Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer (CINTS-R)

Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer --- a Multicenter Randomized Controlled Trial (CINTS-R)

Rectal cancer still remains one of the most popular tumors, however, distance metastasis still remains as high as 30% and the long-term survival outcomes are still unsatisfying. The recent conception of total neoadjuvant therapy and immune therapy is becoming popular and the oncologic effects are encouraging, especially in terms of circulating tumor DNA (ctDNA), the prognostic value of ctDNA has been demonstrated by our prior study. This study will carry out accurate ctDNA-guided neoadjuvant therapy on the basis of previous studies of the research group, and give appropriate treatment plans and treatment intensity to patients with different disease degrees. At the same time, combined with the latest progress in clinical diagnosis and treatment, the potential beneficiaries of immunotherapy were screened scientifically, and the combined immunotherapy was implemented accordingly.

Study Overview

• Status: Recruiting
• Conditions: Circulating Tumor DNA; Locally Advanced Rectal Carcinoma
• Intervention / Treatment: Other: circulating tumor DNA

Detailed Description

Rectal cancer still remains one of the most popular tumors, a multidisciplinary approach including neoadjuvant chemoradiotherapy, total mesorectal excision and adjuvant chemotherapy has resulted a satisfying oncologic outcome in terms of reducing local recurrence and improving local control of disease for the treatment of rectal cancer, however, distance metastasis still remains as high as 30% and the long-term survival outcomes is still unsatisfying.

The recent conception of total neoadjuvant therapy and immune therapy is becoming popular and the oncologic effects are encouraging, especially in terms of circulating tumor DNA (ctDNA), the prognostic value of ctDNA has been demonstrated by our prior study. This study demonstrated that ctDNA is an effective marker of tumor burden in real time and for the first time identified baseline ctDNA mutation frequency before nCRT as an independent prognostic factor for recent LARC recurrence and metastasis. This suggests that patients with different tumor burden according to baseline ctDNA mutation frequency should be given neoadjuvant therapy with corresponding intensity, in order to improve systemic disease control in patients with high risk of recurrence and metastasis, and to avoid overtreatment in patients with low risk.

In conclusion, this study will carry out accurate ctDNA-guided neoadjuvant therapy on the basis of previous studies of the research group, and give appropriate treatment plans and treatment intensity to patients with different disease degrees. At the same time, combined with the latest progress in clinical diagnosis and treatment, the potential beneficiaries of immunotherapy were screened scientifically, and the combined immunotherapy was implemented accordingly. With the development of this study, several precision medicine research results obtained by our research group will be expected to be translated into clinical practice as soon as possible, which will improve the efficacy of LARC patients, reduce the rate of adverse reactions, and ultimately promote the improvement of the treatment level of rectal cancer and the more reasonable use of public medical resources.

The patients with locally advanced rectal cancer staged as cT3-4N0/cTanyN+ will be included in this study. Patients will be randomized into two groups, the experimental group will receive different strategies after next generation sequencing of tumor tissue and IMC, those with MSI-H or TMB-H will be advised to receive immune therapy, and the others will be arranged to randomly receive NCRT (baseline VAF<0.5%) or total neoadjuvant therapy (TNT) (baseline VAF≥0.5% or a positive post-CRT ctDNA) according to the VAF value of ctDNA; the control group will receive modified NCRT only.

• Study Type: Interventional
• Enrollment (Estimated): 470
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lin guole, doctor; Phone Number: 13801081483; Email: linguole@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100005
      • Recruiting
      • Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences,
      • Contact: Lin guole, doctor; Phone Number: 13801081483; Email: linguole@126.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Aged 18-75 years;
2. ECOG score 0-2;
3. Rectal adenocarcinoma confirmed by pathology;
4. The lower margin of the tumor was less than 12cm from the anal margin;
5. Patients with clinical stage cT3-4N0M0 or cTanyN+M0;
6. Newly treated patients who have not received treatment including radiotherapy, chemotherapy and surgery;
7. Liver, kidney and other organs have good function and can tolerate radiotherapy, chemotherapy and surgery;
8. Patients and family members can understand the study protocol, voluntarily participate in the study and sign informed consent.

Exclusion Criteria:

1. ECOG score > 2;
2. Patients with multiple primary colorectal cancers;
3. A history of other malignant tumors (other than cured basal cell carcinoma, cervical carcinoma in situ, surgically treated localized prostate cancer, or surgically resected breast ductal carcinoma in situ) within the past 5 years;
4. Complicated with intestinal obstruction, intestinal perforation, gastrointestinal bleeding and other patients requiring emergency surgery;
5. pregnant or lactating women;
6. Patients with a history of severe mental illness, immune disease, hormone medication;
7. Patients contraindicated by MRI examination, chemoradiotherapy, immunotherapy or surgery;
8. Participated in other clinical researchers in the past 3 months;
9. Any other circumstances that the investigator considers inappropriate for inclusion.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Traditional neoadjuvant chemoradiotherapy group; Eligible patients randomized into arm A will receive traditional neoadjuvant chemoradiotherapy, including long-course radiotherapy with a total number of 45-50.4Gy in 25-28 fractions, and with concurrent 3 times of oral capecitabine, the strategies of capecitabine are: During radiotherapy: capecitabine 1650mg/m2/d, orally administered twice a day, d1-d14, every 3 weeks as a course; During the non-radiotherapy period: capecitabine 2000mg/m2/d, orally administered twice daily, d1-d14, every 3 weeks as a course
Experimental: ctDNA-guided neoadjuvant treatment group; After sequencing tumor tissue, those with MSI-H/TMB-H or POLD/POLE2 mutation willed be arranged to receive immune therapy following NCRT，Terelizumab，200mg. The others are arranged to randomly receive TNT (VAF>0.4%) or NCRT (VAF<0.4%) according to VAF value by the level of ctDNA. TNT： Long course radiotherapy combined with 2 courses of single-agent capecitabine chemotherapy → 6 courses of CapeOX (Capecitabine 2000mg/m2/ day, twice orally, d1-14; Oxaliplatin 100-130mg/m2, intravenous infusion, d1; Every 3 weeks for a course of treatment.) chemotherapy was performed 2 to 3 weeks after the end of chemotherapy.	Other: circulating tumor DNA; This study will further testify the prognostic value of ctDNA in the treatment term of locally advanced rectal cancer, the higher the VAF value, the higher the risk of recurrence and metastasis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
two-year disease-related treatment failure, 2y-DrTF	the incidence of any of the following events occurring after treatment: identification of distant metastasis or progression to unresectable disease before surgery, non-radical resection of the primary tumour, local recurrence or distant metastasis after radical surgery, new primary colorectal tumour, or treatment-related death.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to recurrence, TTR	The median time from randomization to the first observation of recurrence.	2 years
Two-year overall survival, 2yOS	Refers to the proportion of patients still alive at 2 years after surgery	2 years
two-year disease-free survival (2yDFS)	the percentage of patients who remain free of cancer recurrence or death from any cause two years after surgery.	2 years
clinical complete response (cCR) and near complete response (ncCR) rate	cCR and ncCR rate evaluated based on comprehensive examinations according to NCCN guidelines.	up to 1 year
pathologically complete response (pCR) rate	the percentage of patients who are assessed as pathologically complete response (pCR) by pathologist.	up to 1 year
pathological tumour regression grade (pTRG)	pathological tumor regression grade which is determined according to the criteria of the American Joint Committee on Cancer (AJCC) 8th edition	up to 1 year
Quality of life assessment (QoL)	it will be assessed by European Organization for Research and Treatment of Cancer (EORTC) questionnaires at each follow-up visit.	5 years

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2023
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: October 27, 2022
• First Submitted That Met QC Criteria: October 27, 2022
• First Posted (Actual): November 1, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 19, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Locally advanced rectal cancer; Randomized Controlled Trial; circulating tumor DNA; Neoadjuvant chemoradiotherapy; Total neoadjuvant therapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms
• Other Study ID Numbers: 2022-PUMCH-C-005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified participant data from the final research dataset used in the published manuscript will be available from the corresponding author at reasonable request. They may only be shared under the terms of a Data Use Agreement. Data from this clinical trial will only be shared in compliance with national regulations.
• IPD Sharing Time Frame: The datasets analyzed during the current study and other supporting information will be available no earlier than 1 year following the date of publication.
• IPD Sharing Access Criteria: IPD and supporting information can be accessed based on reasonable request by contacting the corresponding author.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

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