A Study of Total Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

A Prospective, Multicenter, Randomized Controlled Trial of Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

A Phase II Study of Total Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

Study Overview

• Status: Active, not recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Procedure: TME; Combination product: Concurrent Chemoradiotherapy; Drug: XELOX; Drug: mFOLFOX

Detailed Description

Recommended treatment of patients with locally advanced rectal cancer (LARC) includes preoperative chemoradiation (CRT), total mesorectal excision (TME) and postoperative adjuvant chemotherapy (ACT). However, treatments fail to show an improved therapeutic effect on high-risk patients now. Total neoadjuvant therapy (TNT) is a new try for rectal cancer treatment,and this trial aims to identify and select the more promising TNT sequence.

This trail is a multicenter, randomized, phase II trial . Eligible patients age from 18 to 75 years with histologically confirmed rectal adenocarcinoma. MRI is mandatory, and patients of stage II or III rectal cancer are eligible if any of the following criteria are fulfilled: Categories T4,Categories N2, MRF involvement, EMVI positive, and lateral lymph node involvement. Patients are randomly assigned to 3 groups, group 1: concurrent chemoradiotherapy → TME → adjuvant chemotherapy (control group);or group 2: concurrent chemoradiotherapy → consolidation chemotherapy → TME (CNCT group);Or group 3: induction chemotherapy → concurrent chemoradiotherapy →TME ( INCT group).The primary end point is the rate of tumor down-staging, which is defined as stage yp0-II after surgery,and watch-and-wait strategy after complete clinical response (cCR) was allowed. Secondary end points include acute toxicity, compliance with TNT, surgical complications, 3-year overall survival (3yOS),3-year disease free survival (3yDFS),3-year distant metastatic free survival(3yDMFS),3-year locoregional recurrence-free survival(3yLRRFS) and quality of life.

• Study Type: Interventional
• Enrollment (Estimated): 255
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jing Jin, M.D.; Phone Number: 0086-13601365130; Email: jingjin1025@163.com

Study Locations

• China
  • Beijing, China, 100021
    • Department of Radiation Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. 18-75 years old, regardless of gender
2. Histologically confirmed rectal adenocarcinoma;
3. Up to 12 cm above the anal verge on the basis of rigid rectoscopy.
4. MRI of the rectum is acceptable;
5. Patients in stage II or III rectal cancer are eligible if any of the following criteria are fulfilled: Categories T4,Categories N2, MRF involvement, EMVI positive, and lateral lymph node involvement.
6. ECOG score 0-1 or KPS score ≥80.

Exclusion Criteria:

1. History of malignant tumor in other parts;
2. Cannot complete MRI; Allergic to 5-fu drugs; Allergic to platinum drugs;
3. During thrombolytic and anticoagulant therapy, the patient has bleeding diathesis or coagulation dysfunction; Or aneurysm, stroke, transient ischemic attack, arteriovenous malformation in the past year;
4. History of kidney, urine test found proteinuria or clinical renal function was significantly abnormal;
5. History of digestive tract fistula, perforation or severe ulcer;
6. Active infection is present; Clinically obvious heart disease; New York heart association (NYHA) of Ⅱ level or congestive heart failure; Unstable symptomatic arrhythmia or peripheral vascular disease ≥ grade II; Myocardial infarction and cerebrovascular accident occurred within 6 months before enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: adjuvant chemotherapy group; concurrent chemoradiotherapy → TME → adjuvant chemotherapy (control group)	Procedure: TME; Total mesorectal excision; Combination product: Concurrent Chemoradiotherapy; Radiotherapy: 50Gy in 25 fractions to the primary tumor and to mesorectal, presacral,and internal iliac lymph nodes. Concurrent chemotherapy: Capecitabine 1650 mg/m2/d; Drug: XELOX; Intravenous infusion of oxaliplatin (130 mg/m2 over 2 h) on day 1 and oral administration of capecitabine (1000 mg/m2 twice daily) from day 1 to day 14, is repeated every 3 weeks for 6 cycles. 6 courses，3 weeks per course; Other Names: CAOPX; Drug: mFOLFOX; Administration of l-LV (400 mg/m2) and oxaliplatin (85 mg/ m2) by intravenous infusion over 2 h, followed by rapid intravenous infusion (iv) of 5-FU (400 mg/m2) and then slow infusion (civ) of 5-FU (2400 mg/m2 over 46 h), is repeated every 2 weeks for 9 cycles.
Experimental: consolidation chemotherapy group (CNCT group); concurrent chemoradiotherapy → consolidation chemotherapy → TME (CNCT group)	Procedure: TME; Total mesorectal excision; Combination product: Concurrent Chemoradiotherapy; Radiotherapy: 50Gy in 25 fractions to the primary tumor and to mesorectal, presacral,and internal iliac lymph nodes. Concurrent chemotherapy: Capecitabine 1650 mg/m2/d; Drug: XELOX; Intravenous infusion of oxaliplatin (130 mg/m2 over 2 h) on day 1 and oral administration of capecitabine (1000 mg/m2 twice daily) from day 1 to day 14, is repeated every 3 weeks for 6 cycles. 6 courses，3 weeks per course; Other Names: CAOPX; Drug: mFOLFOX; Administration of l-LV (400 mg/m2) and oxaliplatin (85 mg/ m2) by intravenous infusion over 2 h, followed by rapid intravenous infusion (iv) of 5-FU (400 mg/m2) and then slow infusion (civ) of 5-FU (2400 mg/m2 over 46 h), is repeated every 2 weeks for 9 cycles.
Experimental: induction chemotherapy group (INCT group); induction chemotherapy → concurrent chemoradiotherapy →TME ( INCT group).	Procedure: TME; Total mesorectal excision; Combination product: Concurrent Chemoradiotherapy; Radiotherapy: 50Gy in 25 fractions to the primary tumor and to mesorectal, presacral,and internal iliac lymph nodes. Concurrent chemotherapy: Capecitabine 1650 mg/m2/d; Drug: XELOX; Intravenous infusion of oxaliplatin (130 mg/m2 over 2 h) on day 1 and oral administration of capecitabine (1000 mg/m2 twice daily) from day 1 to day 14, is repeated every 3 weeks for 6 cycles. 6 courses，3 weeks per course; Other Names: CAOPX; Drug: mFOLFOX; Administration of l-LV (400 mg/m2) and oxaliplatin (85 mg/ m2) by intravenous infusion over 2 h, followed by rapid intravenous infusion (iv) of 5-FU (400 mg/m2) and then slow infusion (civ) of 5-FU (2400 mg/m2 over 46 h), is repeated every 2 weeks for 9 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The rate of tumor down-staging	Tumor down-staging is considered as Stage yp0-II after surgery, and watch-and-wait strategy after complete clinical response (cCR) was allowed.	6-8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of compliance with TNT	Rate of compliance with TNT	6-8 months
3y OS	3-year overall survival (3yOS)	3years
3y DFS	3-year disease free survival (3yDFS)	3years
3y DMFS	3-year distant metastatic free survival(3yDMFS)	3 years
3y LRRFS	3-year locoregional recurrence-free survival(3yLRRFS)	3 years
EORTC QLQ-C30	EORTC QLQ-C30 to assess the quality of life	3 years
EORTC QLQ-CR29	EORTC QLQ-CR29 to assess the quality of life	3 years
Wexner continence grading scale	Wexner continence grading scale	3 years
CTCAE 4.0	Severe acute adverse reaction rate（≥III degree）	6-8months
Incidence of surgical complications	Incidence of surgical complications	6-8 months

Collaborators and Investigators

• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Collaborators: Xijing Hospital; Peking Union Medical College Hospital; Peking University Cancer Hospital & Institute; Jilin Provincial Tumor Hospital; Cancer Hospital of Guizhou Province
• Investigators: Study Director: Jing Jin, M.D., Chinese Academy of Medical Sciences and Peking Union Medical College

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2020
• Primary Completion (Actual): July 12, 2022
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: August 3, 2020
• First Submitted That Met QC Criteria: September 9, 2020
• First Posted (Actual): September 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Radiotherapy; Rectal Cancer; High Risk; Total Neoadjuvant Therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms
• Other Study ID Numbers: NCC201809007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No