Cervical Cancer, Intraepithelial Neoplasia
Conditions
Keywords
HPV16, Intraepithelial Neoplasia, Cervical Cancer, mRNA vaccine
Brief summary
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 related Cervical, vaginal, and vulvar intraepithelial neoplasia (LSIL and HSIL) patients (cohort A) and HPV-16 related cervical cancer patients (cohort B).
Detailed description
This study is divided into three dose groups in two cohorts. 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. For cohort A, the subjects shall continue to receive safety follow-up until 14 days after the last administration. Colposcopy and biopsy were performed at week 24. For cohort B, the subjects shall continue to receive safety follow-up until 14 days after the last administration. Imaging evaluation was performed every 6 weeks.
Interventions
NWRD09 administered by intramuscular injection according to the study protocol.
Sponsors
Newish Technology (Beijing) Co., Ltd.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3+3 dose climb
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 60 Years
Healthy volunteers
No
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. 3. Histologically confirmed HPV-16-associated cervical, vaginal, and vulvar intraepithelial neoplasia (LSIL and HSIL). In the case of LSIL, it is necessary to meet persistent HPV16 infection for more than 6 months. 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. 4. 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. 5. 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 one lines of standard therapy or are intolerant to toxic side effects, or for which there is no standard treatment at present (Treatment failure refers to: disease progression during or after treatment with systemic antineoplastic regimens; Intolerance refers to: the patient has grade 3-4 adverse reactions after receiving standard therapy, and the patient refuses to continue the original treatment). 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety（Cohort A and B） | From first administration of NWRD09 to 14 days after the last administration | All adverse events (AE) will be determined based on the rate and severity grade of events, including incidence and severity of serious adverse events (SAE) (according to NCI-CTCAE Standard version 5.0 of common Terms for Adverse Events). |
| Dose-limiting toxicity (DLT) （Cohort A and B） | 14 days after the first administration | It would be determined based on the rate and severity grade of events or abnormalities through evaluating systemic or local adverse events, clinical laboratory test results, vital signs that is definitely, probably, or possibly related to the test drug occurring within 21 days of the first dosing will be classified as DLT during dosing climb. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) （Cohort B） | To week 24. | bjective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1. |
| Progression-free survival (PFS) （Cohort B） | To week 24. | Progression-free survival (PFS), defined as the time from the NWRD09 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first. |
| Immunogenicity （Cohort A and B） | To week 24. | Immunologic reactogenicity by measuring HPV16 E6/E7 specific T cell response (IFN-γ ELISPOT) in blood samples. |
| Disease control rate (DCR) （Cohort B） | To week 24. | Disease control rate (DCR), defined as is the percentage of evaluable cases with response (PR + CR) and stable disease (SD) after treatment, DCR = CR + PR + SD. |
| Duration of response (DOR) （Cohort B） | To week 24. | Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause. |
| Histopathology outcome and HPV Viral clearance （Cohort A） | To week 24. | Number of subjects with virologically-proven clearance of HPV 16 and number of subjects with histopathological regression of cervical lesions to CIN 1 or normal. |
Countries
China
Contacts
Primary ContactGuodong Sun, Master
Outcome results
None listed