Surufatinib in Combination With Neoadjuvant Chemo-immunotherapy and Concurrent Chemoradiotherapy for Patients With Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma

Official title

A Prospective, Single-arm, Phase II Clinical Trial of Surufatinib in Combination With Neoadjuvant Chemo-immunotherapy and Concurrent Chemoradiotherapy for Patients With Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma

Overview

The combination of surufatinib with neoadjuvant chemo-immunotherapy and definitive concurrent chemoradiotherapy represents a promising new therapeutic strategy that may further improve the prognosis of patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC). Therefore, we propose to conduct a prospective, single-arm, phase II clinical trial to evaluate the efficacy and safety of this regimen in patients with unresectable, locally advanced ESCC.

Detailed description

This is a prospective, single-arm, phase II clinical trial designed to evaluate the efficacy and safety of surufatinib in combination with neoadjuvant chemo-immunotherapy and concurrent chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma. Patients will first receive two cycles of neoadjuvant therapy consisting of albumin-bound paclitaxel, cisplatin, toripalimab, and surufatinib. This will be followed by definitive concurrent chemoradiotherapy.

Interventions

• Drug Neoadjuvant immunochemotherapy
  Albumin-bound paclitaxel 260 mg/m² on day 1, cisplatin 25 mg/m² on days 1-3, and toripalimab 240 mg on day 1 of each 3-week cycle (q3w), for a total of 2 cycles.
• Drug Surufatinib Administration
  Surufatinib 200 mg orally once daily (po, qd) on days 1-14, administered concurrently with immunochemotherapy. During radiotherapy, surufatinib will be administered at the start of each radiotherapy phase.
• Drug Concurrent Chemotherapy
  Toripalimab 240 mg on day 1 of each 3-week cycle (q3w), starting one day prior to the initiation of radiotherapy. Weekly administration of albumin-bound paclitaxel 50 mg/m² and cisplatin 25 mg/m² on day 1 during the radiotherapy course.
• Radiation Radiotherapy
  All patients will undergo thoracic intensity-modulated radiotherapy (IMRT), delivered once daily, 5 days per week, at a total prescribed dose of 50 Gy.

Primary outcome measures

• 2-year progression-free survival rate [Time frame: 2 years]

Secondary outcome measures (7)

• Median overall survival (OS) [Time frame: 2 years]
• Objective Response Rate (ORR) [Time frame: 2 months after CCRT]
• Locoregional Progression-Free Survival (LRPFS) [Time frame: 2 years]
• Distant Metastasis-Free Survival (DMFS) [Time frame: 2 years]
• Treatment-related adverse events [Time frame: 1 year after treatment]
• Patient-reported quality of life [Time frame: 1 year after treatment]
• Patient-reported esophageal-specific symptoms [Time frame: 1 year after treatment]

Eligibility criteria

Inclusion criteria

• Histologically or cytologically confirmed diagnosis of esophageal squamous cell carcinoma (ESCC).
• Locally advanced, unresectable esophageal cancer assessed by endoscopic ultrasound and imaging studies, including esophagography, contrast-enhanced CT scans of the lower neck, chest, and upper abdomen, MRI of the lower neck and chest, whole-body bone scintigraphy, or PET/CT; staged as T2-4, N0-3, M0-1 (M1 limited to supraclavicular lymph node metastasis).
• Male or female patients aged 18 to 80 years.
• No prior chemotherapy, radiotherapy, surgery, targeted therapy, or immunotherapy.
• Expected life expectancy of at least 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate organ and bone marrow function defined as: Forced expiratory volume in one second (FEV1) ≥ 1000 mL; Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count ≥ 100 × 10⁹/L; Hemoglobin ≥ 90 g/L; Creatinine clearance ≥ 50 mL/min calculated by the Cockcroft-Gault formula (Cockcroft and Gault, 1976); Total bilirubin ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
• Signed and dated informed consent form must be obtained prior to any study-related procedures.

Exclusion criteria

• Participation in another clinical trial simultaneously, except for observational (non-interventional) studies.
• Prior use of any targeted therapy.
• Major surgery within 4 weeks prior to study entry (excluding vascular access procedures).
• Uncontrolled comorbidities, including but not limited to active or ongoing infections, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, arrhythmias, active peptic ulcer disease or gastritis, intestinal perforation, bowel obstruction, active bleeding disorders, or psychiatric/social conditions that may impair compliance with study requirements or the ability to provide informed consent.
• Performance status (PS) score of 2-4.
• Presence of any of the following organ or bone marrow dysfunctions: Forced expiratory volume in one second (FEV1) < 1000 mL; Absolute neutrophil count (ANC) < 1.5 × 10⁹/L; Platelet count < 100 × 10⁹/L; Hemoglobin < 90 g/L; Creatinine clearance < 50 mL/min calculated by the Cockcroft-Gault formula (Cockcroft and Gault, 1976); Total bilirubin > 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 × ULN.
• Any condition that may interfere with the assessment of efficacy or safety of surufatinib.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun yat-sen University Cancer Center — Guangzhou

Publications

• Zhang P, Chen Z, Shi S, Li Z, Ye F, Song L, Zhang Y, Yin F, Zhang X, Xu J, Cheng Y, Su W, Shi M, Fan S, Tan P, Zhong C, Lu M, Shen L. Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer. Cancer Immunol Immunother. 2024 May 7;73(7):119 PMID 38713205
• Xu J, Shen L, Zhou Z, Li J, Bai C, Chi Y, Li Z, Xu N, Li E, Liu T, Bai Y, Yuan Y, Li X, Wang X, Chen J, Ying J, Yu X, Qin S, Yuan X, Zhang T, Deng Y, Xiu D, Cheng Y, Tao M, Jia R, Wang W, Li J, Fan S, Peng M, Su W. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Nov;21(11):1500-1512. doi: 1 PMID 32966811
• Xu J, Shen L, Bai C, Wang W, Li J, Yu X, Li Z, Li E, Yuan X, Chi Y, Yin Y, Lou W, Xu N, Bai Y, Zhang T, Xiu D, Wang X, Yuan Y, Chen J, Qin S, Jia R, Lu M, Cheng Y, Zhou Z, Li J, He J, Su W. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Nov;21(11):1489-1499. doi: 10.1016/S1470-2045(20)30493-9. E PMID 32966810
• Syed YY. Surufatinib: First Approval. Drugs. 2021 Apr;81(6):727-732. doi: 10.1007/s40265-021-01489-y. PMID 33788183
• Wang J, Yu JP, Wang JL, Ni XC, Sun ZQ, Sun W, Nie B, Jiang JT, Sun SP, Wu CP. [Pathologic response and changes of serum VEGF during chemoradiotherapy may predict prognosis in non-surgical patients with esophageal carcinoma]. Zhonghua Zhong Liu Za Zhi. 2016 Aug;38(8):589-95. doi: 10.3760/cma.j.issn.0253-3766.2016.08.005. Chinese. PMID 27531478
• Zhu Y, Wen J, Li Q, Chen B, Zhao L, Liu S, Yang Y, Wang S, Lv Y, Li J, Zhang L, Hu Y, Liu M, Xi M. Toripalimab combined with definitive chemoradiotherapy in locally advanced oesophageal squamous cell carcinoma (EC-CRT-001): a single-arm, phase 2 trial. Lancet Oncol. 2023 Apr;24(4):371-382. doi: 10.1016/S1470-2045(23)00060-8. PMID 36990609
• Shinoda M, Ando N, Kato K, Ishikura S, Kato H, Tsubosa Y, Minashi K, Okabe H, Kimura Y, Kawano T, Kosugi S, Toh Y, Nakamura K, Fukuda H; Japan Clinical Oncology Group. Randomized study of low-dose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303). Cancer Sci. 2015 Apr;106(4):407-12. doi: 10.1111/cas.12622. Epub 2015 Mar 9. PMID 25640628
• Suntharalingam M, Winter K, Ilson D, Dicker AP, Kachnic L, Konski A, Chakravarthy AB, Anker CJ, Thakrar H, Horiba N, Dubey A, Greenberger JS, Raben A, Giguere J, Roof K, Videtic G, Pollock J, Safran H, Crane CH. Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial. JAMA PMID 28687830

Identifiers

NCT: NCT07086469 · GASTO-10132

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗