| Eligibility |
Inclusion Criteria:
1. Biopsy confirmed patients with un-resectable American Joint Committee on Cancer
(AJCC), Stage III or IV melanoma who have measurable disease. Measurable disease is
required, and is defined as tumor can be measured in one dimension along the longest
diameter
2. Patients must have tumors that are not responsive having completed prior therapy with
a Progressive Death (PD)-1 / PD-Ligand-1 (PDL-1), antagonist alone or in combination
with anti-Cytotoxic T Lymphocyte Antigen 4 (CTLA-4). If the patient is positive for
BRAF, the patient must have progressed on at least one BRAF inhibitor in addition to a
PD-1 / PD-L1 inhibitor alone or in combination with CTLA4 for metastatic melanoma
3. Patients must be progressing after having completed one standard of care therapy for
metastatic melanoma
4. Tumor specimens must be available for tumor lysates and immunological studies.
5. Tumors must be available for intratumoral injection of dengue virus. This includes
cutaneous and subcutaneous lesions with ultrasound-guided injection.
6. Eastern Cooperative Oncology Group (ECOG), Performance Status of = 2 (corresponds to a
Karnofsky Performance Status (KPS) of = 70).
7. Patients must be 18 years or older and able to give informed consent.
8. Adequate bone marrow function of White Blood Cell (WBC) count to = 1,500/microliter
(uL); platelet count = 100,000/mm3; absolute neutrophil count (ANC) > 1,500/mm3
9. Patients must have adequate renal function by serum creatinine of = 2.0
milligrams/decaliter (mg/dL).
10. Adequate hepatic function of bilirubin = 2.5 mg/dL; Serum Glutamic Oxaloacetic acid
Transaminase/ Serum Glutamic Pyruvic Transaminase (SGOT/SGPT) < 3× upper limit of
normal (ULN).
11. Patients must have the required wash out periods from prior therapy:
12. Topical therapy: 2 weeks.
13. Chemotherapy and radiotherapy: 4 weeks.
14. Other investigational therapy: 4 weeks
15. Patients of reproductive potential and their partners must agree to use an effective
(>95% reliability) form of contraception during the study and for 4 weeks following
the last study drug. Patients who become pregnant during the course of the study will
be withdrawn from the trial.
16. Women of reproductive potential must have a negative urine pregnancy test.
17. Patients should have a life expectancy of > 4 months.
18. Patient should be able to comply with the treatment schedule and have the ability to
understand and the willingness to sign the informed consent document.
19. Patients with manageable Central Nervous System (CNS), metastases may be selected to
this trial. CNS metastasis patients are eligible if the CNS metastases have had no
progression for at least 4 weeks (as defined by Magnetic Resonance Imaging
[MRI]/Computerized Tomography [CT]).
Exclusion Criteria:
1. Patients with positive antibody to any Dengue Virus serotype by tetravalent ELISA
assay.
2. Patients with prior vaccinations or positive Ab detected by ELISA to: West Nile, St.
Louis Encephalitis, or Yellow Fever
3. Pre-existing autoimmune or antibody mediated disease including systemic lupus
erythematous, rheumatoid arthritis, multiple sclerosis, Sjogren's syndrome, autoimmune
thrombocytopenia, but excluding controlled thyroid disease, or the presence of
autoantibodies without clinical autoimmune disease.
4. Known history of human immunodeficiency virus (HIV) or any active immunosuppressive
systemic infection or a suppressed immune system, including acquired immuno-deficiency
syndrome (AIDS) or HIV positivity and known hepatitis B or C infections (HCV or HBC),
as assessed by serology.
5. Patients on immunosuppressive therapy. Concurrent steroid use of not more than an
equivalent of 10 mg of prednisone is allowed.
6. Any other open wounds.
7. Previous organ transplantation.
8. Patients with clinically significant dermatological disorders, as judged by the
clinical investigator (e.g., eczema or psoriasis), any skin lesions or ulcers, any
history of atopic dermatitis, or any history of Darier's disease (Keratosis
Follicularis).
9. Patients with White Blood Cell count <1,500/uL; platelet count <100,000/mm3; absolute
neutrophil count (ANC) 1,500/mm3 (Grade 2)
10. Patients with inadequate renal function by serum creatinine of >1.5 x ULN (Grade 2)
11. Patients with inadequate liver function by SGPT/SGOT > 3x ULN, and bilirubin >2.5
mg/dl (Grade 2)
12. Patients with active infection or with a fever >101°F (38.5°C) within 3 days prior to
the first scheduled treatment.
13. Concurrent participation in other treatment related clinical studies. Non-treatment
studies (e.g. observation or tumor cell analysis studies) are allowed.
14. Prior malignancy (active within 3 years of screening) except basal cell or completely
excised non-invasive squamous cell carcinoma of the skin, or in situ squamous cell
carcinoma of the cervix.
15. Significant cardiovascular disease (i.e., New York Heart Association (NYHA) class 3
congestive heart failure; myocardial infarction within the past 6 months; unstable
angina; coronary angioplasty within the past 6 months; uncontrolled atrial or
ventricular cardiac arrhythmias).
16. Female patients who are pregnant or lactating.
17. Patients taken off Checkpoint Blockade agents: Ipilimumab, Nivolumab, Pembrolizumab,
for Grade 3 or greater autoimmune toxicity. [7]
18. Patients who are positive for B-RafV600 mutation and are responding to targeted
therapy.
19. Any other medical history, including laboratory results, deemed by the investigator to
be likely to interfere with his/her participation in the study, or to interfere with
the interpretation of the results.
20. Patients with endocrinopathy greater than grade III.
21. Patients who have undergone a splenectomy in their previous medical history will be
excluded from this trial. Evidence of a splenectomy will be from history or records.
22. Prior history or serologic evidence of other flavivirus infections (yellow fever, St.
Louis encephalitis, West Nile virus)
23. Prior history of having received a flavivirus vaccine
24. Patients who are actively taking Non Steroid Anti Inflammatory Drugs (NSAID) including
aspirin
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