A Phase I/IIa Clinical Trial to Investigate BVAC-E6E7 in Subjects with HPV Positive HNSCC.

BVAC-E6E7 is an immunotherapeutic vaccine designed to treat unresectable recurrent or metastatic head and neck squamous cell carcinoma positive to HPV 16 or 18. This clinical trial for BVAC-E6E7 consists of two phases: PhaseⅠfocuses on safety and tolerance to determine the maximum tolerated dose (MTD), while Phase Ⅱ evaluates its efficacy.


Eligibility Criteria:
Inclusion Criteria:

1. Adult male and female aged 19 and above at the time of acquisition informed consent form.
2. Patients who have agreed to provide blood and tissue samples during the clinical trial.
3. Patients with Head and neck squamous cell carcinoma histologically confirmed as HPV type 16 or 18 positive \* The biopsy results obtained during screening process or the genotyping (PCR, microarray test) results from stored tissue (formalin-fixed paraffin-embedded) prior to screening should be confirmed positive to HPV type 16 or 18.
4. Patients who are histologically or cytologically diagnosed with recurrent/metastatic Head and neck squamous cell carcinoma (excluding Nasopharyngeal carcinoma).
5. Patients with at least one measurable or evaluable lesion confirmed by CT or MRI according to RECIST v1.1. \[It can be considered as an evaluable lesion if the disease has progressed in the previously irradiated area.\]
6. Patients who meet one of the following criteria and have no available standard treatment due to contraindication, intolerance or refusal of administration.

   ① Patients who have progressed or recurred the cancer during or after the completion of primary or subsequent platinum based palliative systemic chemotherapy to treat the recurrent or metastatic Head and neck cancer.

   ② Patients who have confirmed the progression of cancer within 24 weeks after the final administration of immune checkpoint blocker (ICI) or completion of combination treatment including platinum agents with a radical purpose.

   ③ Patients who are ineligible for platinum based chemotherapy due to contraindications, intolerance or refusal of administration of platinum based chemotherapy.
7. Patients with ECOG performance status of 0 or 1
8. Patients with at least a 3-month life expectancy.
9. Male patients who has not received the vasectomy should agree usage barrier contraceptive method (i.e. condom) and agree to use appropriate contraception for themselves and their partners for at least 6 months after the completion of IP administration.

   * Appropriate contraceptive method: absolute abstinence, hormone contraceptive agent with unknown drug-interaction (e.g. levonorgestrel intrauterine system (IUS) (Mirena) or Medroxyprogesterone) and surgical sterilization operation (Vasectomy, Bilateral salpingectomy and ligation, etc.). However, Intermittent abstinences (ovulation period, symptothermal method or late-ovulation) or Coitus interruptus are not considered as appropriate contraceptive method.

Exclusion Criteria:

1. Patients with a history of malignant tumor, excluding Head and neck squamous cell carcinoma, within 3 years prior to the screening (However, patients who are judged by investigator to have been cured of Basal cell carcinoma (BCC) / Squamous cell carcinoma (SCC) of the skin, localized prostate cancer, papillary thyroid cancer, or cervical intraepithelial neoplasia (CIN) are able to enroll.)
2. Nasopharyngeal cancer or Head and neck cancer other than squamous cell carcinoma.
3. Patients having below cardiovascular disease at the time of the screening process.

   ① Myocardial infarction or Unstable angina within 6 months prior to the first IP administration (baseline).
   * Severe heart failure or congestive heart failure of class Ⅲ or higher according to the New York Heart Association (NYHA).

     * Ventricular arrhythmia requiring treatment. ④ Severe conduction disorder (e.g. 3rd degree AV block) ⑤ Uncontrolled hypertension according to the judgement by investigator.
4. Patients who have confirmed clinically significant symptoms or uncontrolled central nervous system, brain metastasis, or carcinomatous meningitis (However, patients who have not confirmed the progression disease for at least 4 weeks after central nervous system or metastatic brain treatment and have not required treatment using steroid or other meditation within 7 days prior to the IP administration can be enrolled.)
5. Patients with a history or confirmed active immune disease (e.g. rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, multiple sclerosis, or T cell lymphoma) after receiving systemic treatment (e.g. disease-modifying agent, corticosteroid or immunosuppressive drug) \[However, alternative treatment (thyroxine, insulin, physiologic corticosteroid alternative treatment due to dysfunction of adrenal gland or pituitary gland) are not considered as systemic treatments.\]
6. Patients who are unable to collect the blood for production of the IP, according to the judgement of investigator, due to thromboembolism disease or bleeding diatheses.
7. Patients with a positive human immunodeficiency virus (HIV) test result
8. Patients with active hepatitis B or C according to the hepatitis B virus (HBV) and hepatitis C virus (HCV) test result.

   ① Patients positive for HBsAg and HBV DNA.

   ② Patients positive for anti-HCV and HCV RNA.
9. Patients with autoimmune disease or history of chronic or recurrent autoimmune diseases.
10. Patients with a history of organ transplantation.
11. Hematopoietic stem cell transplantation (HSCT) patients.
12. Patients who have confirmed severe or uncontrolled active inflammation within 12 weeks prior to screening process.
13. Patients with a history of hypersensitivity to the components of IP.
14. Patients who have administrated a leukocyte product within 12 weeks prior to screening process.
15. Patients who have received chemotherapy, radiotherapy or targeted therapy within 4 weeks prior to baseline \[However, patients who have not recovered to NCI-CTCAE v5.0 Grade 1 or baseline levels from chemotherapy-related toxicities. (excluding Alopecia and vitiligo), even after 4 weeks, are not eligible for enrollment.\]
16. Patients who have administrated live-vaccine or live attenuated vaccine within 4 weeks prior to baseline.
17. Patients who have administrated immunosuppressant within 2 weeks prior to baseline. (However, usage corresponding to the following immunosuppressant is allowed.)

    * Steroid for nasal cavity, aspiration, topical, or local site (e.g. Intra-articular injection)
    * Prednisolone 10 mg/day or systemic corticosteroid at a physiologic dose that does not exceed the equivalent amount.
    * Steroids used for pretreatment of hypersensitivity (e.g. pretreatment of CT)
18. Patients who meet the following laboratory test standards in the screening test

    * ANC \< 1,500/mm³
    * Platelet count \< 75,000/mm³
    * Hemoglobin \< 9.0 g/dL (If the hemoglobin recovers above 9.0g/dL during the screening period, the patient is eligible for enrollment. However, blood transfusions within 7 days before screening to meet that standard is not allowed.)
    * Serum creatinine \>1.5 × ULN
    * Total bilirubin \>1.5 × ULN
    * AST or ALT \>2.5 × ULN (If liver metastasis confirmed \>5 × ULN)
19. Pregnant or lactating women
20. Patients who have administrated IP for other clinical trials or applied investigational device within 4 weeks before screening. \[However, the patients who correspond to one of the following, even after 4 weeks, are not eligible for enrollment.\]

    ① Patients who have participated in a clinical trial of immune therapeutic vaccine within 1 year before the screening or in an immunotherapy clinical trial within 6 weeks before the screening.

    ② Patients with adverse drug reaction of Grade 2 or higher clearly associated with a previously participated immunotherapy clinical trial.
21. Patients who are not eligible to enroll in this clinical trial according to the judgement of investigator for any other reason.