Please select the eligibility criteria that correspond to the clinical trial below.
Title: Relevance of Imiquimod as Neo-adjuvant Treatment to Reduce Excision Size and the Risk of Intralesional Excision in Lentigo Malignant of the Face
Brief Summary: Lentigo malignant (LM) is an intraepidermal melanocytic proliferation occurring on photoexposed skin. In our project, this term applies both to Dubreuilh's melanosis and to Dubreuilh's intraepidermal melanoma. It consequently excludes invasive melanoma. Although surgery is the treatment of choice, it remains without consensus on the margins (5 mm or 10 mm) excision for a localized tumor on the face.

Several studies have shown that imiquimod, activating local immunity by interferon production, induced LM or MLM regression and could also decrease the frequency of relapses.

The principal aim of our project is to study the effect of imiquimod versus placebo in pre-operative neoadjuvant treatment aimed at reducing both surgical margins, as from the first surgical procedure, and the frequency of short and medium term recurrence of LM. Furthermore, the improvement in patient quality of life could also be significant.


Options:
A: Inclusion Criteria:

* Patients from both sexes aged over 18 years and operable
* Presenting with LM of the face, the neck, or the scalp (in case of hairless scalp only) histologically confirmed by biopsy
* Patients presenting with a primitive lesion, of a surface ≥ to 1cm² and ≤ to 20cm², with the possibility of graft or flap reconstruction
* LM previously untreated by surgery
* LM without prior treatment with liquid nitrogen or any other local treatment within 3 months
* ECOG ≤ 2
* Leucocytes ≥ 3,000/mm³
* Neutrophil count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Haemoglobin ≥ 9.0g/dL
* Absence of severe evolutive infection
* Absence of known HIV infection
* Absence of corticotherapy and treatment by immunosuppressive agents
* Absence of excoriation and scarring biopsy prior to application of study treatment
* Membership to a social security insurance scheme.
* Negative pregnancy test conducted during the inclusion consultation for non-menopausal women.
* Effective contraception for patients of childbearing age
* Signed informed consent

Exclusion Criteria:

* LM located on the eyelids are excluded, together with LM in anatomic sites other than the face, the neck or the scalp
* Melanomas other than LM
* Invasive LM
* LM with a surface area \< to 1cm² or \> to 20cm²
* LM of which the macroscopic contours cannot be defined
* Patients who are allergic to imiquimod excipient (eg hydroxybenzoate)
* Patients with a hypersensitivity to active substances or to any of the excipients of the placebo (for example propyl parahydroxybenzoate)
* Patients treated by immunosuppressive agents, immunomodulators, cytotoxic agents or corticosteroids (local and systemic) during the 4-week period prior to the selection visit
* Patients with auto-immune disease (except vitiligo) or transplant patients
* Cutaneous reconstruction not possible
* Presence of associated evolutive neoplasia since less than 5 years (with the exception of basal cell carcinoma, Bowen's carcinoma and carcinoma in situ of the cervix)
* Patient refusing surgery under local or general anaesthesia
* Pregnant women
B: Inclusion Criteria:

* Adults at least 18 years of age.
* World Health Organization (WHO) Performance Status 0 or 1.
* Cytologically or histologically confirmed resectable stage III cutaneous melanoma (unknown primary also allowed) with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months.
* No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
* Patient willing to undergo quadruple tumor biopsies and extra blood withdrawal during screening, week 3 and in case of relapse.
* The biopsies at screening should contain at least 30% tumor cells in order to get a reliable IFN-gamma signature
* No immunosuppressive medications within 6 months prior trial registration.
* Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN.
* Normal LDH.
* Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab.
* Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.

Exclusion Criteria:

Distantly metastasized melanoma

* Uveal or mucosal melanoma.
* History of in-transit metastases within the last 6 months.
* No measurable lymph node lesion according to RECIST 1.1.
* Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy.
* Patients with any active gastrointestinal disorder that could interfere with the absorption of domatinostat (as per judgement of the investigator), such as ulcerative colitis, Crohn's disease, diabetic gastroparesis, or other syndromes characterized by malabsorption.
* Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy.
* Prior targeted therapy targeting BRAF and/or MEK.
* Prior radiotherapy.
* Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection; if treated and being at least one year free from HCV patients are allowed to participate.
* Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
* Allergies and Adverse Drug Reaction:

  * History of allergy to study drug components;
  * History of severe hypersensitivity reaction to any monoclonal antibody.
* Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
* Patients with a marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval \>450 msec (Grade 1 NCI-CTCAE); Long-QT-Syndrome) and patients receiving agents known to prolong the QT interval and known risk of Torsades de Pointes.
* Patients with significant current cardiovascular disease including:

  * Unstable angina pectoris within 6 months prior to screening
  * Uncontrolled hypertension
  * Congestive heart failure (New York Heart Association (NYHA) Class III or IV) related to primary cardiac disease
  * Conditions requiring anti-arrhythmic therapy (patients with status post pace maker implantation can be included)
  * Symptomatic ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry
* Women who are pregnant or lactating
* Use of other investigational drugs before study drug administration 30 days and 5 half-times before trial registration.
C: Inclusion Criteria:

* ≥18 years of age
* Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory
* Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. Prior treatment with immunotherapy (with the exception of prior ipilimumab, which is only allowed if given in the adjuvant setting), cytokine therapy, biological or vaccine regimen is permitted. Prior use of sorafenib is allowed
* Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
* Women of childbearing potential and men with reproductive potential must agree to use effective contraception during the study. Additionally women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
* Adequate screening organ function

Exclusion Criteria:

* Any prior use of BRAF inhibitors or MEK inhibitors.
* Subjects who have received dacarbazine or paclitaxel prior to randomization will not be eligible to receive the same chemotherapy as study medication (i.e. a subject who received prior dacarbazine cannot receive dacarbazine on this trial and would thus receive paclitaxel if randomized to the control arm)
* History of another malignancy. Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above
* Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed)
* Brain metastases with the following exceptions that are ALL confirmed by the GSK Medical Monitor:

All known lesions must be previously treated with surgery or stereotactic radiosurgery, and Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to randomization (must be documented with two consecutive MRI or CT scans using contrast), and asymptomatic with no corticosteroids requirement for ≥ 30 days prior to randomization, and no enzyme-inducing anticonvulsants for ≥ 30 days prior to randomization

* History or evidence of cardiovascular risk including any of the following:

  * QTcB ≥ 480 msec.
  * History or evidence of current clinically significant uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for \>30 days prior to randomization are eligible
  * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization.
  * History or evidence of current ≥ Class II congestive heart failure as defined by New York Heart Association
* History of interstitial lung disease or pneumonitis
* History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR):

  * History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
  * Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or CSR such as:
* Evidence of new optic disc cupping.
* Intraocular pressure \> 21 mm Hg as measured by tonography
D: Inclusion Criteria:

* Patients must have HLA-A2 status known prior to randomization; typing may be obtained through a local laboratory facility or through a reference lab utilized by the initiating institution; if typing is not available through these means, it may be obtained from the University of Pittsburgh
* All patients must have disease completely resected with one of the following in order to be eligible:

  * Completely resected disease
  * Any locoregional recurrence after prior adjuvant interferon or failure on S008
  * Any local recurrence of disease after adequate surgical excision of the original primary
  * Mucosal melanoma
  * Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary)
* The following groups of patients may be entered onto this trial only if they are ineligible for S0008 or are, in the opinion of the managing physician, medically unfit to receive standard high-dose interferon:

  * Any clinically evident satellite or in-transit disease
  * Stage II disease with gross extracapsular extension
  * Recurrence in a previously resected nodal basin
  * Four or more involved lymph nodes or matted lymph nodes
  * Ulcerated primary melanoma and any involved lymph nodes

    * NOTE: Patients who are eligible for S0008 will be strongly encouraged to participate in that study in preference to this one
* Patients must have been surgically rendered free of disease with negative margins on resected specimens; patients rendered free of disease by non-surgical means are not eligible
* Patients must be randomized within 112 days (16 weeks) of surgical resection; if more than one surgical procedure is required to render the patient disease-free, all required surgeries must be accomplished within this 16 week time period
* Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after the resection(s) that make(s) them eligible for this trial; one systemic treatment after a prior surgery is allowed, and must have been completed \>= 8 weeks prior to randomization; (when chemotherapy and biotherapy are given together as one planned treatment \[biochemotherapy\], this counts as one regimen); NOTE: Previous radiation therapy, including after the resection, is allowed as long as 30 days elapse between the radiation and initiation of therapy
* Prior treatment with GM-CSF or any peptides used in this protocol, is not allowed
* Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Patients must not have an active infection requiring treatment with parenteral antibiotics
* Patients must not have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that may interfere with compliance on any of the E4697 treatment regimens
* Patients must not have a diagnosis or evidence of organic brain syndrome or significant impairment of basal cognitive function or any psychiatric disorder that might preclude participation in the full protocol
* Patients must be able to self-administer or arrange for administration of subcutaneous injections
* Patients who have other current malignancies are not eligible
* Patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or Clark I melanoma in situ are eligible; patients who meet this criteria must be disease-free at time of randomization
* Patients with prior history of basal or squamous skin cancer are eligible; patients who meet this criteria must be disease-free at time of randomization
* Patients who have had multiple primary melanomas are eligible
* Patients with other malignancies are eligible if they have been continuously disease free for \> 5 years prior to the time of randomization
* Patients must not have autoimmune disorders, conditions of immunosuppression or treatment with systemic corticosteroids, including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or any steroid containing inhalers; replacement doses of steroids for patients with adrenal insufficiency are allowed; patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization are eligible if, in the judgment of the treating physician, the patient is not likely to require these classes of drugs during the study
* Women of childbearing potential must not be pregnant (negative beta human chorionic gonadotropin \[bHCG\] within 2 weeks prior to randomization) or breast-feeding
* Women of childbearing potential and sexually active males must be counseled to use an accepted and effective method of contraception (including abstinence) while on treatment and for a period of 18 months after completing or discontinuing treatment
* All patients must have brain computed tomography (CT) or magnetic resonance imaging (MRI), chest CT or chest x-ray (CXR), and abdominal (liver) CT or MRI within 4 weeks prior to randomization; positron emission tomography (PET) scans are also acceptable in place of CT, CXR and/or abdominal MRI if obtained within 4 weeks prior to randomization; patients with lesions on the lower extremity must also have pelvic imaging within this time period; this is also strongly recommended for patients with lesions on the lower trunk; PET scans are acceptable
* Patients with resection of visceral disease must have imaging of the affected area/organ documenting disease-free status within 2 weeks prior to randomization
* White blood cells (WBC) \>= 3,000/mm?
* Platelet count \>= 100,000/mm?
* Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) =\< 2 x institutional upper limit (IUL) of normal
* Bilirubin =\< 2 x IUL of normal
* Serum creatinine =\< 1.8 mg/dl
* Alkaline phosphatase and lactate dehydrogenase (LDH) must be performed within 4 weeks prior to randomization; LDH must be normal; patients with abnormal alkaline phosphatase which is =\< 1.25 times the institutional upper limit of normal who have a negative CT or MRI of the liver and negative bone scan or a negative PET scan are eligible
* Patients with bone pain must have a bone scan within 4 weeks prior to randomization to document the absence of tumor

Answer: A