Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial)

Abstract

Background Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain. Methods This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6–8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes. Discussion To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC. Trial registration Name of the registry: ClinicalTrials.gov. Trial registration number: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1.

Neoadjuvant Arterial Embolization Chemotherapy Combined PD-1 Inhibitor for Locally Advanced Rectal Cancer (NECI Study): a protocol for a phase II study

“…However, several single-arm clinical trials of neoadjuvant combination therapy, including immunotherapy, are designed to assess clinical outcomes more quickly. [28][29][30] Therefore, there is an urgent need to examine an effective treatment for locally advanced rectal cancer. Based on the convenience of the mrTRG assessment, every patient recruited in this study can reach the primary endpoint in 12 weeks so that we can assess the curative effect of this combination therapy quickly.…”

Interim result of phase II, prospective, single-arm trial of long-course chemoradiotherapy combined with concurrent tislelizumab in locally advanced rectal cancer

“…This NCRT-PD1-LARC was a prospective, multicenter, single-arm, phase II trial (Clinical trial number: NCT04911517). The study design was described previously ( 24 ). To allow patient enrollment in accordance with clinical practice, we undertook a protocol amendment to include patients with mid-to-low locally advanced rectal cancer (0-10cm above anal verge) with cT3-4aN0M0 or cT1-4a N1-2M0 pre-staged by MRI.…”

“…Thus, the PACIFIC-2 aimed to evaluate the benefit of concurrent durvalumab with chemoradiation (NCT03519971). Given these results, we designed this phase II, multicenter, prospective, single-arm trial to evaluate the efficacy and safety of LR-CRT combined with concurrent tislelizumab in patients with LARC ( 24 ). In this manuscript, we will report the interim result of this study.…”

Current progress and future perspectives of neoadjuvant anti-PD-1/PD-L1 therapy for colorectal cancer

“…An American trial reported in 2021 assessed whether the addition of pembrolizumab to neoadjuvant chemoradiotherapy can lead to an improvement in the neoadjuvant rectal (NAR) score instead of pCR compared with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) (77). As shown in Figure 3, the NAR score is calculated according to the following formula as a predictive indicator of survival after preoperative chemoradiotherapy for rectal cancer (78). Patients with stage II/III LARC with distal location (cT 3-4 , ≤ 5 cm from anal verge, N 0-2 ), with bulky disease (any cT 4 or tumor within 3 mm of mesorectal fascia), at high risk for metastatic disease (cN 2 ), and/ or who were not candidates for sphincter-sparing surgery (SSS) were enrolled.…”

“…Our center also initiated a prospective, multicenter, phase 2 clinical trial to explore safety and efficacy of long-course neoadjuvant chemoradiotherapy plus tislelizumab followed by TME for LARC (78). As of 30 June 2022, a total number of patients (n = 43) were enrolled, while 30 (29 pMMR/non-MSI-H and 1 dMMR/MSI-H) patients had undergone TME surgery, with the R0 resection rate of 100% and sphincter-saving resection rate of 90.0% (27/30).…”