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

Phase 2Not Yet RecruitingNCT07800000

Wang Xin34 enrolled

Overview

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.

Interventions

Induction therapyDRUG

Patients receive becotatug vedotin (2.0 mg/kg intravenously on Day 1) plus pucotenlimab (200 mg intravenously on Day 1) and capecitabine (1000 mg/m² orally twice daily) every 3 weeks for 2 consecutive cycles.

Concurrent chemoradiotherapy-immunotherapyRADIATION

Following induction therapy, patients without disease progression receive capecitabine (825 mg/m² orally twice daily) combined with pucotenlimab (200 mg intravenously on Day 1) and mitomycin-C (10 mg/m² intravenously on Day 1 and Day 28), administered in parallel with definitive pelvic radiotherapy. Radiotherapy doses were prescribed following NCCN, ESTRO and EORTC guideline recommendations.

Maintenance therapyDRUG

After completion of concurrent chemoradiotherapy-immunotherapy, patients receive pucotenlimab (200 mg intravenously) every 3 weeks for up to 1 year as maintenance treatment.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

The Complete response (CR) rate at 40 weeks

The CR rate at 40 weeks is defined as the number of patients who have no residual or metabolically active local tumour identified by digital rectal examination, colonoscopy with pathological assessment, and MRI, plus no distant metastasis confirmed by thoracic-abdominal CT at 40 weeks, divided by the total number of patients evaluable for CR status at 40 weeks.

Time frame: 40 weeks after treatment

Safety

Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v) 5.0, vital signs, and clinical laboratory test results in the Safety Analysis Set

Time frame: Up to 18 months

Secondary Outcomes

Objective Response Rate (ORR)

The ORR is defined as the proportion of subjects achieving a complete response or partial response after completion of 2 cycles of induction therapy and prior to the initiation of concurrent chemoradiotherapy-immunotherapy.

Time frame: At the end of Cycle 2 (each cycle is 21 days)

Disease Control Rate (DCR)

The DCR is defined as the proportion of subjects achieving a complete response, partial response, or stable disease upon completion of induction therapy.

Time frame: At the end of Cycle 2 (each cycle is 21 days)

Event-free survival (EFS)

The EFS is defined as the time from the first study-drug administration to the earliest occurrence of disease progression, recurrence, initiation of new therapy, or death.

Time frame: From the first study-drug administration up to 3 years after the end of treatment.

Overall Survival（OS）

The OS is defined as the time from the first study-drug administration to death from any cause.