Trial Title:
Low-dose Radiation Combined With Neoadjuvant Immunochemotherapy for Esophageal Squamous Cell Carcinoma
NCT ID:
NCT06446726
Condition:
Esophageal Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Paclitaxel
Albumin-Bound Paclitaxel
Cisplatin
Tislelizumab
Conditions: Keywords:
Esophageal squamous cell carcinoma
low-dose radiation
neoadjuvant immunochemotherapy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Cohort (30 cases): Patients receive neoadjuvant low-dose radiotherapy (4 Gy/2f) combined
with a domestic PD-1 inhibitor (tislelizumab) and chemotherapy as neoadjuvant treatment.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Tislelizumab
Description:
Patients will undergo two cycles of immunotherapy, each cycle lasting 21 days. Day 3 and
Day 24: Tislelizumab, fixed dose of 200 mg
Arm group label:
neoadjuvant low-dose radiotherapy and immunochemotherapy group
Other name:
Tislelizumab, fixed dose of 200 mg
Intervention type:
Radiation
Intervention name:
Low-dose radiotherapy
Description:
Patients will undergo two cycles of low-dose radiotherapy. Day 1/2 and Day 22/23:
Low-dose radiotherapy (8 Gy/4f)
Arm group label:
neoadjuvant low-dose radiotherapy and immunochemotherapy group
Other name:
Low-dose radiotherapy (8 Gy/4f)
Intervention type:
Drug
Intervention name:
Nab-paclitaxel
Description:
Patients will undergo two cycles of chemotherapy. Day 3 and Day 24: Nab-paclitaxel 260
mg/m2
Arm group label:
neoadjuvant low-dose radiotherapy and immunochemotherapy group
Other name:
Nab-paclitaxel 260 mg/m2
Intervention type:
Drug
Intervention name:
Cisplatin
Description:
Patients will undergo two cycles of chemotherapy. Day 3 and Day 24: Cisplatin 75 mg/m2.
Arm group label:
neoadjuvant low-dose radiotherapy and immunochemotherapy group
Other name:
Cisplatin 75 mg/m2
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.
Detailed description:
According to 2020 GLOBOCAN data, esophageal cancer ranks fifth in incidence among all
malignant tumors in China, with new cases reaching 324,000 and annual deaths at 301,000.
These figures indicate a significant burden of esophageal cancer in China, accounting for
55% of esophageal cancer cases globally. Unlike in Western countries, most esophageal
cancer patients in China have squamous cell carcinoma, and 40% are diagnosed at an
advanced stage. Surgery is a key treatment for locally advanced esophageal cancer, but
patients may achieve better clinical outcomes if they receive neoadjuvant therapy before
surgery. However, the prognosis for these patients remains relatively poor. From 2009 to
2015, the overall 5-year relative survival rate for esophageal cancer was 21.4%, with
local tumors at 46.7%, regional metastasis at 25.1%, and distant metastasis at only 4.8%.
In recent years, immunotherapy has shown significant survival benefits in patients with
advanced esophageal cancer. Immuno-chemotherapy has now become the standard first-line
treatment for advanced esophageal cancer. Currently, the introduction of immunotherapy as
neoadjuvant treatment in locally advanced esophageal cancer is a highly regarded research
area. Many studies are underway involving the combined application of neoadjuvant
chemotherapy and immunotherapy, as well as neoadjuvant chemoradiotherapy and
immunotherapy. Regarding safety, tislelizumab is similar to foreign similar drugs, mostly
causing grade 1-2 adverse reactions, and is within a controllable range. Our center's
previous research results have shown that tislelizumab can be used as a neoadjuvant
immunotherapy drug for esophageal squamous cell carcinoma, with good perioperative
safety.
It is worth noting that recent study reports indicate that the pathological complete
response (PCR) rate of neoadjuvant chemotherapy combined with immunotherapy in small
sample studies ranges from 17% to 22%, showing significant heterogeneity. Recently,
Chinese scholars published a study in the international authoritative academic journal
"Nature Medicine," indicating that using a PD-L1 antibody for immunotherapy combined with
surgery, although the PCR rate was only 8%, the long-term survival effect was comparable
to traditional chemoradiotherapy. This further proves that compared to traditional
neoadjuvant chemoradiotherapy, neoadjuvant immunotherapy has broad development potential.
However, the local control effects of immunotherapy alone or combined with chemotherapy
are still unsatisfactory, which may affect the radical outcome of surgery and the
long-term survival of patients. Therefore, combining more effective local treatment
methods with immunotherapy is undoubtedly a more promising treatment option.
Low-dose radiotherapy (LDRT) is generally defined as a treatment not exceeding 2 Gy per
session, totaling no more than 10 Gy, and is considered a non-ablative treatment [13].
The low toxicity of low-dose radiotherapy makes it a treatment option for those not
suitable for body-targeted radiation therapy. Furthermore, although low-dose radiotherapy
does not directly kill cancer cells, it can promote tumor regression by readjusting the
tumor immune microenvironment.
Low-dose radiotherapy damages cell DNA, causing previously hidden or
difficult-to-recognize tumor antigens to be exposed on the cell surface. This change
promotes the cross-presentation of tumor-specific antigens, increases lymphocyte
infiltration into the tumor site, enhances tumor-specific immune responses, and further
improves the efficacy of immune checkpoint inhibitors. Preoperative immunotherapy can
activate the patient's immune system, enabling it to recognize tumor antigens and
establish immune memory. This allows the immune system to continue to function in immune
surveillance after the surgical removal of the tumor. Currently, the main focus of
clinical research is on how to maximize the synergistic effects between different
treatment modalities to achieve the best survival outcomes for patients with locally
advanced esophageal cancer while minimizing treatment side effects.
This study is a Phase IIA clinical trial, a preliminary study of efficacy and safety.
This study envisions a comprehensive treatment of neoadjuvant low-dose radiotherapy
combined with chemotherapy and immunotherapy (chemo-immuno), which, by reducing the
radiotherapy dose, can enhance local control efficacy and reduce adverse reactions caused
by the combined treatment mode. Therefore, it is proposed to perform neoadjuvant low-dose
radiotherapy combined with chemo-immuno treatment in patients with locally advanced
esophageal squamous cell carcinoma, adjust the preoperative radiotherapy dose from 40
Gy/20f to 4 Gy/2f, evaluate the efficacy and safety of this treatment mode, and provide
more evidence for the neoadjuvant treatment model for locally advanced esophageal cancer
patients. Additionally, exploratory analyses of preoperative and postoperative tissue and
blood samples will be conducted to understand the impact of preoperative low-dose
radiotherapy combined with immunotherapy on the esophageal cancer immune
microenvironment; suitable biological markers will be selected to identify the optimal
beneficiary group.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. 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)
2. Candidates eligible for an R0 curative resection
3. ECOG performance status of 0-1
4. Male or female patients aged ≥18 years and ≤75 years
5. 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
6. 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%)
7. 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
8. 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)
9. 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
10. Expected survival >6 months
11. Patients agree to undergo surgical treatment as well as radiotherapy, chemotherapy,
and immunotherapy
12. 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
13. No esophageal perforation or active esophageal bleeding, and no tracheal or major
thoracic vascular invasion
14. According to the solid tumor response evaluation criteria (RECIST version 1.1), at
least one measurable lesion by imaging
Exclusion Criteria:
1. Patients who are unsuitable for the immunotherapy and chemotherapy specified in the
protocol
2. 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
3. Patients with a history of primary tumor infiltration causing fistula
4. Patients assessed as having a high risk of fistula or signs of perforation
5. 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)
6. 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
7. Patients with a history of interstitial lung disease, non-infectious pneumonia, or
poorly controlled pulmonary diseases including pulmonary fibrosis or acute lung
diseases
8. 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
9. Patients with a history of allogeneic organ transplant (excluding corneal
transplant) or allogeneic hematopoietic stem cell transplant
10. Patients known to be allergic to the study drug tiragolumab, or to the active
ingredients or excipients in the combined chemotherapy drugs
11. 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
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Start date:
June 30, 2024
Completion date:
December 30, 2026
Lead sponsor:
Agency:
Sichuan University
Agency class:
Other
Source:
Sichuan University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06446726
