Hexaminolevulinate Photodynamic Therapy (HAL-PDT) With Deferred Surgery Versus Surgery for High-grade Squamous Intraepithelial Lesions (HSIL)

A Prospective, Open-label, Randomized, Controlled, Non-inferiority Phase II Study Comparing HAL-PDT With Deferred Surgery Versus Immediate Surgery in Subjects With High-grade Squamous Intraepithelial Lesions (HSIL)

High-grade squamous intraepithelial lesions (HSIL), encompassing cervical intraepithelial neoplasia grade 2 (CIN2) with p16 positivity and grade 3 (CIN3), are precancerous conditions that require effective intervention. This Phase II study aims to comprehensively evaluate the efficacy, safety, and impact on quality of life of hexaminolevulinate photodynamic therapy (HAL-PDT) with deferred surgery compared to immediate surgical treatment in subjects with HSIL.

This is a prospective, open-label, randomized, controlled, non-inferiority trial. A total of 230 subjects are planned to be enrolled, with 115 subjects allocated to each treatment group (HAL-PDT with Deferred Surgery or Immediate Surgery ).

The primary endpoint is the pathological regression rate at 12 months, defined as histological findings of normal tissue or low-grade squamous intraepithelial lesions (LSIL) via colposcopy-directed biopsy. Key secondary endpoints include Human Papillomavirus (HPV) clearance rates at 6 and 12 months, pathological regression rate at 6 months, quality of life assessed by the EORTC QLQ-CX24 questionnaire, safety profiles (incidence, severity, and duration of AEs and SAEs, as well as their relationship to the study treatments), and the proportion of subjects developing cervical cancer within 12 months.

High-grade squamous intraepithelial lesions (HSIL), encompassing cervical intraepithelial neoplasia grade 2 (CIN2) with p16 positivity and grade 3 (CIN3), are well-established precursors to invasive cervical cancer. Immediate excisional procedures such as loop electrosurgical excision procedure (LEEP) or cold knife conization remain the standard of care; however, they are associated with significant long-term morbidities, including cervical stenosis, cervical incompetence, and adverse obstetric outcomes in women of childbearing age. Hexaminolevulinate photodynamic therapy (HAL-PDT) is a non-invasive, tissue-preserving modality that offers a potential alternative.

This Phase II trial is designed to test the hypothesis that HAL-PDT (HAL-PDT Q2W×6 ) with deferred surgery achieves a 12-month pathological regression rate non-inferior to that of immediate surgery, while providing a favorable safety and quality-of-life profile.

A total of 230 subjects are planned for enrollment, with 115 allocated to each treatment arm. The primary efficacy analysis will be performed on both the Intention-to-Treat (ITT) and Per-Protocol (PP) populations to test the non-inferiority margin, which is pre-specified based on clinically acceptable thresholds. Safety analyses will be conducted on the Safety Set (SS).

Inclusion Criteria:

• Voluntarily participate in this clinical study, fully understand the study content, procedures, and potential adverse reactions, and be able to sign the written informed consent form.
• Able to complete the study in accordance with the study protocol.
• Subject age ≥18 years.
• Presence of High-Grade Squamous Intraepithelial Lesion (HSIL) (CIN2 P16 positive/CIN3), specifically: HSIL with histopathological diagnosis of grade II/III (CIN2 P16 positive/CIN3) within 3 months prior to the first treatment.
• Adequate colposcopy, including: (a) Complete visibility of the cervical transformation zone, including the squamocolumnar junction; (b) Complete visibility of lesion margins.
• The investigator determines that non-surgical treatment is acceptable for the participant.
• The investigator determines that the cervical size is suitable for placement of the HAL-PDT device.
• Meets the following conditions: Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result prior to the start of treatment. No plan for pregnancy during the study period; no sexual activity or use of effective and reliable contraception from the end of the last menstrual period to the start of the study, and agreement to use condoms for barrier contraception during the study period. WOCBP is defined as a female who has experienced menarche, has not undergone hysterectomy or bilateral oophorectomy, and has not reached natural menopause (i.e., no menstruation at all for the past 24 consecutive months).

Exclusion Criteria:

• Cervical adenocarcinoma in situ or other glandular lesions, invasive cervical cancer, or suspected malignant lesions.
• CIN2 with P16 negative.
• Lesions extending to the vaginal wall, cervical canal, or vaginal fornix, or lesions located on the vulva.
• Prior physical or surgical treatment to the cervix resulting in incomplete cervical structure (e.g., cold knife conization), or receipt of physical or surgical therapy for CIN2 or CIN3 after the current histopathological diagnosis.
• The first study treatment day falls within 7 half-lives of the last antiviral medication.
• Severe pelvic inflammatory disease, severe cervicitis, or other severe gynecological infectious diseases found on colposcopic or clinical examination.
• Investigator judges that vaginal bleeding during treatment may affect treatment outcomes.
• Receipt of any inactivated vaccine within 2 weeks prior to the first treatment, or any live vaccine within 4 weeks prior to the first treatment.
• Previous severe cardiovascular, cerebrovascular, neurological, psychiatric, endocrine, or hematopoietic disease that has not been cured; known severely compromised immune function, or need for long-term use of corticosteroids or immunosuppressants; history of malignancy within 5 years.
• History of clinically significant immunosuppression or confirmed autoimmune disease; or primary immunodeficiency.
• Known or newly identified active sexually transmitted diseases (STDs), including but not limited to HIV, syphilis, genital herpes, unless adequately treated and tested negative before study treatment.
• Presence of a cardiac pacemaker.
• Suspected or known porphyria, or known allergy to the study drug, its chemically similar compounds, or photosensitizers.
• Allergy to silicone.
• Pregnant or breastfeeding women.
• Delivery or miscarriage within 6 weeks prior to enrollment.
• Participation in any other clinical trial within 30 days prior to study treatment.
• Poor compliance or judged by the investigator to be unsuitable for participation in this clinical study.