Clinical trial NCT05601505: Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer
Official title: Circulating Tumor DNA-guided Neoadjuvant Treatment Strategy for Locally Advanced Rectal Cancer --- a Multicenter Randomized Controlled Trial (CINTS-R)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Locally Advanced Rectal Carcinoma
Circulating Tumor DNA
Keywords: Locally advanced rectal cancer
circulating tumor DNA
Neoadjuvant chemoradiotherapy
Total neoadjuvant therapy
Randomized Controlled Trial
Lead sponsor: Peking Union Medical College Hospital
Sponsor class: OTHER
First posted: 2022-11-01
Enrollment: 470
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: two-year disease-related treatment failure, 2y-DrTF
timeFrame: 2 years
Secondary outcomes:
measure: Time to recurrence, TTR
timeFrame: 2 years
measure: Two-year overall survival, 2yOS
timeFrame: 2 years
measure: two-year disease-free survival (2yDFS)
timeFrame: 2 years
measure: clinical complete response (cCR) and near complete response (ncCR) rate
timeFrame: up to 1 year
measure: pathologically complete response (pCR) rate
timeFrame: up to 1 year
measure: pathological tumour regression grade (pTRG)
timeFrame: up to 1 year
measure: Quality of life assessment (QoL)
timeFrame: 5 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences,
state: Beijing
Study officials:
References: