## Protocol Section
### Identification Module
**NCT ID:** NCT06430658

**Acronym:** NEXUS-2

**Brief Title:** Neoadjuvant Comprehensive Treatment for Unresectable Esophageal Cancer

**Official Title:** NEoadjuvant Total rX for Borderline Unresectable Esophageal Squamous Cell Carcinoma: a Prospective Randomized, Three-Arm, Open-Label Phase II Trial (NEXUS-2)

#### Organization Study ID Info
**ID:** NEXUS-2
#### Organization
**Class:** OTHER
**Full Name:** Cancer Institute and Hospital, Chinese Academy of Medical Sciences
### Status Module
#### Completion Date
**Date:** 2027-12-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-21

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2026-12-31

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-04-01

**Type:** ACTUAL

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-28
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-13
**Study First Submit QC Date:** 2024-05-21
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Cancer Institute and Hospital, Chinese Academy of Medical Sciences

#### Responsible Party

**Investigator Affiliation:** Cancer Institute and Hospital, Chinese Academy of Medical Sciences

**Investigator Full Name:** YIN LI

**Investigator Title:** Principal Investigator

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Patients diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC) that is deemed unresectable face a bleak prognosis. Recent phase 1/2 studies have demonstrated the efficacy and safety of augmenting neoadjuvant concurrent chemoradiotherapy with immunotherapy in treating resectable ESCC. The present study is a prospective, 3-arm, randomized trial that seeks to evaluate the efficacy of diverse conversion therapy modalities in patients with unresectable ESCC. The study objectives include R0 resection rate, treatment-related adverse events, morbidity and mortality, 1-year progression-free survival (PFS), and 1-year overall survival (OS) rates.

Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). Tislelizumab was specifically engineered to minimize binding to FcɤR on macrophages, thereby abrogating antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti-PD-1 therapy.

This trial will provide valuable insights into the effectiveness of the three conversion therapy modalities and help to inform clinical decision-making for patients with unresectable locally advanced ESCC.

### Conditions Module

**Conditions:**

- Esophagus Cancer

**Keywords:**

- Esophagus Cancer

- Chemoradiotherapy

- conversion surgery

- immunotherapy

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 90

**Type:** ESTIMATED

**Phases:**

- PHASE2

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Surgery was evaluated after chemoradiotherapy (40-41.4Gy/1.8-2Gy/20-23 fractions) followed by two cycles of chemotherapy and immunotherapy

**Intervention Names:**

- Combination Product: Tislelizumab (BGB-A317) with chemoradiotherapy

**Label:** ChemoRT+Immuno

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Surgery was evaluated after two cycles of chemotherapy and immunotherapy followed by chemoradiotherapy(40-41.4Gy/1.8-2Gy/20-23 fractions)

**Intervention Names:**

- Combination Product: Tislelizumab (BGB-A317) with chemoradiotherapy

**Label:** Immuno+ChemoRT

**Type:** EXPERIMENTAL

#### Arm Group 3

**Description:** Surgery was evaluated after concurrent definitive chemoradiotherapy (50-50.4Gy/1.8-2Gy/25-28fractions) and immunotherapy.

**Intervention Names:**

- Combination Product: Tislelizumab (BGB-A317) with chemoradiotherapy

**Label:** ChemoRT

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- ChemoRT

- ChemoRT+Immuno

- Immuno+ChemoRT

**Description:** Different sequences and methods of treatment to convert surgery

**Name:** Tislelizumab (BGB-A317) with chemoradiotherapy

**Type:** COMBINATION_PRODUCT

### Outcomes Module

#### Primary Outcomes

**Description:** Minimal distance tumor/circumferential resection margin (CRM) \> 1 mm.

**Measure:** R0 resection rate

**Time Frame:** 4 months

#### Secondary Outcomes

**Description:** Defined as the proportion of patients still alive within one year from treatment initiation.

**Measure:** 1-year OS rate

**Time Frame:** 1 year after all treatment

**Description:** Defined as the proportion of patients without disease progression or death within one year from treatment initiation.

**Measure:** 1-year PFS

**Time Frame:** 1 year after all treatment

**Description:** To investigate whether ctDNA variation can be used for MRD monitoring in patients with unresectable locally advanced ESCC.

**Measure:** Efficacy of circulating tumor DNA (ctDNA) in minimal residual disease (MRD) monitoring

**Time Frame:** 6 month

**Description:** Adverse event during chemoRT or immunotherapy

**Measure:** Safety profile

**Time Frame:** 4 month

**Measure:** Pathological response

**Time Frame:** 4 month

**Measure:** Postoperative complications

**Time Frame:** 4 month

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Histologically confirmed sorely ESCC without other histology subtypes.
2. Thoracic esophageal cancer.
3. No prior anti-cancer treatment, including but not limited to surgery, radiotherapy, chemotherapy, targeted therapy, or immunotherapy.
4. Borderline unresectable locally advanced ESCC deemed by investigators as suspicious of but not confirmed T4b according to the American Joint Committee on Cancer (AJCC) 8th edition staging classification or extracapsular lymph node involvement (ELNI).
5. The Karnofsky Performance Scale (KPS) ≥70.
6. Normal primary organ functions, including but not limited to hemoglobin (Hb) ≥ 100g/L; white blood cell (WBC) ≥ 3.5×10\*9/L; neutrophil count (NEUT) ≥ 1.5×10\*9/L; platelets (PLT) ≥ 100×10\*9/L; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5×UNL; total bilirubin (TBIL) ≤ 1.5×UNL; creatinine ≤ 1.5UNL; blood urea nitrogen (BUN) ≤ 1.0×UNL.

Exclusion Criteria:

1. Synchronous and metachronous primary malignancies in but not limited to the upper aerodigestive tract, except for cured basal cell carcinoma of the skin and carcinoma in situ of the cervix.
2. Patients have undergone any type of anti-cancer treatment.
3. Baseline clinical stage M1 per AJCC 8th edition of staging classification, including supraclavicular lymph node metastases.
4. Investigators assessed major vessel involvement with high-risk hemorrhage.
5. A higher probability of esophageal perforation during conversion therapy.
6. Active infectious diseases, including but not limited to tuberculosis, hepatitis B virus, or hepatitis C virus.
7. Allergic to anti-cancer agents, including but not limited to anti-PD-1 or chemotherapy agents.
8. Given cardiopulmonary dysfunction, patients can not tolerate conversion therapy or surgery.
9. Pregnant or lactating women and women of childbearing potential who lacked effective contraception.
10. Non-compliance with the inclusion criteria judged by investigators.

**Maximum Age:** 75 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** beryl_wx2000@163.com

**Name:** Xin Wang, Doctor

**Phone:** 13311583220

**Role:** CONTACT

**Contact 2:**

**Email:** zy_zhengw@163.com

**Name:** Ziyu Zheng, B.M

**Phone:** 13552252161

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Beijing

**Contacts:**

***Contact 1:***

- **Email:** beryl_wx2000@163.com

- **Name:** Xin Wang, MD

- **Phone:** +861013311583220

- **Role:** CONTACT

**Country:** China

**Facility:** Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC)

**Status:** RECRUITING

**Zip:** 100021

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000005770

- Term: Gastrointestinal Neoplasms

- ID: D000004067

- Term: Digestive System Neoplasms

- ID: D000009371

- Term: Neoplasms by Site

- ID: D000009369

- Term: Neoplasms

- ID: D000006258

- Term: Head and Neck Neoplasms

- ID: D000004066

- Term: Digestive System Diseases

- ID: D000004935

- Term: Esophageal Diseases

- ID: D000005767

- Term: Gastrointestinal Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC04

- Name: Neoplasms

- Abbrev: All

- Name: All Conditions

- Abbrev: BC06

- Name: Digestive System Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M5534

- Name: Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M5550

- Name: Carcinoma, Squamous Cell

- Relevance: LOW

- As Found: Unknown

- ID: M8088

- Name: Esophageal Neoplasms

- Relevance: HIGH

- As Found: Esophagus Cancer

- ID: M1733

- Name: Esophageal Squamous Cell Carcinoma

- Relevance: LOW

- As Found: Unknown

- ID: M8886

- Name: Gastrointestinal Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M7256

- Name: Digestive System Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M9348

- Name: Head and Neck Neoplasms

- Relevance: LOW

- As Found: Unknown

- ID: M8883

- Name: Gastrointestinal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7255

- Name: Digestive System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M8085

- Name: Esophageal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T2141

- Name: Esophageal Cancer

- Relevance: HIGH

- As Found: Esophagus Cancer

### Condition Browse Module - Meshes

- ID: D000004938

- Term: Esophageal Neoplasms

### Intervention Browse Module - Ancestors

- ID: D000074322

- Term: Antineoplastic Agents, Immunological

- ID: D000000970

- Term: Antineoplastic Agents

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M137899

- Name: Tislelizumab

- Relevance: HIGH

- As Found: Meet

- ID: M2853

- Name: Immunomodulating Agents

- Relevance: LOW

- As Found: Unknown

- ID: M1346

- Name: Antineoplastic Agents, Immunological

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: C000707970

- Term: Tislelizumab

### Misc Info Module

- Version Holder: 2024-05-31
