HPV 16-positive and/or HPV 18-positive Recurrent and/or For Patients With Metastatic Head and Neck Cancer to Evaluate GX-188E DNA Vaccination, GX-I7 and Nivolumab Combination Therapy

Inclusion Criteria:

1. 19 years of age or older
2. Histologically confirmed, advanced or metastatic, HPV-positive (positive on p16immunohistochemistry and positive on HPV-16 or HPV-18 nucleic acid test) R/M HNSCCpatients
3. Patients with disease progression after platinum-based chemotherapy are eligible forparticipation.
4. Patients with recurrence within 6 months after conventional platinum-basedchemotherapy are considered platinum-based treatment failure.
5. Patients who have received first-line or second-line chemotherapy are eligible toparticipate. That is, patients whose treatment in this trials is the second or thirdlince chemotherapy can be enrolled.
6. PD-L1 (DAKO 28-8 TPS) ≥1%
7. Eastern Cooperative Oncology Group (ECOG) Activity Status 0-1
8. Patients with a life expectancy of at least 6 months
9. Patients must agree to provide a storage tumor tissue sample or a fresh biopsy samplefor baseline biomarker tissue analysis including PD-L1 staining. Patients withouttissue for storage and without tumor lesions for which biopsies can be obtained willbe excluded from the study.
10. The patient must have adequate organ function as defined below. Specimens must becollected within 28 days prior to be administered the investigational drug. [hematology]

• Absolute neutrophil count (ANC) ≥1,500/μL
• Platelets ≥100,000/μL
• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L1 [kidney]
• Creatinine or creatinine clearance measured or calculated2 (GFR may be usedinstead of creatinine or CrCl) ≤1.5 × ULN or, For subjects with creatinine > 1.5xlaboratory ULN, ≥30 mL/min [liver]
• Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ULN for subjects with totalbilirubin concentration >1.5 × ULN (except for subjects with Gilbert syndrome,total bilirubin <3xULN and ALT <3xULN)
• AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN, for subjects with livermetastases) [Blood coagulation]
• As long as the international standardized ratio (INR) or prothrombin time (PT),activated partial thromboplastin time (aPTT) ≤1.5 × ULN, PT, or aPTT is withinthe therapeutic range of the intended use of anticoagulants, the subject isanticoagulant If you are not receiving

11. Patients with RECIST measurable disease defined as: Tumor lesions with a long axis diameter (LD) ≥1 cm on axial CT or MRI images (reconstruction interval ≤5 mm) or lymph nodes ≥1.5 cm in the short axis on CT (reconstruction interval ≤5 mm)
12. For women of childbearing potential (WOCBP), a patient with a negative serum or urinepregnancy test result within 72 hours prior to the first administration of theinvestigational drug. If the urine test result cannot be confirmed as positive ornegative, a serum pregnancy test should be performed. A woman who has started menarche and has not reached amenorrhea for at least 12consecutive months without a postmenopausal condition, an identified cause other thanmenopause, and who has not undergone surgical sterilization (removal of the ovariesand/or uterus) is considered a woman of childbearing potential.
13. Women of childbearing potential must agree to use an appropriate double contraceptivemethod for the entire course of this study and up to 120 days after the lastadministration of the study drug. Women who are menopausal (over 45 years of age andhave not menstruated for more than 1 year) and women who are surgically infertile areexempt from this requirement. Note: Abstinence is acceptable as long as it is thesubject's normal lifestyle and the subject's preferred method of contraception.
14. A patient who is willing to participate in a clinical trial in accordance with theguidelines of each laboratory and can give written consent through the subject consentform.

Exclusion Criteria:

1. When the disease is suitable for topical therapy for the purpose of cure
2. If it is confirmed that there is another malignant disease that is currently ongoingor required active treatment within the past 3 years. NOTE: Subjects with cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma,or carcinoma in situ (eg breast cancer) who have received potentially curativetreatment are not excluded.
3. Patients expected to require another antineoplastic treatment during the trial; Thistreatment includes systemic chemotherapy, radiotherapy (except palliative care),biological therapy, or immunotherapy not specified in the protocol.
4. Patients with a history of active central nervous system (CNS) metastasis and/orcarcinoma meningitis. Patients with asymptomatic or controlled CNS metastases may beeligible.
5. Past treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs or drugs that actdirectly on other stimulatory or co-inhibitory T-cell receptors (e.g., CTLA-4, OX40,CD137)
6. Patients with active autoimmune disease requiring systemic immunosuppressive therapy (eg, use of disease modulators, corticosteroids, or immunosuppressants) within thepast 2 years. Replacement therapy (e.g., replacement of thyroxine, insulin, orphysiological corticosteroids due to adrenal or pituitary insufficiency) is allowedbecause it is not considered a form of systemic treatment.
7. Patients who underwent allogeneic solid organ transplant or allogeneic bone marrowtransplant
8. Non-PD-1/PD-L1/PD-L2, anticancer monoclonal antibody (mAb) (eg, bevacizumab,cetuximab, etc.) has been administered within 4 weeks prior to the firstadministration of the investigational drug, or for more than 4 weeks Patients who havenot yet recovered (eg, Grade 1 or lower or to baseline levels) from adverse events dueto medications administered prior to a time point.
9. Patients who received systemic chemotherapy including other investigational drugswithin 4 weeks prior to the first administration of this study drug, or who receivedtargeted small molecule therapy with a half-life of less than 48 hours within 2 weeksNote: Subjects must have had any adverse reactions caused by previous treatment tohave returned to Grade 1 or less or baseline levels. Grade 2 neuropathy and/or grade 2anemia may be appropriate. Note: If a subject has undergone major surgery, the subject must have adequatelyrecovered from toxicity and/or complications from the intervention prior to initiationof treatment.
10. Patients who have received radiation therapy within 2 weeks prior to starting theinvestigational drug. Subjects must have recovered from any radiation-relatedtoxicity.
11. Patients who have transfused blood products (including platelets or red blood cells)within 4 weeks prior to the first administration of the investigational drug or havereceived colony stimulating factors (including G-CSF, GM-CSF, or recombinanterythropoietin)
12. Patients with bilateral hydronephrosis that cannot be relieved by ureteral stents orpercutaneous renal fistuloplasty.
13. Patients with severe (≥ Grade 3) hypersensitivity to nivolumab and/or one of itsexcipient components
14. Patients with a history of (non-infectious) interstitial pneumonia requiring steroidsor currently suffering from interstitial pneumonia
15. Patients diagnosed with immunodeficiency or who are receiving long-term systemicsteroid therapy (a dose exceeding the same dose of 10 mg of prednisone per day) orhave received any other immunosuppressive treatment within 7 days prior to the firstadministration of the investigational drug
16. Patients with risk factors for intestinal obstruction or intestinal perforation (including, but not limited to, for example, acute diverticulitis, abdominal boils,and abdominal carcinomatosis)
17. A patient who is currently participating in or has participated in a clinical trialfor another investigational drug in the past and has received clinical trial treatmentor used a clinical trial device within 4 weeks prior to the first administration ofthe investigational drug Note: Subjects who have entered the follow-up phase of theclinical trial can participate in this trial if more than 4 weeks have passed sincethe last administration of the previous investigational drug.
18. Unstable/improper heart function:

• Symptomatic ischemia
• uncontrolled or clinically significant abnormal conduction (eg, ventriculartachycardia during antiarrhythmic therapy is excluded); Appropriate forfirst-degree AV block or asymptomatic LAFB/RBBB
• myocardial infarction within the past 6 months
• Congestive Heart Failure (New York Heart Association Grade III - IV)

19. Patients with active infection requiring systemic treatment
20. Confirmed human immunodeficiency virus (HIV) infection and/or history of hepatitis Bor C, hepatitis B surface antigen (HBsAg)/hepatitis B virus (HBV) DNA or hepatitis Cantibody If the RNA test is confirmed positive. Active hepatitis C is defined as apositive Hep C Ab result and a quantitative HCV RNA result found above the lower limitof detection of the assay.
21. Patients with a history of active tuberculosis (TB, Bacillus Tuberculosis)
22. Patients who received live vaccine within 30 days prior to the first administration ofthe investigational drug. Examples of live vaccines include, but are not limited to:measles, mumps, rubella, chickenpox/shingles, yellow fever, rabies, BCG, and typhoidvaccines. Injectable seasonal flu vaccines are generally acceptable because they arelive virus vaccines, but nasal flu vaccines (eg FluMist®) are not allowed because theyare live attenuated vaccines.
23. When it is confirmed that the subject has a mental illness or substance abuse disorderthat may interfere with his/her ability to cooperate with the requirements of thistrial
24. Patients with implanted electronic devices (e.g. pacemakers)
25. Women of childbearing potential with a positive urine pregnancy test (eg within 72hours) prior to administration of the study drug. If the urine test is not positive ornegative, a serum pregnancy test is required.
26. Pregnant or lactating patients
27. Conditions or treatments of any kind that are likely to confound the trial results,interfere with the subject's participation throughout the trial period, or for whichparticipation in the trial is not determined to be in the subject's best interest; Ahistory of, or current evidence of, laboratory test abnormalities