A Phase Ib/II Trial of Neoadjuvant Tiragolumab, Atezolizumab, Paclitaxel, Cisplatin and Radiotherapy Followed by Surgery for Locally Advanced Esophageal Squamous Cell Carcinoma
The prognosis of ESCC is poor with a five-year overall survival rate of 10 to 30 %. Randomized clinical trials have demonstrated that TMT, consisted of neoadjuvant concurrent CCRT and radical esophagectomy, improves the overall survival for patients with resectable locally advanced disease. As a consequence, it is mandatory to develop new pharmacotherapeutic regimen for TMT. In our previous prospective studies, we found higher levels of serum immune-related biomarkers, VEGF-A, TGF-β1, and soluble PD-L1, before neoadjuvant CCRT were independent associated with inferior overall survival and disease-free survival for locally advanced ESCC treated with neoadjuvant CCRT plus radical esophagectomy. In the present clinical trial, we plan to investigate whether incorporation of tiragolumab (Anti-TIGIT) and atezolizumab (Anti-PD-L1) into standard TMT will be safe while improve the pathological complete response rate. By the present research, we expect to develop a new TMT regimen for this poor prognostic disease.
• Histologically proved squamous cell carcinoma of esophagus
• Locally advanced disease, which are defined by TNM system of American Joint Committee on Cancer (AJCC) Cancer Staging System (8th edition) in 2017, fulfilling one of the following criteria:
∙ T1-2N2-3M0
• Tumor judged to be operable and resectable with curative intent on the screening assessment
• Age ≥ 20 years
• Medical fit for curative surgery
• ECOG Performance Status 0 or 1
• Adequate bone marrow reserves within 2 weeks prior to registration, defined as:
∙ absolute neutrophil count (ANC) ≥ 1.5×109/L (1,500/μl)
‣ platelets ≥ 100×109/L (100,000/µl)
‣ hemoglobin ≥ 9.0 g/dl (may have been transfused)
• Adequate liver function reserves within 2 weeks prior to registration, defined as:
∙ hepatic transaminases (AST and ALT) ≤ 2.5 × upper limit of normal (ULN)
‣ serum total bilirubin ≤ 1.5 × upper limit of normal (ULN)
• Adequate renal function within 2 weeks prior to registration: Creatinine ≤1.5 mg/dL
⁃ Negative hepatitis B surface antigen (HBsAg) at screening or Positive HBsAg with HBV DNA \< 500 IU/mL (or 2500 copies/mL) at screening. Patients with detectable HBsAg or detectable HBV DNA should be managed institutional guidelines.
⁃ a. Patients receiving anti-viral medication must have initiated treatment at least 2 weeks prior to protocol treatment and should continue treatment for at least 6 months after the final dose of study treatment
⁃ Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
⁃ Negative serum or urine pregnancy test for women of childbearing potential
⁃ Women of childbearing potential and male participants must practice highly effective contraception with a failure rate of \< 1% per year during the treatment period and for 5 months after the final dose of atezolizumab and for 90 days after the final dose of tiragolumab
⁃ Patients must be able to comply with the study protocol and follow-up schedules and provide study-specific informed consent