Induction Chemotherapy Plus Cadonilimab for Locally Advanced Cervical Cancer

Induction Chemotherapy Plus Cadonilimab Followed by Chemoradiotherapy for Locally Advanced Cervical Cancer: A Multicenter, Open-label, Single-arm, Phase II Trial

This is an investigator-initiated, single-arm, phase II clinical study evaluating the efficacy and safety of cadonilimab combined with induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced cervical cancer (LACC). Despite standard concurrent chemoradiotherapy, patients with LACC remain at high risk of recurrence and distant metastasis. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, has demonstrated promising antitumor activity in cervical cancer. This study aims to investigate whether induction immunochemotherapy with cadonilimab combined with cisplatin and albumin-bound paclitaxel can improve tumor response before definitive radiotherapy. In addition, the study will explore the association between treatment efficacy and dynamic changes in PD-L1 expression, peripheral blood immune-related biomarkers, and tumor microenvironment immune cell populations during treatment. The primary endpoint is objective response rate (ORR) assessed according to RECIST version 1.1, while secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

This is an investigator-initiated, single-arm, phase II clinical study designed to evaluate the efficacy, safety, and tolerability of cadonilimab combined with induction chemotherapy in patients with locally advanced cervical cancer (LACC). The study also aims to explore the association between treatment efficacy and dynamic changes in PD-L1 expression, peripheral blood immune-related biomarkers, and tumor microenvironmental immune cell populations during treatment. A Simon two-stage design is adopted in this study. In the first stage, 9 patients will be enrolled. If 7 or fewer patients achieve an objective response, the study will be terminated for futility. Otherwise, the study will proceed to the second stage, with continued enrollment up to a total sample size of 29 patients. Patients will receive induction immunochemotherapy consisting of cadonilimab combined with cisplatin and albumin-bound paclitaxel for 2 cycles, followed by concurrent chemoradiotherapy (CCRT). During CCRT, cisplatin will be administered weekly at a dose of 30-40 mg/m² for 5 cycles. External beam radiotherapy (EBRT) will be delivered using 6-MV X-rays at a total dose of 45-60 Gy in 25 fractions, followed by brachytherapy with a prescribed dose of 30 Gy in 5 fractions. The primary endpoint is objective response rate (ORR) assessed according to RECIST version 1.1. Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and treatment tolerability.

Inclusion Criteria:

1. Patients with good compliance.
2. Age ≥ 18 years (calculated on the day of signing the informed consent).
3. Histologically or pathologically diagnosed with cervical cancer (squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma) and measurable lesions.
4. Initial diagnosis of stage IB3-IVA (according to FIGO 2018 staging).
5. ECOG performance score of 0-2.
6. Main organ functions meet the protocol criteria within 7 days before treatment.

Exclusion Criteria:

1. Patients with other histological types of cervical cancer, such as neuroendocrine carcinoma or sarcoma.
2. Evidence of distant metastasis, including groin lymph node metastasis and lymph node metastasis above the L1 level.
3. Previously underwent total hysterectomy (removal of the uterus body + cervix). History of subtotal hysterectomy or cervical wedge resection that preserves the cervix is allowed.
4. With anatomical abnormalities or tumor geometry-related contraindications that prevent the use of brachytherapy.
5. Within 2 years, had other active malignant tumors, except for locally curable tumors that have been cured, such as squamous cell carcinoma of the skin, basal cell carcinoma of the skin, superficial bladder cancer, and ductal carcinoma in situ of the breast.
6. With clinically significant bilateral hydronephrosis that, in the investigator's judgment, cannot be relieved by nephrostomy or ureteral stent placement.
7. Previously received immune checkpoint inhibitors (e.g., anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies) or any treatment targeting tumor immune mechanisms involving immune co-stimulatory factors (e.g., antibodies targeting ICOS, CD40, CD137, GITR, OX40).
8. Within 2 weeks, requires the use of glucocorticoids (> 10 mg/day prednisone or equivalent dose of glucocorticoids) or other immunosuppressive drugs for systemic treatment exceptions include: a) Allowed treatment with inhaled, ophthalmic, or local doses ≤ 10 mg/day prednisone or equivalent dose of glucocorticoids. b) Physiological glucocorticoid replacement therapy at a dose ≤ 10 mg/day prednisone or equivalent dose of glucocorticoids. c) Glucocorticoids used for prophylaxis against hypersensitivity reactions (e.g., premedication for CT scans).
9. Within 2 weeks, received drugs with immunomodulatory effects (e.g., thymosin, interferon, interleukin-2).
10. Presence of active systemic infections requiring systemic treatment (including active pulmonary tuberculosis, active syphilis caused by Treponema pallidum, and fungal infections requiring systemic treatment) note: exclusion does not apply to antiviral drugs used for hepatitis B virus infection.
11. Within 4 weeks, experienced severe infections, including but not limited to complications requiring hospitalization, sepsis, or severe pneumonia.
12. Within 4 weeks, underwent major surgical treatment (as determined by the investigator), open biopsy, or significant trauma or requires scheduled major surgical treatment during the study. Diagnostic systematic pelvic/aortic lymphadenectomy is allowed.
13. Received live vaccines within 4 weeks .
14. With active or history of documented autoimmune diseases exceptions include: vitiligo, alopecia, psoriasis, or eczema that do not require systemic treatment hypothyroidism caused by autoimmune thyroiditis requiring stable dose of hormone replacement therapy type 1 diabetes requiring stable dose of insulin replacement therapy.
15. Any of the following cardiovascular diseases: a) New York Heart Association (NYHA) functional classification ≥ II for heart failure. b) Presence of severe arrhythmias requiring long-term drug intervention asymptomatic patients with stable ventricular rate in atrial fibrillation are allowed to enroll. c) Occurrence of cerebrovascular events (CVA) within 6 months . d) Left ventricular ejection fraction (LVEF) < 50%.
16. Known primary or secondary immunodeficiency, including positive human immunodeficiency virus (HIV) antibody test.
17. Subjects with active hepatitis B virus (HBV) infection, non-active or asymptomatic carriers of hepatitis B surface antigen (HBsAg) with HBV DNA > 1000 IU/mL, and subjects with active hepatitis C virus (HCV) infection. Note: Non-active or asymptomatic carriers with treated and stable hepatitis B infection with HBV DNA ≤ 1000 IU/mL are allowed to enroll. Subjects with cured hepatitis C infection, positive HCV antibody (HCVAb), and negative HCV RNA are allowed to enroll.
18. With active or documented history of inflammatory bowel disease (such as Crohn's disease, ulcerative colitis) or active diverticulitis.
19. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
20. Known history of severe hypersensitivity reactions to other monoclonal antibodies.
21. Pregnant or breastfeeding women.
22. The investigator believes that there may be risks associated With receiving the investigational drug or any condition that may interfere With the evaluation of the investigational drug, subject safety, or interpretation of study results (such as having other severe diseases or mental disorders).