Radiotherapy Combined With Immunochemotherapy in Metastatic Esophageal Squamous Cell Carcinoma

Official title

First-line Anti-PD-1 Therapy Plus Chemotherapy With or Without Radiotherapy in Metastatic Esophageal Squamous Cell Carcinoma: A Phase II Multi-center Trial (SCR-ESCC-01)

Overview

SCR-ESCC-01 is a multicenter, randomized, phase II study aiming to investigate the benefit of early involvement of low-dose radiotherapy(LDRT) and conventionally fractionated radiotherapy(CFRT) in the first-line anti-PD-1 based treatment of metastatic ESCC. It begins with a safety run-in phase, followed by a randomized controlled comparison against standard immunochemotherapy.

Detailed description

In metastatic esophageal squamous cell carcinoma (ESCC), radiotherapy is often administered for palliative purposes to alleviate dysphagia. Recent studies suggest that combining radiotherapy with immunotherapy may have a synergistic effect on treatment outcomes. This study aims to investigate the efficacy and safety of adding Low-Dose Radiotherapy (LDRT) combined with Conventionally Fractionated Radiotherapy (CFRT) to first-line immunochemotherapy.

Study Design:The protocol follows a sequential two-phase design:

1. Phase IIa (Safety Run-in / Pilot Phase):An initial cohort of approximately 20-25 patients will receive the experimental regimen (LDRT + CFRT + Immunochemotherapy) in a single-arm setting. The primary objective of this phase is to evaluate safety and feasibility.

Safety Stopping Rule: A strict stopping rule is defined for the transition to the randomized phase. If 2 or more patients in the run-in cohort experience treatment-related death (Grade 5 Treatment-Related Adverse Events), the study will be terminated and will not proceed to Phase IIb. 2. Phase IIb (Randomized Controlled Phase):Upon confirmation that the safety criteria are met (i.e., \< 2 treatment-related deaths and acceptable toxicity profile), subsequent patients will be randomly assigned (1:1) to:

Arm A (Experimental): PD-1 inhibitor plus chemotherapy (paclitaxel and platinum regimen) combined with LDRT and CFRT.

Arm B (Control): PD-1 inhibitor plus chemotherapy alone. Primary Endpoint:The primary endpoint for the randomized phase is median progression-free survival (PFS).

Interventions

• Radiation LDRT+CFRT
  LDRT: Primary tumor and all visible metastatic lesions, DT: 2Gy/2fx, d1-2, Q3W × 4 cycles ; CFRT: Primary tumor, DT:40-50Gy/20-25fx, starting from the 5th immunotherapy cycle
• Drug Immunotherapy
  PD-1 inhibitor 200mg, Q3W, until disease progression or unacceptable toxicity or treatment reaches 2 years
• Drug Chemotherapy
  Paclitaxel+ Cisplatin, Q3W × 4cycles or Paclitaxel+ Carboplatin, Q3W × 4 cycles

Primary outcome measures

• PFS [Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months]
• Safety and Feasibility of the Combined Regimen (Safety Run-in Phase) [Time frame: From start of treatment up to 30 days after the last dose.]

Secondary outcome measures (2)

• OS [Time frame: From date of randomization until the date of death from any cause, assessed up to 36 months]
• Incidence of Grade III and higher treatment-related adverse events [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• Age ≥18;
• Metastatic esophageal squamous cell carcinoma (stage IVB, M1) confirmed by pathology;
• ECOG performance status: 0-1 point;
• No prior anti-tumor treatment;
• Adequate hematologic, renal, hepatic, and cardiac functions that meet the requirements for chemotherapy and immunotherapy assessed by investigators.

Exclusion criteria

• Non-squamous cell esophageal carcinoma or ESCC mixed with other pathological types of esophageal cancer;
• Patients who are potentially curable with surgery as assessed by investigators;
• Pleural metastasis or malignant pleural effusion, pericardial effusion;
• Any prior anti-tumor therapy for esophageal cancer, i.e., surgery, radiotherapy, chemotherapy, or immunotherapy;
• High risk of gastrointestinal bleeding, esophageal fistula, or perforation;
• Patients with Patient-Generated Subjective Globe Assessment (PG-SGA) score≥9;
• Unstable cardiac diseases or symptoms;
• History of interstitial pulmonary disease, non-infectious pneumonitis; pulmonary fibrosis, or other uncontrolled acute pulmonary disease;
• Active autoimmune disease or history of autoimmune disease;
• Conditions of immunodeficiency or active infection requiring systemic therapy;
• Pregnant or breastfeeding;
• Patients with synchronous second primary cancer and a history of malignancy within the past 5 years (excluding completely cured cervical carcinoma in situ or basal cell or squamous cell skin carcinoma).

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Shanghai Ruijin Hospital — Shanghai
• Shanghai Chest Hospital — Shanghai

Publications

• Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K; KEYNOTE-590 Investigators. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a PMID 34454674
• Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, Li J, Fu Z, Gu K, Liu Z, Wu L, Zhang X, Feng J, Niu Z, Ba Y, Zhang H, Liu Y, Zhang L, Min X, Huang J, Cheng Y, Wang D, Shen Y, Yang Q, Zou J, Xu RH; ESCORT-1st Investigators. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Sq PMID 34519801
• Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, Wang B, Sun G, Ji Y, Cao G, Liu H, Cui T, Li N, Qiu W, Li G, Hou X, Luo H, Xue L, Zhang Y, Yue W, Liu Z, Wang X, Gao S, Pan Y, Galais MP, Zaanan A, Ma Z, Li H, Wang Y, Shen L; ORIENT-15 study group. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (OR PMID 35440464
• Wang ZX, Cui C, Yao J, Zhang Y, Li M, Feng J, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Chen L, Guo Z, Liu B, Pan H, Cang S, Jiang Y, Wang J, Ye M, Chen Z, Jiang D, Lin Q, Ren W, Wang J, Wu L, Xu Y, Miao Z, Sun M, Xie C, Liu Y, Wang Q, Zhao L, Li Q, Huang C, Jiang K, Yang K, Li D, Liu Y, Zhu Z, Chen R, Jia L, Li W, Liao W, Liu HX, Ma D, Ma J, Qin Y, Shi Z, Wei Q, Xiao K, PMID 35245446
• Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin. 2017 Jan;67(1):65-85. doi: 10.3322/caac.21358. Epub 2016 Aug 29. PMID 27570942
• Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. Epub 2017 May 24. PMID 28551359
• Theelen WSME, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts JGJV, Dumoulin DW, Bahce I, Niemeijer AN, de Langen AJ, Monkhorst K, Baas P. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Sep 1;5(9):1276- PMID 31294749
• Herrera FG, Ronet C, Ochoa de Olza M, Barras D, Crespo I, Andreatta M, Corria-Osorio J, Spill A, Benedetti F, Genolet R, Orcurto A, Imbimbo M, Ghisoni E, Navarro Rodrigo B, Berthold DR, Sarivalasis A, Zaman K, Duran R, Dromain C, Prior J, Schaefer N, Bourhis J, Dimopoulou G, Tsourti Z, Messemaker M, Smith T, Warren SE, Foukas P, Rusakiewicz S, Pittet MJ, Zimmermann S, Sempoux C, Dafni U, Harari A, PMID 34479871

Identifiers

NCT: NCT05978193 · SCR-ESCC-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗