Neoadjuvant Moderately Hypofractionated Radiotherapy Combined with Chemotherapy and Immunotherapy for High-risk LARC

NCT ID: NCT06599827

Last Updated: 2024-09-19

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-20
• Study Completion Date: 2029-09-20

Brief Summary

This study aims to evaluate the effectiveness and safety of combining moderately hypofractionated radiotherapy with chemotherapy and anti-PD-1 antibodies as a neoadjuvant treatment for high-risk locally advanced rectal cancer.

Detailed Description

This study investigates a novel treatment approach involving moderately hypofractionated radiotherapy (3-3.5Gy×10) combined with chemotherapy and immunotherapy for patients with high-risk locally advanced rectal adenocarcinoma, aiming to optimize treatment efficacy and patient outcomes.

Neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer, improving surgical resection rates, local control, and sphincter preservation. Conventional long-course radiotherapy is the standard modality for neoadjuvant therapy, but it has drawbacks such as long treatment duration, high cost, and prolonged preoperative waiting time. Short-course radiotherapy, on the other hand, offers shorter treatment duration, lower cost, and shorter preoperative waiting time, but it is associated with higher rates of local recurrence. Immunotherapy has demonstrated promising anti-tumor activity in colorectal cancers with deficient mismatch repair (dMMR) and/or microsatellite instability-high (MSI-H) status, but its role in proficient mismatch repair (pMMR) and/or microsatellite stable (MSS) colorectal cancers remains unclear. However, studies have shown that the combination of chemoradiotherapy and immunotherapy can increase the pathologic complete response rate compared to chemoradiotherapy alone, suggesting that radiotherapy may serve as a stimulator of adaptive immunity and synergize with immunotherapy. Therefore, this study aims to explore the following regimen: neoadjuvant moderately hypofractionated radiotherapy at a dose of 3.5 Gy × 10 fractions to the tumors and 3 Gy × 10 fractions to the pelvic lymph node drainage area, combined with chemotherapy (capecitabine and oxaliplatin) and immunotherapy (Serplulimab).

This prospective, single-center, non-randomized Phase II trial is designed to explore the efficacy and safety of the treatment regimen. Patients will receive CapeOx chemotherapy, anti-PD-1 monoclonal antibody immunotherapy, and a course of moderately hypofractionated radiotherapy. The trial protocol prioritizes safety monitoring and efficacy assessments through standardized clinical and imaging evaluations.

Conditions

Rectal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental group

This study examines combined radiotherapy, chemotherapy, and immunotherapy for high-risk locally advanced rectal cancer. After a week post-radiotherapy, patients start CapeOx chemotherapy with anti-PD-1 mAb. Surgery follows after 3 cycles of this regimen.

Group Type: EXPERIMENTAL

moderately hypofractionated radiotherapy

Intervention Type: RADIATION

35 Gy in 10 fractions to mesorectal and metastatic lymph nodes, and 30 Gy in 10 fractions to pelvic lymphatic drainage area, weekly over 5 days at 3-3.5 Gy/day.

chemotherapy

Intervention Type: DRUG

CapeOx-Capecitabine 1000 mg/m² orally twice daily (days 1-14, every 21 days) + Oxaliplatin 130 mg/m² IV (day 1, every 21 days).

immunotherapy

Intervention Type: DRUG

Serplulimab 300 mg IV infusion on day 1 every 21 days.

Total mesorectal excision (TME) surgery

Intervention Type: PROCEDURE

Total mesorectal excision (TME) surgery assessment post 3 cycles of chemotherapy and immunotherapy; eligible patients undergo TME surgery.

Interventions

moderately hypofractionated radiotherapy

35 Gy in 10 fractions to mesorectal and metastatic lymph nodes, and 30 Gy in 10 fractions to pelvic lymphatic drainage area, weekly over 5 days at 3-3.5 Gy/day.

Intervention Type: RADIATION

chemotherapy

CapeOx-Capecitabine 1000 mg/m² orally twice daily (days 1-14, every 21 days) + Oxaliplatin 130 mg/m² IV (day 1, every 21 days).

Intervention Type: DRUG

immunotherapy

Serplulimab 300 mg IV infusion on day 1 every 21 days.

Intervention Type: DRUG

Total mesorectal excision (TME) surgery

Total mesorectal excision (TME) surgery assessment post 3 cycles of chemotherapy and immunotherapy; eligible patients undergo TME surgery.

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

1. Age ≥18 and ≤75 years.

2. MRI-confirmed rectal adenocarcinoma with the lower edge of the lesion ≤10cm from the anal verge.

3. Immunohistochemistry confirms proficiency in DNA mismatch repair (pMMR), or genetic testing confirms microsatellite instability-low (MSI-L) or microsatellite stable (MSS) status.

4. Pelvic MRI showing one of the following high-risk factors: cT4a/b; N2; extramural vascular invasion (EMVI+); mesorectal fascia involvement (MRF+); enlarged lateral lymph nodes.

5. ECOG performance status of 0-1.

6. No prior surgery, radiotherapy, chemotherapy, or targeted therapy.

7. Tolerable to radiotherapy, chemotherapy, and immunotherapy with laboratory results: WBC ≥4.0 × 10^9/L, platelets ≥100 × 10^9/L, hemoglobin ≥80g/L, ALT <2ULN, TB <35μmol/L, Scr <1.5ULN or creatinine clearance rate ≥50mL/min, TSH ≤ULN (if abnormal, consider T3 and T4 levels; if T3 and T4 are normal, patients can still be included).

8. Voluntary participation with signed informed consent.

Exclusion Criteria

1. Distant metastases.

2. Stage I or II rectal cancer not requiring neoadjuvant therapy.

3. Severe cardiovascular, pulmonary, neurological, renal, gastrointestinal, or systemic diseases.

4. Untreated chronic hepatitis B carrier with HBV DNA >500 IU/ml, HCV RNA positive patients, except for inactive hepatitis B surface antigen carriers, stable hepatitis B (HBV DNA <500 IU/ml), and cured hepatitis C patients.

5. History of active autoimmune diseases or potential relapse of autoimmune diseases.

6. Patients who received corticosteroids (equivalent to prednisone >10mg/day) or other immunosuppressive therapy within 2 weeks prior to study drug administration.

7. History of thyroid dysfunction.

8. Severe chronic or active infections requiring systemic antifungal or antiviral therapy, including tuberculosis.

9. Known allergy or hypersensitivity to multiple drugs.

10. History of pelvic radiation.

11. History of inflammatory bowel disease.

12. Unwillingness to participate or sign informed consent.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shanghai Zhongshan Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jian Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Fudan University

Locations

Zhongshan Hospital, Fudan University

Shanghai, Shanghai Municipality, China

Countries

China

Central Contacts

Genwen Chen, MD, PhD

Role: CONTACT

chengenwen@fudan.edu.cn

86-021-64041990 ext. +86-1580212730

Facility Contacts

Genwen Chen, MD, PhD

Role: primary

chengenwen@fudan.edu.cn

+86-15802123840

Other Identifiers

B2024-271

Identifier Type: -

Identifier Source: org_study_id