Clinical trial NCT06599827: Neoadjuvant Moderately Hypofractionated Radiotherapy Combined with Chemotherapy and Immunotherapy for High-risk LARC
Official title: Neoadjuvant Moderately Hypofractionated Radiotherapy Combined with Chemotherapy and Immunotherapy for High-risk PMMR/MSS Locally Advanced Rectal Cancer: a Prospective, Exploratory Phase II Trial（iMHRT-LARC）
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Rectal Cancer
Keywords: Moderately Hypofractionated Radiotherapy
Immunotherapy
Locally Advanced Rectal Adenocarcinoma
Chemotherapy
Lead sponsor: Shanghai Zhongshan Hospital
Sponsor class: OTHER
First posted: 2024-09-19
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Patients will receive CapeOx chemotherapy, anti-PD-1 mAb immunotherapy, and moderately hypofractionated radiotherapy.
Primary purpose: TREATMENT

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.

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 \&amp;lt;2ULN, TB \&amp;lt;35μmol/L, Scr \&amp;lt;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 \&amp;gt;500 IU/ml, HCV RNA positive patients, except for inactive hepatitis B surface antigen carriers, stable hepatitis B (HBV DNA \&amp;lt;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 \&amp;gt;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.

Primary outcomes:
measure: pathologic complete response (pCR)
timeFrame: 30-day
Secondary outcomes:
measure: disease-free survival (DFS)
timeFrame: 3-year
measure: event-free survival (EFS)
timeFrame: 3-year
measure: objective response rate (ORR)
timeFrame: 3-month
measure: overall survival (OS)
timeFrame: 3-year
measure: adverse events
timeFrame: 3-year
measure: Quality of Life (QoL)-LARS socre
timeFrame: 3-year
measure: Quality of Life (QoL)-Wexner score
timeFrame: 3-year
measure: Quality of Life (QoL)-FISI score
timeFrame: 3-year
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Zhongshan Hospital, Fudan University
state: Shanghai
Study officials:
affiliation: Fudan University
name: Jian Wang, MD
role: PRINCIPAL_INVESTIGATOR
References: