing pre-treatment 
measurements with changes at time of tumor progression on therapy. 
 
17.33 At the completion of the study, any unused/remaining material will be stored in 
the Biospecimens Accessioning and Processing (BAP) at Mayo Clinic Florida for 
future research according to the patient consent permission. Potential future 
research may include immunohistochemistry (IHC) analyses to analyze 
predictive biomarkers, changes in expression pattern with therapy, and 
correlation with response and/or adverse events. When a protocol is developed, it 
will be presented for IRB review and approval. 
 
17.4 
Background and Methodology 
 
17.41 Immunohistochemistry will be performed to assess expression of PDL1, PD1, 
CD3, CD8, and CD4. These markers will be assessed both at baseline, 6 weeks, 
and 12 weeks in both the lesion treated with imiquimod and untreated lesion 
(when available). We will analyze the possible association of baseline expression 
as well as change in expression with response to treatment. 
 
17.42 RNA expression of a panel of immune related genes will be assessed using 
Nanostring immune panel of 500+ immune related genes. We will analyze the 
possible associations of baseline and change in baseline immune genes with 
response to treatment in the lesion treated with imiquimod and untreated lesions 
(when available). 
 
.

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18.0 
Records and Data Collection Procedures  
 
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Event monitoring 
See Section 4.0 and data submission table for the event monitoring schedule. 
18.3 
CRF completion 
This study will use Medidata Rave for remote data capture (rdc) of all study data. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation 
This study requires supporting documentation for diagnosis and progression prior to 
study entry as well as for evidence of response to study therapy and progression after 
study therapy. Supporting documentation for diagnosis will include  a copy of the 
imaging report demonstrating metastatic melanoma This report should be submitted 
within 14 days of registration. 
For progression of disease prior to study entry, supporting documentation includes the 
evidence needed to determine the patient’s progression prior to enrollment. These 
documents should be submitted within 14 days of registration. 
For response to treatment, supporting documentation includes a copy of the imaging 
report.  
For patients who progress after study therapy supporting documentation includes a copy 
of the imaging report.  
18.6 
Labelling of materials 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Incomplete materials 
Any materials deemed incomplete by the MCCC Operations Office will be considered 
“not received” and will not be edited or otherwise processed until the missing 
 
 
 
 
 
 

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19.0  
Budget 
 
 
19.1 
Costs charged to patient: routine clinical care 
 
 
19.2 
Tests to be research funded: 
 
 
Correlatives per Section 17 
 
 
19.3 
Other budget concerns: 
 

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20.0 
References 
1. Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br J Dermatol. 2000;143:843-5. 
2. Ugurel S, Wagner A, Pfohler C, Tilgen W, Reinhold U. Topical imiquimod eradicates skin metastases of 
malignant melanoma but fails to prevent rapid lymphogenous metastatic spread. Br J Dermatol. 2002;147:621-
4. 
3 
Bong AB, Bonnekoh B, Franke I, Schon M, Ulrich J, Gollnick H. Imiquimod, a topical immune response 
modifier, in the treatment of cutaneous metastases of malignant melanoma. Dermatology. 2002;205:135-8. 
4. Green DS, Bodman-Smith MD, Dalgleish AG, Fischer MD. Phase I/II study of topical imiquimod and 
intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol. 
2007;156:337-45. 
5. Kibbi N, Ariyan S, Faries M, Choi JN. Treatment of In-Transit Melanoma With Intralesional Bacillus Calmette-
Guerin (BCG) and Topical Imiquimod 5% Cream: A Report of 3 Cases. J Immunother. 2015;38:371-5. 
6. Shi VY, Tran K, Patel F, Leventhal J, Konia T, Fung MA, et al. 100% Complete response rate in patients with 
cutaneous metastatic melanoma treated with intralesional interleukin (IL)-2, imiquimod, and topical retinoid 
combination therapy: Results of a case series. J Am Acad Dermatol. 2015;73:645-54. 
7. Joseph RW, Cappel M, Tzou K, Bagaria S, Gilstrap C, Swaika A, Jambusaria-Pahlajani A: Treatment of in-
transit and metastatic melanoma in two patients treated with ipilimumab and topical imiquimod. Melanoma Res 
2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair.