Efficacy and Safety Comparison of Short-course Radiotherapy Followed by CapeOX Chemotherapy Plus Toripalimab With or Without Concurrent Surufatinib in Neoadjuvant Therapy for Mid-to-low Localized Rectal Cancer of High-risk Criteria

Phase 3RecruitingNCT07505472

The First Hospital of Jilin University212 enrolled

Overview

Why is this study conducted? The purpose of this study is to improve the treatment efficacy, particularly the pathological complete response rate, in patients with high-risk/extremely high-risk locally advanced rectal cancer (LARC). In recent years, with the combination of neoadjuvant chemoradiotherapy and immunotherapy, some progress has been made in the treatment of rectal cancer, but there are still problems of regional recurrence and distant metastasis. Therefore, developing new treatment strategies for these patients is particularly important. The treatment of rectal cancer usually involves surgery, radiation therapy, and chemotherapy. The current treatment methods have gradually shifted towards neoadjuvant chemoradiotherapy combined with immunotherapy, and have shown good potential in some clinical trials. These studies suggest that combining short-range radiotherapy, anti angiogenic drugs, and immune checkpoint inhibitors may play an important role in improving patient prognosis and enhancing tumor response rates. However, the efficacy and safety of these plans in high-risk patients still need further validation. In this context, the aim of our study is to compare the efficacy and safety of neoadjuvant short-course radiotherapy followed by four cycles of CapeOX chemotherapy combined with toripalimab, with or without concurrent surufatinib, in patients with mid-to-low locally advanced rectal cancer with high-risk factors identified by MRI (including any one or more of the following: cT4, cN2, EMVI+, MRF/CRM+, or lateral lymph node metastas. This study aims to promote treatment optimization for LARC patients and provide new ideas for future treatments. Why are you invited to participate in this study? We would like to invite you to participate in this study as you have been diagnosed with high-risk or extremely high-risk locally advanced rectal cancer, which meets the inclusion criteria of this study. Specifically, you need to meet the conditions for pathological diagnosis, have a suitable tumor location, and not have serious comorbidities or other excluded diseases (such as recurrent rectal cancer, cardiac dysfunction, etc.). The final selection will be determined by the research doctor based on your actual situation. What do you need to do to participate in this study? Participating in this study will require you to follow a series of steps. You need to undergo regular medical examinations and evaluations, including blood tests, imaging examinations, and anorectal function assessments. During the research period, you may also need to fill out a questionnaire and provide some biological samples (such as blood samples), which will be used for the analysis of drug efficacy. The frequency and specific content of each follow-up will be informed by the research team to ensure your participation throughout the entire treatment process. I hope you can cooperate with these research steps to help us better understand the effectiveness of this treatment plan. What are the risks of participating in this study? This study involves the use of neoadjuvant short course radiotherapy, PD-1 monoclonal antibody (Terizumab), and anti angiogenic therapy (Sofantinib). Participants may face the following risks: Risk of neoadjuvant short course radiotherapy: Participants may experience severe side effects (≥ grade 3), including but not limited to severe diarrhea, third degree neutropenia, and third degree radiation dermatitis. These side effects may seriously affect the quality of life of patients. Risk of PD-1 monoclonal antibody: Terriptylimab may cause immune related adverse reactions (irAEs), which can involve any organ. The commonly known irAEs include skin toxicity (such as papules and itching, with an incidence of 30% to 40%), diarrhea and/or colitis (8% to 19%), fatigue (16% to 24%), immune related hepatitis (5%), hypothyroidism (4% to 10%), and hyperthyroidism (4%). Overall, nearly two-thirds (about 2/3) of patients receiving immune checkpoint inhibitor therapy will experience varying degrees of irAEs, and the incidence of serious adverse events cannot be ignored. Risk of anti angiogenic therapy: The use of sorafenib may lead to adverse reactions related to its anti angiogenic and immunomodulatory effects. Known common adverse reactions include proteinuria, hypertension, bleeding, liver dysfunction, diarrhea, etc., with an incidence rate of over 20%. Among serious adverse events (≥ grade 3), hypertension (29.7%), proteinuria (14.5%), liver dysfunction (12.8%), and bleeding (4.5%) are the most common. In rare cases, treatment-related deaths may occur due to gastrointestinal bleeding, cerebral hemorrhage, etc. Handling of research related injuries? This study is an intervention study that does not add any additional risks beyond routine clinical diagnosis and treatment. If you suffer harm due to participating in the study, compensation or liability will be determined in accordance with relevant laws and regulations.

Interventions

Experimental GroupDRUG

Patients in the experimental group of this study began continuous oral administration of sofentanil at a dose of 200 mg once daily, starting 2 days after completion of neoadjuvant short-course radiotherapy. The final dose was administered on day 14 of the last capecitabine cycle of the CapeOX chemotherapy regimen, resulting in a total oral administration period of 12 weeks. Both the experimental group and control group in this study will commence 4 cycles of CapeOX chemotherapy combined with toripalimab immunotherapy one week after completion of neoadjuvant short-course radiotherapy. \[CapeOX\] regimen: Oxaliplatin 130 mg/m², d1, IV (2-hour infusion); Capecitabine 1250 mg/m², p.o., d1-14, BID, Q3W; Toripalimab 240 mg, IV, d1, Q3W.

Control groupDRUG

One week after the completion of neoadjuvant short-course radiotherapy, patients will receive 4 cycles of CapeOX chemotherapy combined with toripalimab immunotherapy.CapeOX regimen:Oxaliplatin 130 mg/m², intravenous infusion for 2 hours on day 1;Capecitabine 1250 mg/m², orally, twice daily on days 1-14, every 3 weeks;Toripalimab 240 mg, intravenous infusion on day 1, every 3 weeks.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 1\. Patients and their families are able to understand and willing to participate in this clinical study and sign the informed consent form; 2. Age: 18\~75 years old, male or female; 3. Pathologically confirmed rectal tubular adenocarcinoma; Differentiation into Grade 1-3, i.e., high, intermediate, and low-grade adenocarcinoma; pMMR/MSS phenotype; 4. Medium and low rectal cancer with the lower edge of the tumor located within 10cm from the anal verge; 5. Inclusion of treatment-naïve risk factors: cT4/cN2/mrMRF+/EMVI+ or lateral lymph node involvement. 6\. No distant metastases; 7. ECOG score 0-1; 8. Hepatitis B surface antigen (HBsAg) (-) and hepatitis B core antibody (HBcAb) (-). If HBsAg (+) or HBcAb (+), hepatitis B virus deoxyribonucleic acid (HBV-DNA) must \< 1000 copies/mL or 200 IU/mL for enrollment; 9. HCV antibody (-); 10. Negative serum or urine pregnancy test for females of childbearing age; 11. Females of childbearing potential or males with potential reproductive partners should agree to use adequate contraception (such as intrauterine devices, birth control pills, or condoms) for the duration of the study and for 120 days after the end of the study; 12. No history of pelvic radiotherapy; 13. No history of surgery or chemotherapy for rectal cancer; 14. Not accompanied by systemic infections requiring antibiotic treatment; 15. Heart, lung, liver, and kidney function can tolerate surgery; Exclusion Criteria: * 1\. Recurrent rectal cancer; 2. ECOG score of 2 points or above; 3. Occurrence of cardiovascular and cerebrovascular diseases within 6 months prior to the first dose: cerebrovascular accident/stroke, myocardial infarction, unstable angina, poorly controlled arrhythmias (including QTc interval ≥ 450 ms for males and 470 ms for females≥ (QTc interval is calculated by Fridericia's formula); 4. Presence of NYHA standard grade III.\~IV. cardiac insufficiency or cardiac color ultrasound examination: LVEF (left ventricular ejection fraction) \< 50%; 5. Presence of hypertension (systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥90mmHg) that cannot be controlled by antihypertensive drugs; 6. Urine routine showed that urine protein was ≥++, and 24-hour urine protein was \> 1.0g; 7. History of immunodeficiency, including human immunodeficiency virus (HIV) infection; Other acquired, congenital immunodeficiency diseases; History of organ or bone marrow transplantation; 8. Treatment with a live vaccine within 28 days prior to the first dose, except inactivated viral vaccines for seasonal influenza; 9. Previous and current presence of known active or suspected autoimmune disease (except for patients with hypothyroidism controlled by hormone replacement therapy and type I diabetes mellitus who only require control with insulin replacement therapy); 10. Have active tuberculosis; 11. Patients with previous and current interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe impairment of lung function, etc., which may interfere with the detection and management of suspected drug-related pulmonary toxicity; 12. Previous treatment with other small molecule anti-angiogenic targeted drugs or antibody/drug therapy against immune checkpoints, such as PD-1 inhibitors, PD-L1, CTLA4, etc.; 13. Known history of severe allergy to PD-1 monoclonal antibody active ingredient, TKI inhibitor related components, or any investigational drug excipient; 14. Patients with organ bleeding or bleeding tendency, except for rectal primary tumor bleeding (the investigator needs to assess the bleeding risk); 15. Those who have suffered from malignant tumors in the past; 16. Received other types of anti-tumor or experimental therapy; 17. Pregnant or lactating females; 18. Patients with central nervous system diseases or abnormal mental status, which may affect the patient's participation in this study; 19. Patients with other severe, acute and chronic diseases that may increase the risk of participating in the study and study medication, and are judged by the investigator to be unsuitable for participating in the clinical study;

Outcomes

Primary Outcomes

pathologic complete response，pCR

Pathologic complete response (pCR) rate is defined as the percentage of patients who achieve pCR after neoadjuvant therapy within the eligible population . Pathologic complete response (pCR) is characterized by the absence of invasive cancer in the primary rectum and negative regional lymph nodes following adequate or complete sampling (ypT0N0, tumor regression grade \[TRG\] 0 points) . Microscopically, cancer cells in the tumor bed are absent, with possible infiltration of inflammatory cells in the interstitium. Additionally, foamy cells and fibrous tissue proliferation may be observed.

Time frame: 2 year

Secondary Outcomes

2-year sustained clinical complete response (cCR)

Complete tumor regression following neoadjuvant therapy, with no residual tumor detected at the primary site or in lymph node drainage areas via digital rectal examination, multi-site endoscopic biopsy, and imaging studies (yielding clinical T0N0, ycT0N0), accompanied by normal serum carcinoembryonic antigen (CEA) levels. (Evaluation criteria refer to the European Society for Medical Oncology (ESMO) Colorectal Cancer Guidelines 2025 Edition). This state persists for 2 years (approximately 20%-25% of rectal cancer patients experience in situ regrowth at the tumor bed and distant metastasis within 2 years after initial cCR assessment, with the risk of in situ regrowth significantly higher in the first year post-assessment than in the second year). Therefore, sustained clinical complete remission for 2 years is one of the secondary endpoints of this study.

Time frame: 2 year

Complete Remission (CR) Rate

The sum of pCR and cCR. It is calculated as the percentage of patients who achieve pCR and a sustained cCR for 2 years after neoadjuvant therapy, relative to the per-protocol population.

Time frame: 2 year

Major Pathological Remission (MPR)

MPR refers to the percentage of patients in the surgical population whose postoperative pathology confirms that the active tumor component of the primary tumor has been reduced to less than 10%.

Time frame: 2 year

Neoadjuvant Rectal Score NAR

\[5pN - 3(cT - pT) + 12\]2 / 9.61

Time frame: 2 year

3-Year Disease-Free Survival (3y-DFS)

This is defined as the time interval from radical rectal resection to events such as death, local pelvic recurrence, distant metastases, or the end of follow-up, within a 3-year period. Local recurrence is defined as the appearance of clinical, radiographic, or pathological evidence (consistent with the pathological type of the primary tumor) within the pelvic region, as confirmed by digital rectal examination, colonoscopy, CT/MRI, PET-CT, and, if necessary, needle biopsy. Disease progression refers to progression disease (PD) as assessed according to RECIST 1.1 criteria. Distant metastasis is defined as the appearance of metastases outside the pelvis, including in the liver, lungs, bones, para-aortic region, or inguinal lymph nodes.

Time frame: 3 year

3-year Event-Free Survival（3y-EFS）

This is defined as the time interval from the initiation of neoadjuvant therapy to events such as death, local pelvic recurrence, distant metastases, or the end of follow-up, within a 3-year period. Local recurrence is defined as the appearance of clinical, radiographic, or pathological evidence (consistent with the pathological type of the primary tumor) within the pelvic region, as confirmed by digital rectal examination, colonoscopy, CT/MRI, PET-CT, and, if necessary, needle biopsy. Disease progression refers to progression disease (PD) as assessed according to RECIST 1.1 criteria. Distant metastasis is defined as the appearance of metastases outside the pelvis, including in the liver, lungs, bones, para-aortic region, or inguinal lymph nodes.

Time frame: 3 year

5-Year Overall Survival (5y-OS)

This refers to the time interval from the diagnosis of rectal cancer to death or the end of follow-up, within 5 years.

Time frame: 5 year

3-Year Local Recurrence-Free Survival (3y-LRFS)

Defined as the time interval from the initiation of neoadjuvant therapy to events such as local recurrence (including recurrence in the tumor bed and/or regional lymph nodes), death, or the end of follow-up within 3 years.

Time frame: 3 year

3-Year Distant Metastasis-Free Survival (3y-DMFS)

Defined as the time interval from the start of neoadjuvant therapy to the occurrence of distant metastases (including non-regional lymph nodes, distant organs, or lymph nodes), death, or the end of follow-up, within 3 years.

Time frame: 3 year

3-year stoma-free survival (SFS)

This is the time interval from the start of neoadjuvant therapy to the occurrence of permanent ostomy surgery (including diversion stoma that cannot be reversed for any reason), death, or the end of follow-up within 3 years.

Time frame: 3 year

Anal sphincter preservation rate

The percentage of patients who undergo anal sphincter-preserving surgery among all surgical patients.

Time frame: 3 year

R0 resection rate

This is the proportion of patients who achieve R0 resection (i.e., postoperative pathological confirmation of no macroscopic tumor at the surgical margin, and no tumor cells within 1 mm of the margin under microscopy) out of all surgical patients. Calculation formula: R0 resection rate=R0 resection patients/(R0 resection patients+non-R0 resection patients).

Time frame: 3 year

Incidence of Complications within 30 Days after Surgery

This refers to adverse reactions occurring within 30 days after radical surgery, including anastomotic bleeding, anastomotic leakage, obstruction, and other related indicators.

Time frame: 30 days

Safety

The safety assessment will include the monitoring and recording of all treatment-related adverse events (including serious adverse events), laboratory tests (e.g., complete blood count, blood biochemistry, pituitary function tests, blood cortisol levels, plasma adrenocorticotropic hormone \[ACTH\], coagulation profile, urinalysis, thyroid function tests, etc.), 12-lead ECG, vital signs, and physical examination.

Time frame: 3 year

Rectal and Anal Function Assessment

The assessment will include the LARS score, Wexner incontinence score, and rectoanal manometry (when the anus is present). Voiding function will be assessed by measuring residual bladder urine volume. The assessment will be performed at 1 and 2 years before and after neoadjuvant concurrent chemoradiotherapy, watchful waiting, or preoperative and postoperative periods.

Time frame: 3 year

Efficacy and Safety Comparison of Short-course Radiotherapy Followed by CapeOX Chemotherapy Plus Toripalimab With or Without Concurrent Surufatinib in Neoadjuvant Therapy for Mid-to-low Localized Rectal Cancer of High-risk Criteria

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts