Becotatug Vedotin Plus Pucotenlimab and Capecitabine Followed by Concurrent Chemoradiotherapy-Immunotherapy for Locally Advanced Squamous Cell Carcinoma of the Anal Canal

An Open-Label, Single-Arm, Phase Ⅱ Exploratory Clinical Study of Becotatug Vedotin Combined With Pucotenlimab and Capecitabine Followed by Concurrent Chemoradiotherapy Plus Immunotherapy for Locally Advanced Squamous Cell Carcinoma of the Anal Canal

This is a single-arm, exploratory clinical study intended to enroll patients with EGFR-positive Locally Advanced Squamous Cell Carcinoma of the Anal Canal (T2-4N0-1M0). Patients will first receive 2 cycles of induction therapy consisting of Becotatug Vedotin combined with Pucotenlimab and Capecitabine. Patients without disease progression upon radiological assessment will subsequently proceed to the concurrent chemoradiotherapy-immunotherapy phase, which comprises Capecitabine plus Pucotenlimab and mitomycin-C together with definitive concurrent radiotherapy. In the subsequent maintenance phase, patients will receive Pucotenlimab for a total duration of 1 year. The study aims to evaluate the efficacy and safety of Becotatug Vedotin combined with Pucotenlimab and Capecitabine, as well as the potential of this novel full-course treatment paradigm.

This is a single-arm, exploratory clinical study intended to enroll patients with EGFR-positive Locally Advanced Squamous Cell Carcinoma of the Anal Canal (T2-4N0-1M0). The study consists of two phases: a safety lead-in phase and an expansion phase. Six patients will be enrolled first with close monitoring for dose-limiting toxicities (DLTs). Further enrollment into the expansion phase will proceed only after safety is confirmed. The therapeutic regimen remains identical across both phases. The trial will be terminated if any DLT occurs during the safety lead-in phase. The observation period for the safety lead-in phase ends upon completion of 2 cycles of induction therapy.

After subjects provide written informed consent, eligible patients who meet the inclusion criteria following screening will receive induction therapy: Becotatug Bedotin (2.0 mg/kg intravenously on Day 1) combined with Pucotenlimab (200 mg intravenously on Day 1) and Capecitabine (1000 mg/m² orally twice daily). Treatment is administered every 3 weeks for a total of 2 cycles. All patients will undergo radiological assessment after completion of cycle 2 induction therapy. Patients without disease progression will subsequently enter the concurrent chemoradiotherapy-immunotherapy phase, receiving Capecitabine (825 mg/m² orally twice daily), Pucotenlimab (200 mg intravenously on Day 1), and mitomycin-C (10 mg/m² intravenously on Day 1 and Day 28), administered concurrently with definitive radiotherapy. In the maintenance phase, patients receive Pucotenlimab (200 mg) for a total duration of 1 year.

The primary endpoints of this study are the 40-week complete response (CR) rate and safety. Secondary endpoints include the objective response rate (ORR) and disease control rate (DCR) of induction therapy, event-free survival (EFS), overall survival (OS). Tumour response assessment will be performed according to RECIST version 1.1.

Inclusion Criteria:

1. Aged between 18 and 75 years, male or female;
2. Voluntarily signed the informed consent form and is willing to comply with protocol-specified requirements;
3. Histologically confirmed locally advanced anal squamous cell carcinoma of cT2-4N0-1M0 stage;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
5. EGFR immunohistochemistry (IHC) score ≥1+ as assessed by pathological laboratory;
6. At least one measurable target lesion according to RECIST version 1.1;
7. Laboratory parameters meeting all of the following criteria:

（1） Bone marrow function: haemoglobin (Hb) ≥90 g/L; white blood cell count (WBC) ≥3.0×10⁹/L; absolute neutrophil count (ANC) ≥1.5×10⁹/L; platelet count ≥100×10⁹/L; （2）Renal function: serum creatinine (Cr) ≤1.5 × upper limit of normal (ULN), and endogenous creatinine clearance (Ccr) ≥55 mL/min; （3）Liver function: total bilirubin ≤1.5 × ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; （4）Coagulation function: international normalized ratio of prothrombin time (PT-INR) ≤1.5 × ULN, and activated partial thromboplastin time (aPTT) within the normal reference range; 8. Left-ventricular ejection fraction (LVEF) ≥50%; 9. Female subjects of child-bearing potential agree to use contraception during the study and for 6 months after study completion; have a negative serum or urine pregnancy test within 7 days prior to enrolment, and are not breastfeeding. Male subjects agree to use contraception during the study and for 6 months after study completion; 10. No participation in other investigational-drug clinical trials within 4 weeks before enrolment; 11. The subject is capable of understanding and willing to adhere to protocol-required visits, treatment, laboratory tests and other study procedures.

Exclusion Criteria:

1. Diagnosis of another malignancy within the past 5 years (excluding concurrent CIN2+ or cervical cancer; in-situ carcinomas and basal-cell carcinomas outside the pelvic region are permitted).
2. Pre-existing peripheral neuropathy ≥ Grade 2 (per CTCAE Version 5.0).
3. Patients planning to undergo or having previously received organ or bone-marrow transplantation.
4. Any major surgery within 4 weeks prior to the first study treatment (diagnostic biopsy excluded).
5. Any anti-tumour therapy administered within 4 weeks prior to the first study treatment, including radiotherapy, chemotherapy, targeted therapy, immunotherapy, biologic therapy, etc.
6. Presence of uncontrolled clinical cardiac signs or diseases.
7. Active infection or fever (excluding confirmed tumour-related fever).
8. History or evidence of interstitial lung disease or active non-infectious pneumonitis.
9. Patients with other medical conditions rendering them ineligible for enrolment, such as immunodeficiency, active pulmonary tuberculosis, hepatitis B (enrolment is allowed if treated HBV-DNA <500 IU/mL with normal liver function; HPV-positive subjects are eligible; subjects with immunodeficiency with undetectable viral load and normal CD4-T-cell count may be enrolled), positive hepatitis-C virus testing, uncorrectable electrolyte disturbances, uncontrolled pericardial effusion, pleural effusion, and ascites.
10. Known hypersensitivity to any study drug specified in this protocol.
11. Pregnant or breastfeeding women.
12. Subjects deemed ineligible for enrolment at the investigator's discretion.