Becotatug Vedotin Plus Tislelizumab and Low-Dose Lenvatinib for Advanced Esophageal Squamous Cell Carcinoma, Phase II

Becotatug Vedotin Combined With Tislelizumab and Low-Dose Lenvatinib in Patients With Advanced Esophageal Squamous Cell Carcinoma Who Failed First-Line Therapy: A Phase II Exploratory Study

Immunotherapy combined with chemotherapy has become the first-line standard of care for advanced esophageal squamous cell carcinoma (ESCC), significantly improving patient survival. However, with the widespread adoption of first-line immunotherapy, most patients eventually develop immune resistance. After first-line treatment failure, there is currently no established standard effective therapy for second-line ESCC. Therefore, more effective and safer treatment options are urgently needed for second-line advanced ESCC.

This is a prospective, single-arm, single-center, open-label, Phase II clinical study aiming to evaluate the efficacy and safety of Becotatug Vedotin combined with Tislelizumab and low-dose Lenvatinib in patients with advanced ESCC who have failed first-line therapy. Eligible patients will receive Becotatug Vedotin combined with Tislelizumab and low-dose Lenvatinib. The primary endpoint is objective response rate (ORR) assessed per RECIST v1.1. Secondary endpoints include progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety.

Study Overview

• Status: Not yet recruiting
• Conditions: Esophageal Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Becotatug Vedotin; Drug: Tislelizumab; Drug: Lenvatinib

Detailed Description

The study consists of two phases: a dose-run-in phase and a dose-expansion phase.

Phase 1 (Dose-Run-In Phase): After signing informed consent, 6 eligible patients will receive Becotatug Vedotin combined with Tislelizumab and low-dose Lenvatinib during the safety run-in period to evaluate the safety and tolerability of the regimen: Becotatug Vedotin (2.0mg/kg, iv, d1, q3w, for 4-6 cycles) combined with Tislelizumab (200mg, iv, d1, q3w) and low-dose Lenvatinib (4 mg, po，once daily at a fixed time). If no more than 1 patient among the 6 treated patients experiences a dose-limiting toxicity (DLT) and no unexpected unacceptable serious adverse events occur, the study will proceed to Phase 2.

Phase 2 (Dose-Expansion Phase): Eligible patients will receive the same combination regimen of Becotatug Vedotin, Tislelizumab, and low-dose Lenvatinib as in Phase 1. Treatment will continue until disease progression, unacceptable toxicity, withdrawal of informed consent, death, pregnancy, investigator's decision to discontinue treatment, or study termination, whichever occurs first.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rui Li; Phone Number: +86 13602139003; Email: liurui9003@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1.Age ≥ 18 years, male or female. 2.Histopathologically or cytologically confirmed recurrent or metastatic esophageal squamous cell carcinoma.

3.Failed first-line or above standard systemic therapy for advanced disease. 4.Patients must be able to provide tumor specimens (paraffin blocks, paraffin-embedded sections, or fresh tissue sections) from primary or metastatic lesions for pathological testing. The most recent archived tumor tissue specimen may be used. If archived tissue is unavailable, a new biopsy is required.

5.ECOG PS 0-2. 6.Expected survival ≥ 3 months. 7.At least one measurable target lesion assessable by CT or MRI according to RECIST version 1.1 criteria.

8.Adequate organ and bone marrow function, as demonstrated by the following laboratory values:

1. Bone marrow: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L；Platelet count (PLT) ≥ 100×10⁹/L；Hemoglobin (HGB)≥90 g/L.
2. Liver: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×ULN; for patients with liver metastases, ALT and AST≤5×ULN.
3. Kidney: Creatinine clearance (Ccr) ≥ 50 mL/min (calculated using the Cockcroft-Gault formula).
4. Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (except for patients receiving therapeutic anticoagulation).
5. Cardiac function: No severe cardiac dysfunction, with left ventricular ejection fraction (LVEF) ≥ 50%.

9.Female patients of childbearing potential must agree to use contraception during the study and for 6 months after the end of study participation, have a negative serum or urine pregnancy test within 7 days prior to study enrollment, and must not be breastfeeding. Male patients must agree to use contraception during the study and for 6 months after the end of study participation.

10.Patients must be able and willing to comply with the scheduled visits, treatment plans, laboratory tests, and other study-related procedures as outlined in the protocol.

11.Patients must be able to understand the study and voluntarily sign the informed consent form.

Exclusion Criteria:

1. Prior malignancy within 5 years, except for carcinoma in situ, basal cell carcinoma, or other malignancies considered cured with negligible risk of recurrence.
2. Known hypersensitivity to any component of the study regimen.
3. High risk of gastrointestinal bleeding, esophageal fistula, or esophageal perforation.
4. Untreated or unstable parenchymal brain metastases, spinal cord metastasis or compression, leptomeningeal disease, or meningeal metastases.
5. Evidence of active infection, including:1）Hepatitis B (HBsAg positive with HBV DNA ≥ 2000 IU/mL, excluding drug-induced or other causes of hepatitis);2）Hepatitis C (anti-HCV antibody positive with HCV RNA above the lower limit of detection);3）Human immunodeficiency virus (HIV) infection;4）Uncontrolled active bacterial, viral, fungal, rickettsial, or parasitic infections that have not resolved prior to study drug administration.
6. Third-space fluid that cannot be controlled by drainage (e.g., massive ascites, pleural effusion, pericardial effusion), or subjects requiring drainage to control third-space fluid within 14 days prior to first dose.
7. Any severe or uncontrolled systemic disease in the investigator's judgment.
8. Poorly controlled cardiac disease, including:

1）Heart failure > New York Heart Association (NYHA) class II; 2）Unstable angina pectoris; 3）Myocardial infarction within 1 year; 4）Clinically significant supraventricular or ventricular arrhythmias requiring treatment; 5）Long QT syndrome, with QTcF > 450 ms (male) or QTcF > 470 ms (female). 9.History of primary immunodeficiency or active autoimmune disease, or current use of immunosuppressants or systemic corticosteroids (≥ 10 mg/day prednisone or equivalent) continuing within 2 weeks prior to enrollment.

10.History of or concomitant interstitial lung disease (ILD), radiation pneumonitis, severe chronic obstructive pulmonary disease (COPD), severe pulmonary insufficiency, or symptomatic bronchospasm.

11.Positive serum pregnancy test or breastfeeding females who do not agree to use adequate contraception during the study and for 6 months after the last dose of study drug.

12.History of organ transplantation, including allogeneic peripheral stem cell or bone marrow transplantation.

13.Peripheral neuropathy ≥ Grade 2 (per CTCAE version 5.0). 14.Prior receipt of any of the following treatments:

1. Intravenous antibiotic therapy within 7 days prior to first dose.
2. Investigational drug from another clinical trial within 4 weeks prior to first dose.
3. Live attenuated vaccine within 4 weeks prior to first dose. Inactivated seasonal influenza vaccines or approved non-replicating COVID-19 vaccines are permitted.
4. Systemic immunostimulatory agents (including but not limited to interferon, interleukin-2, etc.) within 4 weeks prior to first dose.

5. Major surgical procedure (e.g., abdominal or thoracic surgery, excluding diagnostic puncture, infusion device placement, or gastrointestinal stent placement) within 4 weeks prior to first dose, or anticipation of major surgery not directed at the tumor during the study treatment period.

   15.History of substance abuse (psychoactive drugs) that cannot be abstained from, or psychiatric disorders.

   16.Concurrent participation in another interventional clinical study. 17.Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation in this clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Becotatug Vedotin Combined with Tislelizumab and Low-Dose Lenvatinib; Participants in this single arm receive Becotatug Vedotin (2.0mg/kg, iv, D1, Q3W, 4 to 6 cycles) in combination with Tislelizumab (200 mg, iv, D1 Q3W, continued for up to 35 cycles [approximately 2 years]) and Low-Dose Lenvatinib (4 mg, orally, once daily at a fixed time. Treatment continues until disease progression, unacceptable toxicity, withdrawal of informed consent, death, pregnancy, investigator decision to discontinue, or study termination, whichever occurs first. ).The study consists of a safety run-in phase (approximately 6 participants) followed by an expansion phase (to a total of approximately 36 participants) .

Drug: Becotatug Vedotin; Becotatug Vedotin 2.0 mg/kg administered as an intravenous infusion on Day 1 of each 21-day cycle for 4 to 6 cycles.; Drug: Tislelizumab; Tislelizumab 200 mg administered as an intravenous infusion on Day 1 of each 21-day cycle, continued for up to 35 cycles (approximately 2 years), or until disease progression, unacceptable toxicity, withdrawal of informed consent, death, pregnancy, investigator decision to discontinue, or study termination, whichever occurs first.; Drug: Lenvatinib; Low-Dose Lenvatinib 4 mg administered orally at a fixed time once daily, continued until disease progression, unacceptable toxicity, withdrawal of informed consent, death, pregnancy, investigator decision to discontinue, or study termination, whichever occurs first.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Objective response rate is defined as the proportion of patients who achieve complete response (CR) or partial response (PR) as assessed by the investigator per RECIST version 1.1.	From start of treatment until disease progression, assessed up to 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-free survival is defined as the time from the first dose of study treatment to the first documented disease progression per RECIST version 1.1 or death from any cause, whichever occurs first.	From start of treatment to disease progression or death, assessed up to 36 months.
Overall Survival (OS)	Overall survival is defined as the time from the first dose of study treatment to death from any cause.	From start of treatment to death, assessed up to 36 months.
Disease Control Rate (DCR)	Disease control rate is defined as the proportion of patients who achieve complete response (CR), partial response (PR), or stable disease (SD) as assessed by the investigator per RECIST version 1.1.	From start of treatment until disease progression, assessed up to 24 months.
Duration of Response (DOR)	Duration of response is defined as the time from the first documented objective response (CR or PR) to the first documented disease progression per RECIST version 1.1 or death from any cause, whichever occurs first.	From first documented response to disease progression or death, assessed up to 24 months.
Safety and Tolerability	Safety and tolerability will be assessed by the incidence, nature, and severity of adverse events (AEs) and serious adverse events (SAEs) according to NCI CTCAE version 5.0.	From first dose of study drug until 30 days after the last dose, assessed up to 24 months.

Collaborators and Investigators

• Sponsor: Tianjin Medical University Cancer Institute and Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: June 30, 2026
• First Submitted That Met QC Criteria: June 30, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: June 30, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; lenvatinib; tislelizumab
• Other Study ID Numbers: ESCC-BecoTisLen-E20260709

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No