Locally Advanced Cervical Cancer
Conditions
Brief summary
Concurrent chemoradiotherapy (CRT) is the standard of care for locally advanced cervical cancer (LACC). However, a substantial proportion of patients have contraindications to cisplatin based chemotherapy due to advanced age, renal impairment, cardiac dysfunction, or other comorbidities. For these patients, no evidence based standardised treatment exists. Immunotherapy combined with radiotherapy may offer a chemotherapy sparing alternative. Cadonilimab, a PD 1/CTLA 4 bispecific antibody, has demonstrated significant efficacy in advanced cervical cancer. This study aims to evaluate the efficacy and safety of cadonilimab combined with radical radiotherapy in LACC patients ineligible for concurrent chemotherapy. This is an investigator initiated, prospective, single centre, single arm, open label, Simon's two stage phase II trial. A total of 45 patients will be enrolled. Eligible participants are women aged \>18 years with histologically confirmed cervical squamous cell carcinoma or adenosquamous carcinoma, FIGO 2018 stage IB3-IVA, and absolute or relative contraindications to cisplatin based chemotherapy. All patients will receive radical radiotherapy (external beam radiotherapy 45-50.4 Gy/25-28 fractions plus high dose rate brachytherapy 6-8 Gy × 3-5 fractions) concurrently with three cycles of cadonilimab 10 mg/kg intravenously every 3 weeks. The primary endpoint is complete response (CR) rate assessed at 4 weeks post radiotherapy. Secondary endpoints include 2 year progression free survival, 2 year local control, 2 year locoregional control, 5 year overall survival, safety (CTCAE v5.0 and RTOG late toxicity), and quality of life (EORTC QLQ C30 and QLQ BR23). Assuming a historical CR rate of 69% with radiotherapy alone, we hypothesise that the combination will increase CR to 85%. With α=0.05 (two sided) and 80% power, Simon's optimal two stage design requires 43 evaluable patients; after accounting for 5% dropout, 45 patients will be recruited.
Interventions
DRUGCadonilimab
Cadonilimab will be administered as a 30-60 minute intravenous infusion at a dose of 10 mg/kg every 3 weeks for a total of 3 cycles. The first dose is scheduled within 3 days before or after the start of EBRT.
RADIATIONRT
External beam radiotherapy (EBRT): Intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) with daily image guidance. Total dose: 45-50.4 Gy in 25-28 fractions (1.8-2.0 Gy per fraction), 5 fractions per week. Target volumes include the gross tumour volume (cervix), entire uterus, parametria, and pelvic lymph node regions (including common iliac, presacral, and obturator nodes). Paraaortic lymph node regions are included if involved. Brachytherapy (BT): High dose rate (HDR) intracavitary/interstitial brachytherapy starting in the final week(s) of EBRT or immediately after. Dose: 6-8 Gy per fraction, 3-5 fractions, prescribed to the high risk clinical target volume (HR CTV). Total EQD2 (α/β=10) to point A and HR CTV D90 should exceed 80 Gy.
Sponsors
Ruijin Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female, age ≥18 years. 2. Histologically confirmed cervical squamous cell carcinoma or adenosquamous carcinoma. 3. FIGO 2018 stage IB3-IVA, or medically inoperable disease requiring definitive radiotherapy. 4. ECOG performance status 0-2, life expectancy ≥6 months. 5. Presence of at least one absolute or relative contraindication to concurrent cisplatin based chemotherapy, defined as: * Age ≥70 years; OR * Renal impairment: serum creatinine \>1.5 × upper limit of normal (ULN) or calculated creatinine clearance (CrCl) \<50 mL/min (Cockcroft Gault); OR * Cardiac dysfunction: New York Heart Association class ≥II; OR * Prior allergic reaction to platinum agents; OR * Patient refusal of chemotherapy after thorough counselling. 6. Adequate organ function: * Total bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert's syndrome) * AST and ALT ≤2.5 × ULN 7. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Exclusion criteria
1. Prior or concurrent invasive malignancy unless disease free for ≥5 years (exceptions: non melanoma skin cancer, cured in situ carcinoma). 2. No histological confirmation of cervical cancer. 3. Prior exposure to anti PD 1/PD L1, anti CTLA 4, or other immune checkpoint inhibitors. 4. Congenital or acquired immunodeficiency (e.g., HIV infection). 5. Active hepatitis B (HBsAg positive with detectable HBV DNA) or hepatitis C (HCV RNA positive). 6. Pregnancy or lactation (negative serum/urine β hCG required for premenopausal women). 7. Severe uncontrolled comorbidities precluding safe radiotherapy: * Unstable angina, myocardial infarction, or congestive heart failure requiring hospitalisation within 6 months * Acute bacterial or systemic fungal infection * Chronic obstructive pulmonary disease exacerbation requiring hospitalisation * Active connective tissue disease (e.g., systemic lupus erythematosus, scleroderma) 8. Psychiatric illness or social condition that would limit study compliance. 9. Inability to understand the study purpose or refusal to sign informed consent. 10. Any other condition that, in the investigator's judgment, makes the patient unsuitable for study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete response (CR) rate | 5 year | The proportion of patients with disappearance of all target lesions (cervix and lymph nodes), no new lesions, and normalisation of tumour markers (e.g., SCC Ag), confirmed by pelvic MRI and/or PET CT and maintained for at least 4 weeks according to RECIST v1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 2 year progression free survival | 2 year | — |
| 2 year local control rate | 2 year | — |
| 2 year locoregional control rate | 2 year | — |
| 5 year overall survival | 5 year | — |
| Acute adverse events (AEs) | up to 3 months | adverse events (AEs) according to CTCAE v5.0 |
| Late AE | up to 5 years | RTOG/EORTC |
| Quality of life assessed by EORTC QLQ C30 score | up to 5 years | change from baseline in EORTC QLQ C30 score (0-100), higher scores mean a better outcome. |
Outcome results
None listed