Trial Title:
Neoadjuvant ChemoRadiotherapy Followed by Immunotherapy and Surgery for Resectable Esophageal Squamous Cell Carcinoma（CRIS-2 Trial）
NCT ID:
NCT06509568
Condition:
Esophageal Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Esophageal Squamous Cell Carcinoma
Immunomodulating Agents
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Radiation
Intervention name:
Neoadjuvant chemoradiotherapy followed by immunotherapy
Description:
Patients in the nCRIT group will receive neoadjuvant concurrent chemoradiotherapy:
radiation therapy will be administered using IMRT or VMAT with involved-field irradiation
at a dose of PTV 41.4 Gy/23 fractions/31 days. Chemotherapy will consist of weekly
administration of paclitaxel (albumin-bound) 50 mg/m² and carboplatin (AUC 2) for five
weeks, given on the days of radiotherapy. Patients who do not progress on CT and meet
immunotherapy criteria will receive fixed-dose toripalimab (200 mg IV) on days 8 and 29
after chemoradiotherapy, followed by minimally invasive esophagectomy four weeks after
completing immunotherapy.
Arm group label:
Neoadjuvant chemoradiotherapy followed by immunotherapy (nCRIT)
Intervention type:
Drug
Intervention name:
Neoadjuvant chemoimmunotherapy
Description:
Patients in the nCIT group will receive two cycles of TC chemotherapy combined with
immunotherapy, specifically paclitaxel (albumin-bound) 100 mg/m² on days 1, 8, 15 or
260mg/m² d1, carboplatin (AUC=5) on days 1, and toripalimab (200 mg) on days 1. Minimally
invasive esophagectomy will be performed 4-6 weeks after completing chemotherapy, and
adjuvant immunotherapy is recommended for one year after surgery.
Arm group label:
Neoadjuvant chemoimmunotherapy (nCIT)
Summary:
Based on our previous single-arm Phase Ib study (CRIS trial, NCT06303583), we observed
that neoadjuvant chemoradiotherapy followed by immunotherapy (nCRIT) significantly
increased the pathological complete response (pCR) rate, achieving approximately 60% in
locally advanced esophageal squamous cell carcinoma(ESCC). We plan to initiate a
multicenter, prospective, randomized phase II trial designed to compare the efficacy and
safety of neoadjuvant chemoimmunotherapy (nCIT) versus neoadjuvant chemoradiotherapy
followed by immunotherapy (nCRIT) in treating esophageal squamous cell carcinoma. The
primary study population includes patients with operable or potentially operable thoracic
ESCC classified as cT3-4aN0 or T2-4aN+ based on endoscopy, enhanced chest and abdominal
CT, and whole-body PET scans. Eligible participants are aged 18-75 years with an ECOG
performance status of 0-1. Qualified patients will be randomly assigned in a 1:1 ratio to
either the nCRIT group or the nCIT group.
Patients in the nCRIT group will receive neoadjuvant concurrent chemoradiotherapy:
radiation therapy will be administered using IMRT or VMAT with involved-field irradiation
at a dose of PTV 41.4 Gy/23 fractions/31 days. Chemotherapy will consist of weekly
administration of paclitaxel (albumin-bound) 50 mg/m² and carboplatin (AUC=2) for five
weeks, given on the days of radiotherapy. Patients who do not progress on CT and meet
immunotherapy criteria will receive fixed-dose toripalimab (200 mg IV) on days 8 and 29
after chemoradiotherapy, followed by minimally invasive esophagectomy four weeks after
completing immunotherapy.
Patients in the nCIT group will receive two cycles of TC chemotherapy combined with
immunotherapy, specifically paclitaxel (albumin-bound) 100 mg/m² on days 1, 8, 15 or
260mg/m² d1, carboplatin (AUC=5) on days 1, and toripalimab (200 mg) on days 1. Minimally
invasive esophagectomy will be performed 4-6 weeks after completing chemotherapy, and
adjuvant immunotherapy is recommended for one year after surgery.
The primary endpoint of the study is the pathological complete response (pCR). Secondary
endpoints include treatment safety, CT imaging response rate, R0 resection rate, major
pathological response (MPR), 2-year event-free survival (EFS), 2-year overall survival
(OS) in the intention-to-treat (ITT) population, and analysis of treatment failure
reasons.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age and Consent: Subjects must be male or female, aged ≥18 and ≤75 years at the time
of signing the informed consent form.
2. Performance Status: Subjects must have an Eastern Cooperative Oncology Group (ECOG)
performance status score of 0-1, or a Karnofsky Performance Status (KPS) score of
≥80.
3. Histological Confirmation: Histologically confirmed thoracic esophageal squamous
cell carcinoma (ESCC), with the upper boundary of the lesion not exceeding the
thoracic inlet.
4. Resectability: Subjects must have resectable or potentially resectable T3-4aN0 or
T2-4aN+ ESCC, as per the AJCC/UICC 8th edition clinical staging (cTNM).
5. Lesion Length: The length of the esophageal lesion must be <8 cm.
6. Surgical Eligibility: Subjects must have no contraindications for surgical
procedures.
7. Organ Function: Subjects must have good cardiopulmonary function and other organ
functions to tolerate chemoradiotherapy and surgery.
a. Hematology (without the use of any blood components and cell growth factor
support treatment within 7 days before the start of study treatment): i. Absolute
neutrophil count (ANC) ≥ 1.5×10^9/L (1500/mm^3). ii. Platelet count ≥ 100×10^9/L
(100000/mm^3). iii. Hemoglobin ≥ 90 g/L. b. Renal Function: i. Calculated creatinine
clearance* (CrCl) ≥ 50 mL/min.
*CrCl will be calculated using the Cockcroft-Gault formula: CrCl (mL/min) = (140 -
age) × weight (kg) × F / (SCr (mg/dL) × 72), where F = 1 for males and 0.85 for
females; SCr = serum creatinine. ii. Urine protein < 2+ or 24-hour urine protein
quantification < 1.0 g. c. Liver Function: i. Serum total bilirubin (TBiL) ≤ 1.5 ×
ULN (Upper Limit of Normal). ii. AST and ALT ≤ 2.5 × ULN; for subjects with liver
metastasis, AST and ALT ≤ 5 × ULN.
iii. Serum albumin (ALB) ≥ 28 g/L. d. Coagulation Function: International normalized
ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN (unless the
subject is receiving anticoagulant therapy and INR and APTT are within the expected
therapeutic range).
e. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 60%.
8. Female Subjects of Childbearing Potential: Must have a negative urine or serum
pregnancy test within 3 days prior to the first dose (if the urine pregnancy test is
inconclusive, a serum pregnancy test will be required, and the serum result will be
definitive). If a female subject of childbearing potential engages in sexual
activity with an unsterilized male partner, she must use highly effective
contraception from the start of screening and agree to continue using it for 120
days after the last dose of the study drug. Decisions regarding contraception
discontinuation after this period should be discussed with the investigator.
9. Male Subjects with Female Partners of Childbearing Potential: Must use effective
contraception from the start of screening until 120 days after the last dose of the
study drug. Decisions regarding contraception discontinuation after this period
should be discussed with the investigator.
10. Compliance: Subjects must be adequately informed and sign the informed consent form.
They must also be willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other study requirements.
Exclusion Criteria:
1. Cervical esophageal cancer (lesion located in the cervical esophagus).
2. Metastasis to cervical lymph nodes or lymph nodes around the celiac artery.
3. Invasion of the trachea or aorta.
4. Hoarseness caused by the esophageal tumor.
5. Esophageal fistula or a tendency to develop an esophageal fistula.
6. Pregnant or lactating patients.
7. Severe, poorly controlled diabetes mellitus.
8. Inability to use the stomach for esophageal replacement due to previous surgeries.
9. Previous receipt of chemoradiotherapy.
10. Allergy or contraindication to taxane drugs.
11. Inability to provide informed consent due to psychological, familial, or social
reasons.
12. History of malignancies other than esophageal cancer.
13. Inability to tolerate chemoradiotherapy due to severe cardiac, pulmonary, hepatic,
renal dysfunction, hematologic diseases, or cachexia; BMI < 18.5.
14. Active autoimmune disease, history of autoimmune disease (including but not limited
to colitis, hepatitis, hyperthyroidism, etc.), history of immune deficiency
(including positive HIV test), or other congenital or acquired immune deficiency
disorders, organ transplantation, or allogeneic bone marrow transplantation.
15. Active hepatitis B (HBV DNA ≥ 2000 IU/mL or 10^4 copies/mL), active hepatitis C
(positive hepatitis C antibody with HCV-RNA levels above the detection limit).
16. History of immunodeficiency; positive HIV antibody test; currently on long-term
systemic corticosteroids or other immunosuppressants.
17. Severe infections within 4 weeks prior to the first dose, including but not limited
to complications requiring hospitalization, sepsis, or severe pneumonia; active
infections requiring systemic anti-infective therapy within 2 weeks before the first
dose (excluding antiviral treatment for hepatitis B or C).
18. Known active tuberculosis (TB); suspected active TB should be ruled out by clinical
examination; known active syphilis infection.
19. Receipt of live or attenuated live vaccines within 30 days prior to the first dose
or planned receipt of such vaccines during the study period (inactivated vaccines
are allowed).
20. History of interstitial lung disease or non-infectious pneumonitis.
21. History of myocarditis, cardiomyopathy, malignant arrhythmias; unstable angina
requiring hospitalization, myocardial infarction, congestive heart failure (NYHA
class 2 or above), or vascular disease (e.g., aneurysms at risk of rupture) within
12 months prior to the first dose; or other cardiac conditions that may affect the
safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial
ischemia).
22. Known psychiatric disorders, drug abuse, alcoholism, or a history of substance
abuse.
23. Local or systemic diseases caused by non-malignant tumors; or diseases or symptoms
secondary to tumors that may lead to high medical risk and/or uncertainty in
survival assessment, such as tumor leukemoid reaction (white blood cell count >
20×10^9/L), cachexia (e.g., known weight loss of more than 10% in the 3 months prior
to screening).
24. Any condition that the investigator believes may pose a risk to the subject's
participation in the study, interfere with the evaluation of the study drug, or
affect the interpretation of study results.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Zhejiang Cancer Hospital
Address:
City:
Hangzhou
Country:
China
Status:
Recruiting
Contact:
Last name:
YANG YANG, M.D.
Phone:
+8657188128182
Email:
yangyang@zjcc.org.cn
Investigator:
Last name:
Youhua Jiang
Email:
Principal Investigator
Investigator:
Last name:
Guoqin Qiu
Email:
Principal Investigator
Start date:
August 1, 2024
Completion date:
August 1, 2026
Lead sponsor:
Agency:
Zhejiang Cancer Hospital
Agency class:
Other
Source:
Zhejiang Cancer Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06509568
