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

Primary Purpose

Locally Advanced Rectal Carcinoma, Circulating Tumor DNA

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
circulating tumor DNA
Sponsored by
Peking Union Medical College Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Locally Advanced Rectal Carcinoma focused on measuring Locally advanced rectal cancer, circulating tumor DNA, Neoadjuvant chemoradiotherapy, Total neoadjuvant therapy, Randomized Controlled Trial

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Aged 18-75 years; ECOG score 0-2; Rectal adenocarcinoma confirmed by pathology; The lower margin of the tumor was less than 12cm from the anal margin; Patients with clinical stage cT3-4N0M0 or cTanyN+M0; Newly treated patients who have not received treatment including radiotherapy, chemotherapy and surgery; Liver, kidney and other organs have good function and can tolerate radiotherapy, chemotherapy and surgery; Patients and family members can understand the study protocol, voluntarily participate in the study and sign informed consent. Exclusion Criteria: ECOG score > 2; Patients with multiple primary colorectal cancers; 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; Complicated with intestinal obstruction, intestinal perforation, gastrointestinal bleeding and other patients requiring emergency surgery; pregnant or lactating women; Patients with a history of severe mental illness, immune disease, hormone medication; Patients contraindicated by MRI examination, chemoradiotherapy, immunotherapy or surgery; Participated in other clinical researchers in the past 3 months; Any other circumstances that the investigator considers inappropriate for inclusion.

Sites / Locations

  • Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences,Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Traditional neoadjuvant chemoradiotherapy group

ctDNA-guided neoadjuvant treatment group

Arm Description

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

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.

Outcomes

Primary Outcome Measures

Disease-related treatment failure, DrTF
Refers to the time from the start of treatment to the first interruption of treatment Reasons for treatment interruption include tumor progression, adverse effects, patient selection, and death events

Secondary Outcome Measures

Time to recurrence, TTR
The median time from randomization to the first observation of recurrence.
overall survival, 2yOS
Refers to the proportion of patients still alive at 2 years after surgery

Full Information

First Posted
October 27, 2022
Last Updated
October 27, 2022
Sponsor
Peking Union Medical College Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05601505
Brief Title
Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer
Acronym
CINTS-R
Official Title
Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer --- a Multicenter Randomized Controlled Trial (CINTS-R)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2022 (Anticipated)
Primary Completion Date
November 1, 2024 (Anticipated)
Study Completion Date
November 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Peking Union Medical College Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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 immunetherapy 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 treatment group will receive different strategies after next generation sequencing of tumor tissue and IMC, those with MSI-H or TMB-H or POLE/PLOD1 mutation will be advised to receive immune therapy following neoadjuvant chemoradiotherapy (NCRT), and the others will be arranged to randomly receive NCRT (VAF<0.4%) or total neoadjuvant therapy (TNT) (VAF>0.4%) according to the VAF value of ctDNA; the control group will receive NCRT only.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Locally Advanced Rectal Carcinoma, Circulating Tumor DNA
Keywords
Locally advanced rectal cancer, circulating tumor DNA, Neoadjuvant chemoradiotherapy, Total neoadjuvant therapy, Randomized Controlled Trial

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
465 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Traditional neoadjuvant chemoradiotherapy group
Arm Type
No Intervention
Arm Description
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
Arm Title
ctDNA-guided neoadjuvant treatment group
Arm Type
Experimental
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
circulating tumor DNA
Intervention Description
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.
Primary Outcome Measure Information:
Title
Disease-related treatment failure, DrTF
Description
Refers to the time from the start of treatment to the first interruption of treatment Reasons for treatment interruption include tumor progression, adverse effects, patient selection, and death events
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Time to recurrence, TTR
Description
The median time from randomization to the first observation of recurrence.
Time Frame
2 years
Title
overall survival, 2yOS
Description
Refers to the proportion of patients still alive at 2 years after surgery
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Aged 18-75 years; ECOG score 0-2; Rectal adenocarcinoma confirmed by pathology; The lower margin of the tumor was less than 12cm from the anal margin; Patients with clinical stage cT3-4N0M0 or cTanyN+M0; Newly treated patients who have not received treatment including radiotherapy, chemotherapy and surgery; Liver, kidney and other organs have good function and can tolerate radiotherapy, chemotherapy and surgery; Patients and family members can understand the study protocol, voluntarily participate in the study and sign informed consent. Exclusion Criteria: ECOG score > 2; Patients with multiple primary colorectal cancers; 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; Complicated with intestinal obstruction, intestinal perforation, gastrointestinal bleeding and other patients requiring emergency surgery; pregnant or lactating women; Patients with a history of severe mental illness, immune disease, hormone medication; Patients contraindicated by MRI examination, chemoradiotherapy, immunotherapy or surgery; Participated in other clinical researchers in the past 3 months; Any other circumstances that the investigator considers inappropriate for inclusion.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Lin guole, Doctor
Phone
13801081483
Email
linguole@126.com
Facility Information:
Facility Name
Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences,
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100005
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lin guole, doctor
Phone
13801081483
Email
linguole@126.com

12. IPD Sharing Statement

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Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer

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