NWRD09 for HPV-16 Positive and HPV-16 Related Intraepithelial Neoplasia and Cervical Cancer Patients.

This is a single-arm, open label, two cohorts, multi-center clinical study to evaluate the safety and efficacy of HPV-16 targeted mRNA vaccine (NWRD09) in HPV-16 positive and HPV-16 related cervical, vaginal, and vulvar intraepithelial neoplasia (LSIL and HSIL) patients (cohort A) and HPV-16 related cervical cancer patients (cohort B).

This study is divided into three dose groups in cohort A and cohort B. Each patient will be administered NWRD09 by intramuscular injection. The Maximum Tolerated Dose of NWRD09 will be determined by the classical 3+3 dose escalation schedule. The number of patients will be ranged from 9 to 18.

Eligibility Criteria:
Inclusion Criteria:

Inclusion criteria for cohort A:

Patients had to meet all of the following inclusion criteria:

1. Women aged between 18 and 60 years.
2. HPV16 is positive during the screening period, and other subtypes of HPV co-infection can be included. In the case of HSIL, it is necessary to meet the requirements of satisfactory colposcopy at screening, which is defined as the squamous columnar epithelial junction (class I or class II transformation zone) is fully visible, and the upper limit of the white epithelium acetate or suspected CIN lesions are fully visible.
3. Eligible subjects of childbearing potential must agree to use a reliable method of contraception (hormonal or barrier method or abstinence, etc.) with their partner for the duration of the trial or for at least 6 months after the last dose. For premenopausal women with the possibility of childbearing, blood pregnancy tests must be negative within 7 days prior to the first use of the NWRD09.
4. Have fully understood the study and voluntarily signed the ICF, have good communication with the investigator, and are able to complete all treatments, examinations, and visits stipulated in the study protocol.

Inclusion criteria for cohort B:

Patients had to meet all of the following inclusion criteria:

1. Women aged ≥ 18 years.
2. HPV16-related recurrent or metastatic advanced cervical cancer (Histologically confirmed squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma) patients who have progressed after at least two lines of standard therapy or are intolerant to toxic side effects, or for which there is no standard treatment at present.
3. At least 1 measurable lesion (RECIST 1.1). Tumor lesions that have received prior radiotherapy or other local therapy are considered measurable only if disease progression at the treatment site is clearly documented after completion of treatment.
4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1.
5. Had recovered from all toxicities related to prior anticancer therapies to grade≤1 or baseline level as defined by CTCAE v5.0 (except for the asymptomatic laboratory examination abnormalities such as elevated ALP, hyperuricemia, elevated serum amylase/lipase, elevated blood glucose, etc., and toxicities judged by the investigator to have no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stabilized by hormone replacement therapy, etc.).
6. Major organ functions must meet the following criteria:

   1. Blood routine: absolute neutrophil count (ANC) ≥ 1.5×10\^9/L, platelet count ≥ 80×10\^9/L, hemoglobin ≥ 90 g/L,
   2. Liver function: total bilirubin (TBIL) ≤ 1.5 ULN (≤ 3 ULN for Gilbert's syndrome, liver cancer, or liver metastases), AST and ALT ≤ 2.5 ULN for subjects without liver metastases, and ≤ 5.0 ULN for subjects with liver metastases,
   3. Renal function: creatinine (Cr) ≤ 1.5 ULN, or creatinine clearance (Ccr) ≥ 50 mL/min (using the Cockcroft and Gault formula),
   4. Coagulation function: international normalized ratio (INR) ≤ 1.5, and activated partial thromboplastin time (APTT) ≤ 1.5 ULN.
7. Has life expectancy of at least 3 months in the best judgement of the investigator.
8. Eligible subjects of childbearing potential must agree to use a reliable method of contraception (hormonal or barrier method or abstinence, etc.) with their partner for the duration of the trial or for at least 6 months after the last dose. For premenopausal women with the possibility of childbearing, blood pregnancy tests must be negative within 7 days prior to the first use of the NWRD09.
9. Have fully understood the study and voluntarily signed the ICF, have good communication with the investigator, and are able to complete all treatments, examinations, and visits stipulated in the study protocol.

Exclusion Criteria:

Exclusion criteria for cohort A:

Patients with any of the following were excluded from the study:

1. Any histopathologically confirmed adenocarcinoma or adenocarcinoma in situ (AIS) or invasive cancer.
2. Pregnant, breastfeeding, or planning to conceive during the study period.
3. Received any non-live vaccine injection within 2 weeks prior to the first dose of NWRD09.
4. Received any live vaccine injection within 4 weeks prior to the first dose of NWRD09.
5. Received treatment for LSIL or HSIL within 4 weeks prior to the first dose of NWRD09.
6. Participated in another clinical trial or is in the observation period of another clinical trial within 30 days prior to screening.
7. Continuous (more than 1 week) use of corticosteroids (equivalent to \>10 mg/day of prednisone) within 30 days prior to screening, except for hormone replacement therapy and local administration such as inhaled or ocular treatments.
8. History of immunodeficiency or autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis).
9. Current or anticipated use of disease-modifying antirheumatic drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biological agents (e.g., infliximab, adalimumab, etanercept).
10. Continuous (more than 1 week) use of immunosuppressants (e.g., cyclosporine, tacrolimus, azathioprine, 6-mercaptopurine, and anti-lymphocyte globulin) within 30 days prior to screening.
11. History of solid organ or bone marrow transplantation.
12. Past or current malignancies, except for adequately treated and completely cured ductal carcinoma in situ of the breast, basal cell carcinoma of the skin, superficial bladder tumors, or any other malignancies cured more than 5 years before entering the study.
13. Uncontrolled severe infections (\>Grade 2 NCI-CTCAE adverse events, version 5.0).
14. History of HIV infection or syphilis carrier.
15. Active infection (e.g., acute bacterial infection, tuberculosis, active syphilis, active phase of herpes zoster virus infection, active hepatitis B or C, etc.).

    ① Active hepatitis C is defined as: positive hepatitis C antibody and HCV-RNA positive.

    ② Active HIV infection is defined as: positive HIV antibody.

    ③ Active hepatitis B is defined as: HBV titer ≥ 2000 IU/mL (except for subjects who have received anti-HBV treatment for at least 14 days before the first dose and agree to continue antiviral therapy during the study period).
16. Severe allergy history, or history of atopic diseases, or an allergic constitution, if any of these are met.
17. History of severe or multiple hypersensitivity to drugs or pharmaceutical preparations.
18. History of severe local or systemic reaction to vaccines, defined as:

    1. Local reaction: extensive, indurated redness and swelling involving most of the arm, unresolved within 72 hours.
    2. Systemic reaction: persistent fever ≥ 39.5°C within 48 hours. bronchospasm. laryngeal edema. syncope. convulsions or encephalopathy within 72 hours.
19. Severe dysfunction of other organs or heart and lung diseases.
20. History of definite neurological or psychiatric disorders, including epilepsy or dementia.
21. History of drug abuse or alcoholism.
22. Pregnant or breastfeeding women, or women of childbearing age with a positive blood pregnancy test, or patients and their partners of childbearing potential unwilling to use effective contraception during the clinical study and for 6 months after the end of treatment.
23. Patients deemed unsuitable to participate in this clinical trial by the investigator.

Exclusion criteria for cohort B:

Patients with any of the following were excluded from the study:

1. Cervical carcinoma in situ that can be cured by local treatment or non-HPV related cervical cancer.
2. Has not recovered or be reasonably explained from all toxicities related to prior treatments such as surgery, radiotherapy, chemotherapy, immunotherapy, etc.
3. Participated in another clinical trial or is in the observation period of another clinical trial within 30 days prior to screening.
4. Received any non-live vaccine injection within 2 weeks prior to the first dose.
5. Received any live vaccine injection within 4 weeks prior to the first dose.
6. Continuous (more than 1 week) use of corticosteroids (equivalent to \>10 mg/day of prednisone) within 30 days prior to screening, except for hormone replacement therapy and local administration such as inhaled or ocular treatments.
7. History of immunodeficiency or autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis).
8. Current or anticipated use of disease-modifying antirheumatic drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biological agents (e.g., infliximab, adalimumab, etanercept).
9. Continuous (more than 1 week) use of immunosuppressants (e.g., cyclosporine, tacrolimus, azathioprine, 6-mercaptopurine, and anti-lymphocyte globulin) within 30 days prior to screening.
10. History of solid organ or bone marrow transplantation.
11. Past or current malignancies, except for adequately treated and completely cured ductal carcinoma in situ of the breast, basal cell carcinoma of the skin, superficial bladder tumors, or any other malignancies cured more than 5 years before entering the study.
12. Central nervous system (CNS) metastases and/or carcinomatous meningitis (meningeal metastasis).
13. Clinically significant or recurrent pleural, peritoneal, or pericardial effusion requiring frequent drainage.
14. Uncontrolled severe infections (\>Grade 2 NCI-CTCAE adverse events, version 5.0).
15. History of HIV infection or syphilis carrier.
16. Active infection (e.g., acute bacterial infection, tuberculosis, active syphilis, active phase of herpes zoster virus infection, active hepatitis B or C, etc.).

    ① Active hepatitis C is defined as: positive hepatitis C antibody and HCV-RNA positive.

    ② Active HIV infection is defined as: positive HIV antibody.

    ③ Active hepatitis B is defined as: HBV titer ≥ 2000 IU/mL (except for subjects who have received anti-HBV treatment for at least 14 days before the first dose and agree to continue antiviral therapy during the study period).
17. Severe allergy history, or history of atopic diseases, or an allergic constitution, if any of these are met.
18. History of severe or multiple hypersensitivity to drugs or pharmaceutical preparations.
19. History of severe local or systemic reaction to vaccines, defined as:

    1. Local reaction: extensive, indurated redness and swelling involving most of the arm, unresolved within 72 hours.
    2. Systemic reaction: fever ≥ 39.5°C within 48 hours. bronchospasm. laryngeal edema. syncope. convulsions or encephalopathy within 72 hours.
20. Severe dysfunction of other organs or heart and lung diseases.
21. History of definite neurological or psychiatric disorders, including epilepsy or dementia.
22. History of drug abuse or alcoholism.
23. Pregnant or breastfeeding women, or women of childbearing age with a positive blood pregnancy test, or patients and their partners of childbearing potential unwilling to use effective contraception during the clinical study and for 6 months after the end of treatment.
24. Patients deemed unsuitable to participate in this clinical trial by the investigator.