The Safety, Tolerability, and Efficacy of KD01 in Cervical Malignancies

The recombinant oncolytic adenovirus injection (KD01) primarily consists of a recombinant human type 5 adenovirus with a deletion in the E3 region, where the ADP gene is replaced by the tBID apoptosis protein gene. This virus exhibits a conditional replication capability, with a 27 base pair deletion in the E1A region corresponding to nucleotides 920-946 of Ad5. This trial is a researcher-initiated clinical study aimed at concurrently evaluating the safety, tolerability, and preliminary efficacy of intratumoral administration of KD01 in patients with cervical malignancies.


Eligibility Criteria:
Inclusion Criteria:

* Phase Ia PART 1 (Monotherapy Dose Escalation Phase): Participants with gynecological malignancies who have failed systemic treatment: histologically or cytologically confirmed gynecological malignancies that have progressed after all standard treatments and for which no effective treatment options are available, or for which there is currently no standard treatment.
* Phase Ib PART 2 (Monotherapy Dose Expansion Phase): Participants with histologically or cytologically confirmed cervical squamous cell carcinoma/adenocarcinoma/adeno-squamous carcinoma; FIGO-2018 staging: IB1-IB2, IIA1; no prior surgical, chemotherapeutic, or concurrent chemoradiotherapy treatment; must provide at least 5 tumor tissue samples or undergo biopsy prior to enrollment.
* Phase Ia PART 3 (Combination Therapy Dose Escalation Phase): Participants with histologically or cytologically confirmed cervical malignancies of any pathological type; FIGO-2018 staging: IB3, IIA2-IVA.
* Phase Ib PART 4 (Combination Therapy Dose Expansion Phase): Participants with histologically or cytologically confirmed cervical squamous cell carcinoma/adenocarcinoma/adeno-squamous carcinoma; FIGO-2018 staging: III-IVA, treatment-naive patients.
* Participants must have an injectable lesion deemed acceptable for KD01 injection treatment by the investigator.
* Age between 18 and 75 years (inclusive).
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1.
* Expected survival of ≥3 months.
* No major organ dysfunction, including but not limited to hematopoietic, cardiac, pulmonary, hepatic, or renal function.
* Hematologic system (no blood transfusion or hematopoietic growth factor treatment within 14 days):
* Absolute Neutrophil Count (ANC) ≥ 1.5 × 10\^9/L
* Platelet Count (PLT) ≥ 75 × 10\^9/L
* Hemoglobin (Hb) ≥ 90 g/L
* Liver function:
* Total Bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN)
* Alanine Aminotransferase (ALT) ≤ 3 × ULN; ≤ 5 × ULN for patients with liver metastasis or hepatocellular carcinoma
* Aspartate Aminotransferase (AST) ≤ 3 × ULN; ≤ 5 × ULN for patients with liver metastasis or hepatocellular carcinoma
* Renal function:
* Creatinine (Cr) ≤ 1.5 × ULN
* Creatinine Clearance (Ccr) (only if Cr \> 1.5 × ULN) \> 50 mL/min (calculated using the Cockcroft-Gault formula)
* Coagulation function:
* Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN
* International Normalized Ratio (INR) ≤ 1.5 × ULN
* For non-menopausal participants, a negative blood pregnancy test during the screening period is required; participants must agree to use reliable contraception methods (barrier methods or abstinence) with their partners during the study and for at least 6 months after the last administration of the study drug.
* Participants must provide informed consent for the study and voluntarily sign a written informed consent form prior to participation.

Exclusion Criteria:

* History of severe cardiovascular or cerebrovascular diseases, including but not limited to: a) Severe cardiac rhythm or conduction abnormalities, such as clinically significant ventricular arrhythmias or second to third-degree atrioventricular block; b) QTcF ≥ 460 ms as determined by a 12-lead electrocardiogram at rest; c) Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or higher cardiovascular events occurring within 6 months prior to the first administration; d) New York Heart Association (NYHA) functional classification ≥ II or left ventricular ejection fraction (LVEF) \< 50%, or other structural heart diseases deemed high-risk by the investigator; e) Clinically uncontrolled hypertension.
* Injection lesions located near major blood vessels.
* Presence of clinically significant serous cavity effusion requiring clinical intervention within 4 weeks prior to informed consent.
* History of autoimmune diseases, immune system deficiencies, or patients who have undergone organ transplantation.
* Presence of active infections, or requiring systemic anti-infective treatment (prophylactic anti-infective treatment as per clinical trial institution's standard practice is exempt), or unexplained fever \> 38.5°C during the screening period.
* Positive for human immunodeficiency virus antibodies (HIV-Ab), positive for syphilis antibodies; active hepatitis B (HBsAg positive and HBV-DNA \> 500 IU/ml or above the clinical trial institution's lower limit \[only if the lower limit is above 500 IU/ml\]); active hepatitis C (patients with positive HCV antibodies but HCV-RNA below the clinical trial institution's lower limit are allowed, provided they are receiving preventive antiviral treatment other than interferons).
* Uncontrolled seizures, central nervous system disorders, or psychiatric conditions resulting in cognitive impairment.
* Adverse reactions from previous anti-tumor treatments that have not recovered to ≤ grade 1 severity (according to Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0), except for toxicities such as alopecia that the investigator deems to pose no safety risk.
* Currently requiring antiviral treatment, or having used antiviral medications within 2 weeks prior to the first administration of the investigational drug.
* Received nitrosourea or mitomycin C within 6 weeks prior to the first administration of the investigational drug; oral fluorouracil or small molecule targeted drugs within 2 weeks prior or within 5 half-lives of the drug (whichever is longer); traditional Chinese medicine with anti-tumor indications within 2 weeks prior; any other anti-tumor treatments such as chemotherapy, radiotherapy, biological therapy, endocrine therapy, or immunotherapy within 4 weeks prior to the first administration of the investigational drug.
* Received systemic corticosteroids (prednisone \> 10 mg/day or equivalent doses of similar drugs) or other immunosuppressive treatments within 14 days prior to the first administration of the investigational drug; exceptions include local, ocular, intra-articular, intranasal, and inhaled corticosteroid treatments; short-term use of corticosteroids for prophylactic treatment (e.g., to prevent contrast agent allergies).
* Previous treatment with oncolytic viruses or bacteria.
* Vaccination within 28 days prior to the first administration of the investigational drug.
* Pregnant or breastfeeding women.
* History of severe allergies or allergic constitution.
* Any other conditions deemed unsuitable for inclusion by the investigator.