Study on the Efficacy and Safety of Neoadjuvant Radiotherapy Combined With Tislelizumab, Liposomal Irinotecan, and Capecitabine in the Treatment of pMMR Locally Advanced Rectal Adenocarcinoma With Low Rectal Involvement

Overview

The goal of this clinical trial is to evaluating the efficacy and safety of radiotherapy combined with Tislelizumab, Liposomal Irinotecan, and Capecitabine in patients with locally advanced mid-lower rectal cancer with pMMR.. Patients would be included as:1. Aged between 18-75 years, with no gender restrictions; 2. Biopsy pathology confirmed as pMMR type locally advanced mid-lower rectal adenocarcinoma (tumor lower margin ≤ 10 cm from the anal verge); 3.With the following high-risk factors: T3N+/T4/N2/EMVI+/MRF+/lateral lymph node metastasis/inability to preserve anal function during surgery; 4. No distant metastasis observed in routine chest and abdominal CT scans.

Interventions

• Drug Liposomal Irinotecan+Tislelizumab+Capecitabine+Rradiotherapy
  In this study, the novel drug liposomal irinotecan was added, replacing the conventional formulation of irinotecan, and used as an intensified chemotherapy regimen (liposomal irinotecan + capecitabine) combined with immunotherapy and radiotherapy for neoadjuvant treatment of mid-lower rectal cancer.

Primary outcome measures

• Complete response (CR) rate [Time frame: At surgery, or at the confirmatory organ-preservation assessment approximately 12-16 weeks after the start of neoadjuvant therapy.]

Secondary outcome measures (8)

• Major pathological response (MPR) rate [Time frame: At surgery]
• Sphincter-preservation rate [Time frame: At surgery]
• R0 resection rate [Time frame: At surgery]
• Disease-free survival (DFS) [Time frame: Up to 24 months]
• Local-regrowth-free survival and TME-free survival (watch-and-wait subgroup) [Time frame: Up to 24 months]
• Anorectal function (LARS score) [Time frame: 3, 6, and 12 months after stoma reversal (resected) or after confirmed cCR (watch-and-wait)]
• Adverse events (safety and tolerability) [Time frame: From first dose until 28 days after the last dose]
• Treatment feasibility (regimen completion and dose intensity) [Time frame: From first dose to completion of neoadjuvant therapy (approximately 12-16 weeks)]

Eligibility criteria

Here is the updated format for the \*\*Eligibility Criteria\*\* with bullet points for each item:

Inclusion criteria

• Age: 18-75 years, no gender restriction
• ECOG score 0-1
• Biopsy-confirmed pMMR (proficient mismatch repair) localized advanced low rectal adenocarcinoma (tumor's lower edge ≤ 10 cm from the anus)
• Presence of the following high-risk factors: T3N+/T4/N2/EMVI+/MRF+/lateral lymph node metastasis/inability to undergo sphincter-preserving surgery
• Routine chest and abdominal CT scans showing no distant metastasis
• Bone marrow function: Neutrophil count (ANC) ≥ 1.5 × 10\^9/L, platelet count (PLT) ≥ 100 × 10\^9/L, hemoglobin (Hb) ≥ 70 g/L
• Liver function: ALT, AST ≤ 2.5 × ULN (upper limit of normal); total bilirubin ≤ 1.5 × ULN; serum albumin ≥ 3 g/dL
• Kidney function: Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance ≥ 60 ml/min (calculated using the Cockcroft-Gault formula)
• For females and patients with reproductive potential, a negative pregnancy test must be done within 72 hours before starting the treatment, and the patient must agree to avoid pregnancy during the study treatment and for 6 months after the treatment. For males with reproductive potential partners, the patient must agree to use adequate medically approved contraception during and for 90 days after the final study treatment
• Patients must agree to receive the study's neoadjuvant chemotherapy regimen and sign an informed consent form

Exclusion criteria

• Patients with a history of other malignancies within the past 5 years (except for cured and non-recurring cancers such as in situ carcinoma, basal cell carcinoma of the skin, etc.)
• Patients with active, uncontrolled bacterial, viral, or fungal infections requiring systemic treatment, defined by persistent signs/symptoms related to infection, which do not improve despite appropriate antibiotics, antiviral treatments, and/or other therapies
• Patients with uncontrolled systemic diseases, including unstable angina, myocardial infarction, congestive heart failure, severe unstable ventricular arrhythmia, history of severe pericardial disease, or other cardiovascular diseases; uncontrolled hypertension (defined as systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg despite appropriate antihypertensive treatment), or a history of hypertensive crisis, hypertensive encephalopathy; uncontrolled diabetes (fasting blood glucose ≥ 10 mmol/L), etc.
• Patients known to be allergic or intolerant to the treatment drugs or excipients used in this study
• Any clinical indicators showing contraindications to chemotherapy and surgery
• Patients using strong inhibitors or inducers of enzymes such as CYP3A4, CYP2C8, and UGT1A1
• Pregnant or breastfeeding women, and female patients of reproductive potential who refuse to use appropriate contraceptive measures during the study
• Patients who participated in other clinical trials within 4 weeks before enrollment
• Patients whom the investigator deems unsuitable for participation in the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 2 centers

• Shantou University Medical College Cancer Hospital — Shantou
• The First Affiliated Hospital of Shantou University Medical College — Shantou

Publications

• Bang YJ, Li CP, Lee KH, Chiu CF, Park JO, Shan YS, Kim JS, Chen JS, Shim HJ, Rau KM, Choi HJ, Oh DY, Belanger B, Chen LT. Liposomal irinotecan in metastatic pancreatic adenocarcinoma in Asian patients: Subgroup analysis of the NAPOLI-1 study. Cancer Sci. 2020 Feb;111(2):513-527. doi: 10.1111/cas.14264. Epub 2019 Dec 20. PMID 31789476
• Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, Macarulla T, Lee KH, Cunningham D, Blanc JF, Hubner RA, Chiu CF, Schwartsmann G, Siveke JT, Braiteh F, Moyo V, Belanger B, Dhindsa N, Bayever E, Von Hoff DD, Chen LT; NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a glob PMID 26615328
• Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020 Dec 20;38(36):4231-4239. do PMID 33119477
• Yang Z, Gao J, Zheng J, Han J, Li A, Liu G, Sun Y, Zhang J, Chen G, Xu R, Zhang X, Liu Y, Bai Z, Deng W, He W, Yao H, Zhang Z. Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer (NECTAR): a multi-center phase 2 study. Signal Transduct Target Ther. 2024 Mar 11;9(1):56. doi: 10.1038/s41392-024-01762-y. PMID 38462629
• Rahma OE, Yothers G, Hong TS, Russell MM, You YN, Parker W, Jacobs SA, Colangelo LH, Lucas PC, Gollub MJ, Hall WA, Kachnic LA, Vijayvergia N, O'Rourke MA, Faller BA, Valicenti RK, Schefter TE, George S, Kainthla R, Stella PJ, Sigurdson E, Wolmark N, George TJ. Use of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer: Initial Results From the Pembrolizumab Arm of a Phase 2 Randomized Cli PMID 34196693

Identifiers

NCT: NCT07104604 · CancerShantouUMC 2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗