Study of Neoadjuvant Nivolumab or Placebo Plus Chemotherapy Followed by Surgery and Adjuvant Treatment in Subjects With Resectable ESCC

NCT05213312 | Unknown Phase 2

• 1 other identifier: CA209-6KP
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Esophageal cancer, the 7th most common cancer globally, accounts for more than half a million deaths each year. The incidence of ESCC, the most common histologic type, has been stable, whereas the incidences of esophageal and gastroesophageal junction adenocarcinomas continue to increase in Western countries. Neoadjuvant chemoradiotherapy followed by surgery has become a standard of care for patients with locally advanced resectable esophageal or junctional cancer, especially in western countries. In Asia, nCT is considered as the standard of care for Stage II/III ESCC based on JCOG9204 and JCOG9907 trials. The superiority of nCRT/nCT, in terms of long-term survival, remains to be elucidated. For Stage II/III ESCC patients with multiple stations of lymph nodes involvement, nCT might be more appropriate for the inaccessibility of radiotherapy. There are only limited studies on preoperative immune checkpoint inhibitor in combination with chemotherapy followed by surgery for the locally advanced ESCC. Therefore, this study intends to use Nivolumab 360 mg Q3W combined with standard chemotherapy as the neoadjuvant therapy regimen.

Conditions

Esophageal Squamous Cell Carcinoma

Keywords

Neoadjuvant Immunotherapy; Neoadjuvant Chemotherapy; Esophageal Squamous Cell Carcinoma; Minimally Invasive Esophagectomy

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response (pCR) rate

  pCR rate is defined as the proportion of the subjects in the analysis population who have a complete response in postoperative pathology. It is assessed in the resected specimen following neoadjuvant therapy using standardized work up of the resection specimen in the pathology department and standardized histological criteria for tumor regression grading. The Tumor Regression Grade (TRG) is categorized as follow: grade 1, no evidence of vital residual tumor cells (pCR); grade 2, less than 10% vital residual tumor cells; grade 3, 10 to 50%; grade 4, more than 50%.

  Up to the date of pathological reports obtained since the date of randomization, up to 12 months

Secondary Outcomes (4)

• R0 resection rate

  Up to the date of pathological reports obtained since the date of randomization, up to 12 months

• Events-free Survival (EFS)

  Up to the date of death of any causes since the date of randomization, up to 36 months

• Overall survival (OS)

  Up to the date of death of any causes since the date of randomization, up to 36 months

• Incidence of Treatment-Emergent Adverse Events

  Up to the date of death of any causes since the date of randomization, up to 36 months

Study Arms (2)

NIT+NCT Group (Arm A)

EXPERIMENTAL

1. Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles; 2. Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously. 3. MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy. 4. Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.

Drug: Nivolumab; Drug: Cisplatin; Drug: Paclitaxel; Drug: 5Fluorouracil; Procedure: Esophagectomy (minimally invasive)

NCT Group (Arm B)

PLACEBO COMPARATOR

1. Placebo: NS ivgtt (dose, frequency and duration same as the Nivolumab); 2. Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cisplatin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously. 3. MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy. 4. Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.

Drug: Cisplatin; Drug: Paclitaxel; Drug: 5Fluorouracil; Procedure: Esophagectomy (minimally invasive)

Interventions

Nivolumab DRUG

Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles;

NIT+NCT Group (Arm A)

Cisplatin DRUG

80 mg/m2 on DAY2 with paclitaxel, Q3W or 80 mg/m2 on DAY1, Q3W ivgtt for two cycles

NCT Group (Arm B); NIT+NCT Group (Arm A)

Paclitaxel DRUG

175 mg/m2 on DAY2, with cisplatin Q3W, ivgtt for two cycles

NCT Group (Arm B); NIT+NCT Group (Arm A)

5Fluorouracil DRUG

800 mg/m2 on DAYS1-5 with cisplatin, Q3W for two cycles

NCT Group (Arm B); NIT+NCT Group (Arm A)

Esophagectomy (minimally invasive) PROCEDURE

4-6 weeks after neoadjuvant therapy.

NCT Group (Arm B); NIT+NCT Group (Arm A)

Eligibility Criteria

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

You may qualify if:

• Patients enrolled in the study must meet all of the following conditions:
• The patient volunteers to participate in the study, signs a consent form, has good compliance, and obeys the follow-up, and is willing and able to follow the protocol during the study.
• Male or female, aged ≥18 years and ≤75 years.
• The ECOG PS score is 0-1.
• Histologically-confirmed squamous cell carcinoma of the esophagus. Tumors of the esophagus are located in the thoracic cavity.
• Pre-treatment stage as Stage II-III (cT2N0-1M0, cT3N0-1M0, cT1-3N2M0, AJCC/UICC 8th Edition);
• Expected lifetime \> 1 year.
• Adequate cardiac function. All patients should perform ECG, and those with a cardiac history or ECG abnormality should perform echocardiography with the left ventricular ejection fraction \> 50 %.
• Adequate respiratory function with FEV1≥1.2L, FEV1%≥50% and DLCO≥50% shown in pulmonary function tests.
• Adequate bone marrow function (White Blood Cells \>4x10\^9 /L; Neutrophil \>2.0×10\^9 /L; Hemoglobin \> 90 g/L; platelets\>100x10\^9 /L). AST, ALT ≤ 3 x ULN (If liver metastases exist, AST and ALT allow ≤ 5 x ULN).
• Adequate liver function (Total bilirubin \<1.5x Upper Level of Normal (ULN); Aspartate transaminase (AST) and Alanine transaminase (ALT) \<1.5x ULN).
• Adequate renal function (Glomerular filtration rate (CCr) \>60 ml/min; serum creatinine (SCr) ≤120 μmol/L).
• All acute toxic effects of previous anti-cancer treatment or surgery were all relieved by NCI-CTCAE version 5.0 ≤ 1 (except for hair loss or other toxic effects that the investigator judges to have no risk to the patient's safety).
• Have the ability to act autonomously, have the ability to swallow pills, and have no gastrointestinal diseases that affect oral drug absorption.
• Agree to provide hematology and histology samples.

You may not qualify if:

• Patients who meet any of the following conditions will be excluded:
• Patients have previously received an anti-PD-1, PD-L1 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
• Related to cancer:
• Patients with non-squamous cell carcinoma histology.
• Patients with advanced inoperable or metastatic esophageal cancer (M1).
• Patients without qualified Pre-treatment stage.
• Patients with another previous or current malignant disease.
• Others:
• Any patient with a significant medical condition which is thought unlikely to tolerate the therapies. Such as cardiac disease (e.g. symptomatic coronary artery disease or myocardial infarction within last 12 months), clinically-significant lung disease, clinically-significant bone marrow, liver, renal function disorder.
• Patients who have autoimmune diseases.
• Pregnant or lactating women and fertile women who will not be using contraception during the trial.
• Allergy to any drugs.
• Patients who have received or are receiving other chemotherapy, radiotherapy or targeted therapy.
• Patients who recently or currently taking hormones or immunosuppressive agents.
• Immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) active infection or known HIV seropositivity; including HBV or HCV surface antigen positive (RNA).

Sponsors & Collaborators

• Shanghai Zhongshan Hospital: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

180 Fenglin Road

Shanghai, 200032, China

RECRUITING

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MeSH Terms

Conditions

Esophageal Squamous Cell Carcinoma

Interventions

Nivolumab; Cisplatin; Paclitaxel; Fluorouracil; Esophagectomy

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)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Digestive System Surgical Procedures; Surgical Procedures, Operative

Central Study Contacts

Lijie Tan, Professor

CONTACT

+8613681972151; tan.lijie@zs-hospital.sh.cn

Jun Yin, Professor

CONTACT

+8613917483128; yin.jun2@zs-hospital.sh.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Enrolled patients will receive the following medications: 1. Neoadjuvant immunotherapy : Nivolumab, 360mg intravenous infusion (ivgtt.), on DAY1, Q3W for two cycles; 2. Neoadjuvant chemotherapy (investigator's choice) : Cisplatin, 80 mg/m2 and Paclitaxel, 175 mg/m2 on DAY2, Q3W Or Cistaplin, 80 mg/m2 on DAY1 and 5-fluorouracil, 800 mg/m2 on DAYS1-5, Q3W for two cycles. All given intravenously. 3. MIE : Esophagectomy plus two/three field lymphadenectomy, 4-6 weeks after neoadjuvant therapy. 4. Adjuvant immunotherapy : 4-6 weeks after operation, (for subjects with non-pCR) Nivolumab injection, 240mg intravenous infusion, Q2W for 16 weeks, followed by 480mg intravenous infusion, Q4W. The maximum duration of adjuvant Nivolumab therapy is one year.

Study Record Dates

• First Submitted: December 18, 2021
• First Posted: January 28, 2022
• Study Start: June 1, 2022
• Primary Completion: November 1, 2022
• Study Completion: March 1, 2024
• Last Updated: June 15, 2022

Record last verified: 2022-06

Locations

CN (1)