Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-Label, Randomized, Controlled Multi-Center Study of The Efficacy of Daromun (L19IL2 + L19TNF) Neoadjuvant Intratumoral Treatment Followed by Surgery and Adjuvant Therapy Versus Surgery and Adjuvant Therapy in Clinical Stage IIIB/C Melanoma Patients
Brief Summary: The trial aims to evaluate the efficacy of Daromun neoadjuvant treatment followed by surgery and adjuvant therapy to improve in a statistically significant manner the recurrence-free survival (RFS) of Stage IIIB/C melanoma patients with respect to the standard of care (surgery and adjuvant therapy).


Options:
A: Key inclusion criteria

* Histologically confirmed malignant melanoma
* At least 1 measurable index brain metastasis \>0.5 cm and no larger than 3 cm in diameter that had not been previously irradiated, and/or 2 measurable lesions \>0.3 cm visible on contrast magnetic resonance
* Index brain lesion must have resolved consequences of prior therapy that could have confounded attribution of tumor response including edema and hemorrhage
* Participants in ipilimumab monotherapy arm (including the first 21 who were enrolled in Stage 1) were to be free of neurologic symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy
* Eastern Cooperative Oncology Group performance status of 0 or 1
* Required values for initial laboratory tests:

  * White blood cell count ≥2000/μL
  * Absolute neutrophil count ≥1000/μL
  * Platelets ≥100\*10\^3/μL
  * Hemoglobin level ≥9 g/dL (may have been transfused)
  * Aspartate aminotransferase/alanine aminotransferase (AST/ALT) level ≤2.5\*ULN for participants without liver metastasis
  * AST/ALT level ≤5\*ULN for those with liver metastasis
  * Bilirubin level ≤2\*ULN (except participants with Gilbert's Syndrome, who must have had a total bilirubin level less than 3.0 mg/dL)
* Age 16 years and older
* Males and females
* Women of childbearing potential (WOBP) must be using an adequate method of contraception to avoid pregnancy throughout the study (and for up to 26 weeks after the last dose of investigational product) in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal.

Key exclusion criteria

* History of carcinomatous meningitis, with prior stereotactic or highly conformal radiotherapy and/or whole brain irradiation within 14 days before the first dose of ipilimumab, and documented history of autoimmune disease
* Prior stereotactic or highly conformal radiotherapy and/or whole brain irradiation within 14 days prior to start of ipilimumab dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion or the lesion must have been detected and confirmed to be active and progressing after receiving whole brain irradiation.
B: Inclusion Criteria:

1. Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, eligible for complete surgical resection of all metastases (surgically resectable).
2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
3. Males or females, age ≥ 18 years.
4. ECOG Performance Status/WHO Performance Status ≤ 1.
5. Life expectancy of \> 24 months.
6. Absolute neutrophil count \> 1.5 x 109/L.
7. Hemoglobin \> 9.0 g/dL.
8. Platelets \> 100 x 109/L.
9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl).
10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
11. Serum creatinine \< 1.5 x ULN .
12. LDH serum level ≤ 1.5 x ULN.
13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg, and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV negative serum HBV-DNA is also required.
14. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above.
15. All women of childbearing potential (WOCBP) must have negative pregnancy test results at the screening. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods. WOCBP and effective contraception methods are defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the safety visit (only WOCBP and only for patients in Arm 1).
16. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e. spermicidal gel plus condom) from the screening to three months following the last study drug administration.
17. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
18. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

1. Uveal melanoma or mucosal melanoma
2. Evidence of distant metastases at screening.
3. Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except: cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis \& T1), second primary melanoma in situ or any cancer curatively treated ≥ 5 years prior to study entry.
4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
5. History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
6. Inadequately controlled cardiac arrhythmias including atrial fibrillation.
7. Heart insufficiency (\> Grade II, New York Heart Association (NYHA) criteria).
8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiogram investigations that are considered as clinically significant by the investigator.
9. Uncontrolled hypertension.
10. Ischemic peripheral vascular disease (Grade IIb-IV).
11. Severe diabetic retinopathy.
12. Active autoimmune disease.
13. History of organ allograft or stem cell transplantation.
14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies or any other constituent of the product.
16. Breast feeding female.
17. Anti-tumor therapy (except small surgery) within 4 weeks before enrollment.
18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before enrollment.
19. Planned administration of growth factors or immunomodulatory agents within 7 days before enrollment.
20. Patient requiring or taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
22. Previous enrolment and randomization in the same study.
C: Inclusion Criteria:

* adults, \>/=18 years of age
* metastatic melanoma, stage IIIC or IV (AJCC)
* treatment-naïve (no prior systemic anticancer therapy)
* positive for BRAF V600E mutation
* measurable disease by RECIST criteria
* negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion

Exclusion Criteria:

* active central nervous system metastases
* history of carcinomatous meningitis
* severe cardiovascular disease within 6 months prior to study drug administration
* previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix
D: Inclusion Criteria:

* The participant has histologically or cytologically confirmed melanoma that is stage IV (metastatic)
* The participant has an Eastern Cooperative Oncology Performance Status (ECOG PS) of 0-1
* The participant has completed any prior radiotherapy, biologic/immunotherapy or vaccine therapy (for adjuvant or advanced disease) at least six weeks prior to the first dose of study therapy
* The participant has adequate hematological functions \[absolute neutrophil count (ANC) ≥ 1500 cells/microliter (μL), hemoglobin ≥ 9 grams/deciliter (g/dL) and platelets ≥ 100,000 cells/μL\].
* The participant has adequate hepatic function \[bilirubin within normal limits (WNL), aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5 times the upper limit of normal (ULN), or ≤ 5.0 times the ULN if the transaminase elevation is due to liver metastases\]
* The participant has serum creatinine ≤ 1.5 x ULN \[or a calculated creatinine clearance \> 60 milliliters/minute (mL/min)\]
* The participant's urinary protein ≤ 1+ on dipstick or routine urinalysis \[(UA); if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine for protein must demonstrate \< 1000 milligrams (mg) of protein in 24 hours to allow participation in the study\]
* The participant must have adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 1.5 X ULN

Exclusion Criteria

* The participant has mucosal or intra-ocular melanoma
* The participant has known or suspected brain or leptomeningeal metastases
* The participant has had prior cytotoxic chemotherapy for metastatic malignant melanoma
* The participant has had more than one line of biologic, immunologic or vaccine-based therapy for metastatic malignant melanoma (including therapy for adjuvant or advanced disease)
* The participant has a nonhealing wound or ulcer
* The participant has a known alcohol or drug dependency
* The participant is pregnant or breastfeeding
* The participant has a coexisting medical or psychiatric problem of sufficient severity to limit compliance with the study and/or increase the risks associated with study participation or study drug administration or interfere with the interpretation of study results
* The participant has an ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator

Answer: B