Low-dose Radiation Combined With Neoadjuvant Immunochemotherapy for Esophageal Squamous Cell Carcinoma

NCT06446726 | Recruiting Phase 2

• 1 other identifier: LDRT-2025
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to investigate the efficacy and safety of low-dose radiation combined with neoadjuvant chemotherapy and immunotherapy in the treatment of locally advanced thoracic esophageal squamous cell carcinoma. By reducing the radiation dose from 40 Gy in 20 fractions to 4 Gy in 2 fractions, the goal is to lessen the adverse reactions caused by radiotherapy. Additionally, the study explores whether low-dose radiation therapy can promote the cross-presentation of tumor-specific antigens and increase lymphocyte infiltration into the tumor site. Study also examines whether this approach can enhance tumor-specific immune responses, thereby potentially improving the efficacy of immune checkpoint inhibitors.

Conditions

Esophageal Squamous Cell Carcinoma

Keywords

Esophageal squamous cell carcinoma; low-dose radiation; neoadjuvant immunochemotherapy

Outcome Measures

Primary Outcomes (1)

• Pathologic complete response

  The proportion of subjects with 0% of surviving tumor cells remaining in the primary tumor and in the sampled lymph nodes as evaluated by histology.

  Immediately after the surgery

Secondary Outcomes (4)

• Major pathological response

  Immediately after the surgery

• R0 rate

  During the surgery

• 1/2 year event-free survival

  2 years

• Overall Response Rate

  Immediately after the surgery

Study Arms (3)

4Gy/2f group

EXPERIMENTAL

During the neoadjuvant treatment phase, patients will undergo two cycles of low-dose radiotherapy, combined with chemotherapy and immunotherapy, each cycle lasting 21 days. The specific treatment protocol is as follows: D1/2: Low-dose radiotherapy (4 Gy/2f) D3: Tislelizumab, fixed dose of 200 mg; Nab-paclitaxel 260 mg/m2; Cisplatin 75 mg/m2. The interval between radiotherapy and chemotherapy should not exceed 3 days. Drug infusions follow the sequence of tislelizumab → nab-paclitaxel → cisplatin/carboplatin, with at least a 30-minute interval between each infusion. At the end of the neoadjuvant treatment, patients will undergo surgical treatment 6-8 weeks after the last treatment session.

Drug: Tislelizumab; Radiation: Low-dose radiotherapy; Drug: Nab-paclitaxel; Drug: Cisplatin

6Gy/3f group

EXPERIMENTAL

During the neoadjuvant treatment phase, patients will undergo two cycles of low-dose radiotherapy, combined with chemotherapy and immunotherapy, each cycle lasting 21 days. The specific treatment protocol is as follows: D1/2/3: Low-dose radiotherapy (6 Gy/3f) D4: Tislelizumab, fixed dose of 200 mg; Nab-paclitaxel 260 mg/m2; Cisplatin 75 mg/m2. The interval between radiotherapy and chemotherapy should not exceed 3 days. Drug infusions follow the sequence of tislelizumab → nab-paclitaxel → cisplatin/carboplatin, with at least a 30-minute interval between each infusion. At the end of the neoadjuvant treatment, patients will undergo surgical treatment 6-8 weeks after the last treatment session.

Drug: Tislelizumab; Radiation: Low-dose radiotherapy; Drug: Nab-paclitaxel; Drug: Cisplatin

8Gy/4f group

EXPERIMENTAL

During the neoadjuvant treatment phase, patients will undergo two cycles of low-dose radiotherapy, combined with chemotherapy and immunotherapy, each cycle lasting 21 days. The specific treatment protocol is as follows: D1/2/3/4: Low-dose radiotherapy (8 Gy/4f) D5: Tislelizumab, fixed dose of 200 mg; Nab-paclitaxel 260 mg/m2; Cisplatin 75 mg/m2. The interval between radiotherapy and chemotherapy should not exceed 3 days. Drug infusions follow the sequence of tislelizumab → nab-paclitaxel → cisplatin/carboplatin, with at least a 30-minute interval between each infusion. At the end of the neoadjuvant treatment, patients will undergo surgical treatment 6-8 weeks after the last treatment session.

Drug: Tislelizumab; Radiation: Low-dose radiotherapy; Drug: Nab-paclitaxel; Drug: Cisplatin

Interventions

Tislelizumab DRUG

Patients will undergo two cycles of immunotherapy, each cycle lasting 21 days. Day 3 and Day 24: Tislelizumab, fixed dose of 200 mg

Also known as: Tislelizumab, fixed dose of 200 mg

4Gy/2f group; 6Gy/3f group; 8Gy/4f group

Low-dose radiotherapy RADIATION

Patients will undergo two cycles of low-dose radiotherapy. Day 1/2 and Day 22/23: Low-dose radiotherapy (8 Gy/4f)

Also known as: Low-dose radiotherapy (8 Gy/4f)

4Gy/2f group; 6Gy/3f group; 8Gy/4f group

Nab-paclitaxel DRUG

Patients will undergo two cycles of chemotherapy. Day 3 and Day 24: Nab-paclitaxel 260 mg/m2

Also known as: Nab-paclitaxel 260 mg/m2

4Gy/2f group; 6Gy/3f group; 8Gy/4f group

Cisplatin DRUG

Patients will undergo two cycles of chemotherapy. Day 3 and Day 24: Cisplatin 75 mg/m2.

Also known as: Cisplatin 75 mg/m2

4Gy/2f group; 6Gy/3f group; 8Gy/4f group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed thoracic esophageal squamous cell carcinoma with clinical staging of: cT1b-cT2 N1-2 M0 or cT3-cT4a N0-2 M0 (AJCC/UICC esophageal cancer staging, 8th edition)
• Candidates eligible for an R0 curative resection
• ECOG performance status of 0-1
• Male or female patients aged ≥18 years and ≤75 years
• Adequate major organ and bone marrow function (without transfusion or medication correction): Complete blood count: White blood cells ≥ 3.5×10\^9/L, Absolute Neutrophil Count (ANC) ≥1.5 ×10\^9/L, Platelets ≥100×10\^9/L, Hemoglobin ≥9g/dL
• Radiation oncologist assessment confirms no severe pulmonary ventilatory dysfunction and no acute cardiac failure. (Pulmonary function: FEV1/FVC≥70%, FEV1≥50% of the normal value, DLCO (lung diffusion capacity) actual versus predicted value \>80%)
• Liver function: Total bilirubin ≤1.5 times the upper limit of normal (ULN), Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) ≤2.5 times ULN, Serum albumin ≥3g/dL
• Renal function: Serum creatinine ≤1.5×ULN, or creatinine clearance ≥ 60ml/min (calculated using the Cockcroft/Gault formula): Female: CrCl = (140 - age) x weight (kg) x 0.85 / 72 x serum creatinine (mg/dL) Male: CrCl = (140 - age) x weight (kg) x 1.00 / 72 x serum creatinine (mg/dL)
• Study participants voluntarily join the study and sign a written informed consent form, and are able to comply with the protocol-specified visits and related procedures
• Expected survival \>6 months
• Patients agree to undergo surgical treatment as well as radiotherapy, chemotherapy, and immunotherapy
• Women of childbearing potential must have a negative pregnancy test within 7 days prior to the initiation of treatment; all participants, regardless of gender, are willing to use appropriate contraceptive methods during the trial and for 8 weeks after the last dose of study medication
• No esophageal perforation or active esophageal bleeding, and no tracheal or major thoracic vascular invasion
• According to the solid tumor response evaluation criteria (RECIST version 1.1), at least one measurable lesion by imaging

You may not qualify if:

• Patients who are unsuitable for the immunotherapy and chemotherapy specified in the protocol
• Patients with a history of treatment for ESCC, including experimental drugs, chemotherapy, radiotherapy, or therapies targeting T-cell co-stimulation checkpoint pathways such as anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies or drugs
• Patients with a history of primary tumor infiltration causing fistula
• Patients assessed as having a high risk of fistula or signs of perforation
• Patients who have required systemic corticosteroid treatment (prednisone \> 10 mg/day or equivalent dosage) or other immunosuppressive therapies within 14 days prior to the first administration. However, use of adrenocortical replacement steroids (prednisone ≤ 10 mg/day or equivalent) and minimal systemic absorption of topical, ocular, intra-articular, nasal, and inhaled corticosteroids, as well as short-term (≤ 7 days) use of corticosteroids for non-autoimmune conditions are allowed (dexamethasone can be used for paclitaxel pre-treatment)
• Patients with active autoimmune diseases or a history of autoimmune diseases that might recur. However, participants with well-controlled type 1 diabetes, hypothyroidism requiring only hormone replacement, well-controlled celiac disease, and non-systemic treated skin conditions like vitiligo, psoriasis, or alopecia, or conditions not likely to recur without an external trigger are eligible
• Patients with a history of interstitial lung disease, non-infectious pneumonia, or poorly controlled pulmonary diseases including pulmonary fibrosis or acute lung diseases
• Patients needing systemic antibacterial, antifungal, or antiviral treatment for infections such as tuberculosis. Patients who have had a severe infection including but not limited to hospitalization-required complications, bacteremia, or severe infectious pneumonia within 4 weeks before the first administration, or those who have received therapeutic oral or intravenous antibiotics within 2 weeks before the first administration
• Patients with a history of allogeneic organ transplant (excluding corneal transplant) or allogeneic hematopoietic stem cell transplant
• Patients known to be allergic to the study drug tiragolumab, or to the active ingredients or excipients in the combined chemotherapy drugs
• Patients with significant and severely symptomatic rhythm, conduction, or morphological abnormalities on a resting electrocardiogram, such as complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, atrial fibrillation; unstable angina, congestive heart failure, or chronic heart failure with an NYHA classification of ≥ 2

Sponsors & Collaborators

• Sichuan University: lead

Study Sites (1)

Sichuan University West China Hospital

Chengdu, Sichuan, 610000, China

RECRUITING

Related Publications (4)

• Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schakel K, Garbi N, Jager D, Weitz J, Schmitz-Winnenthal H, Hammerling GJ, Beckhove P. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013 Nov 11;24(5):589-602. doi: 10.1016/j.ccr.2013.09.014. Epub 2013 Oct 24.

  PMID: 24209604 BACKGROUND

• 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, Kandalaft LE, Carmona SJ, Dangaj Laniti D, Irving M, Coukos G. Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy. Cancer Discov. 2022 Jan;12(1):108-133. doi: 10.1158/2159-8290.CD-21-0003. Epub 2021 Sep 3.

  PMID: 34479871 BACKGROUND

• Gupta A, Probst HC, Vuong V, Landshammer A, Muth S, Yagita H, Schwendener R, Pruschy M, Knuth A, van den Broek M. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol. 2012 Jul 15;189(2):558-66. doi: 10.4049/jimmunol.1200563. Epub 2012 Jun 8.

  PMID: 22685313 BACKGROUND

• Barsoumian HB, Ramapriyan R, Younes AI, Caetano MS, Menon H, Comeaux NI, Cushman TR, Schoenhals JE, Cadena AP, Reilly TP, Chen D, Masrorpour F, Li A, Hong DS, Diab A, Nguyen QN, Glitza I, Ferrarotto R, Chun SG, Cortez MA, Welsh J. Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma. J Immunother Cancer. 2020 Oct;8(2):e000537. doi: 10.1136/jitc-2020-000537.

  PMID: 33106386 BACKGROUND

MeSH Terms

Conditions

Esophageal Squamous Cell Carcinoma

Interventions

tislelizumab; Radiotherapy; 130-nm albumin-bound paclitaxel; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Squamous Cell; Esophageal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• Jianxin Xue, professor

  West China Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yong Yuan, Professor

CONTACT

+86 18980606739; yongyuan@scu.edu.cn

Xiaokun Li, Doctor

CONTACT

+86 18081312828; drlixiaokun@163.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: Group 1 (10 patients): Patients received neoadjuvant low-dose radiotherapy (4 Gy/2 fractions) combined with a domestic PD-1 inhibitor (tislelizumab) and chemotherapy as neoadjuvant therapy. Group 2 (10 patients): Patients received neoadjuvant low-dose radiotherapy (6 Gy/3 fractions) combined with a domestic PD-1 inhibitor (tislelizumab) and chemotherapy as neoadjuvant therapy. Group 3 (10 patients): Patients received neoadjuvant low-dose radiotherapy (8 Gy/4 fractions) combined with a domestic PD-1 inhibitor (tislelizumab) and chemotherapy as neoadjuvant therapy.

Study Record Dates

• First Submitted: May 16, 2024
• First Posted: June 6, 2024
• Study Start: June 30, 2024
• Primary Completion: June 30, 2025
• Study Completion (Estimated): December 30, 2026
• Last Updated: June 6, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)