Different Cycles of Preoperative Neoadjuvant Sintilimab in Mismatch-repair Deficient/microsatellite Instability-high, Locally Advanced Colorectal Cancer

Official title

Eight Vs Four Cycles of Preoperative Neoadjuvant Sintilimab in Mismatch-repair Deficient/microsatellite Instability-high, Locally Advanced Colorectal Cancer(OPEN): a Multi-center, Open-label, Prospective Randomized Controlled Trial

Overview

Colorectal cancer is one of the most common malignant tumors, accounting for approximately 10% of new cancer cases and cancer-related deaths worldwide each year. In recent years, with the development of industrialization and urbanization, the increase in the number of elderly patients, and changes in dietary structure and lifestyle habits, the incidence and mortality rates of colorectal cancer in China have risen significantly. Some patients are already in locally advanced or late stages at the time of diagnosis, making treatment more difficult. Among them, patients with MSI-H/dMMR colorectal cancer account for about 10% to 15% of the total. Neoadjuvant therapy for rectal cancer primarily targets resectable mid-to-low rectal cancer patients with T3/4 and any N stage. Currently, neoadjuvant therapy for rectal cancer mainly involves chemoradiotherapy, while patients with a low risk of recurrence may opt for neoadjuvant chemotherapy. For patients with mid-to-low locally advanced rectal cancer, intensified systemic chemotherapy can be chosen before and after preoperative radiotherapy. For patients with technical difficulties in sphincter preservation but a strong desire to preserve the sphincter, higher intensity treatments can be considered, such as the CinClare protocol of concurrent chemoradiotherapy with capecitabine and irinotecan, the FOWARC protocol of concurrent radiotherapy with FOLFOX, or interval chemotherapy, including total neoadjuvant therapy. However, for MSI-H/dMMR patients, neoadjuvant chemoradiotherapy is less effective. Xu Ruihua from the Sun Yat-sen University Cancer Center evaluated the clinical response and safety of four cycles of neoadjuvant treatment with sintilimab in dMMR or MSI-H colorectal cancer. In this study, 16 patients underwent at least one response evaluation. All six patients who underwent radical surgery achieved R0 resection. Tumor shrinkage was observed in 15 patients (94%) at the first evaluation after treatment. Among the 16 evaluable patients, 3 (19%) underwent radical surgery and achieved pCR, 9 (56%) achieved cCR and opted for a watch-and-wait strategy, 3 (19%) did not achieve cCR and underwent radical surgery with residual tumor found in the pathological specimens. One patient (6%) discontinued treatment due to a severe adverse event (grade 3 encephalitis), did not achieve cCR, and refused surgery. The results of immunotherapy in patients with MSI-H/dMMR metastatic colorectal cancer have greatly encouraged researchers to explore its application in neoadjuvant therapy. The NICHE study, the world's first neoadjuvant immunotherapy study in non-metastatic colon cancer, showed a 100% MPR and a 69% pCR rate after neoadjuvant immunotherapy in 32 patients with dMMR colon cancer. Based on this study, the larger NICHE-2 study was conducted, enrolling a total of 112 patients with non-metastatic dMMR colon cancer. These patients received one dose of ipilimumab (1 mg/kg) combined with nivolumab (3 mg/kg) followed by one dose of nivolumab (3 mg/kg) monotherapy within 6 weeks before surgery. The short-term efficacy results showed an MPR of 95% and a pCR rate of 67%, consistent with previous results, with good tolerability and only 4% experiencing grade 3-4 adverse events. Sintilimab targets the same molecule as nivolumab and pembrolizumab but has a different amino acid sequence. Multiple preclinical in vitro studies have validated the effect of sintilimab in blocking the PD-1 pathway. Completed preclinical pharmacodynamics, animal pharmacokinetics, and toxicology studies have shown that sintilimab has clear targets, reliable cell line sources, good drug stability, and has demonstrated good activity in completed preclinical studies. Based on multiple previous studies, the optimal cycle for neoadjuvant immunotherapy has not yet been determined. However, different treatment cycles result in significant differences in pCR, which may be related to the number of treatment cycles. This study aims to explore the postoperative pathological complete response rate of 8 cycles versus 4 cycles of neoadjuvant sintilimab treatment in dMMR/MSI-H locally advanced colon cancer.

Interventions

• Biological Sintilimab
  Subjects were enrolled and received Sintilimab at a dose of 200 mg, administered via intravenous infusion on the first day of each cycle, with each cycle lasting 3 weeks (Q3W)

Primary outcome measures

• the pathological complete response rate (pCR) [Time frame: From randomization up to a median of 5 years after randomization.]

Secondary outcome measures (3)

• Event-free Survival (EFS) [Time frame: From randomization up to a median of 5 years after randomization.]
• Overall Survival (OS) [Time frame: From randomization up to a median of 5 years after randomization.]
• Number of Participants with treatment emergent adverse events (AEs), serious adverse events (SAEs), Immune-mediated Adverse Event (imAEs), AEs leading to death and AEs leading to discontinuation of study treatment [Time frame: Up to approximately 5 years]

Eligibility criteria

Inclusion criteria

• has pathologically confirmed colon cancer or upper rectal cancer (with the lower edge of the tumor more than 10 cm from the anal verge); clinical stage cT3/T4 or N+
• no urgent need for surgery due to bleeding, perforation, or obstruction
• immunohistochemistry of tumor biopsy indicating deficient mismatch repair (dMMR), defined by the loss of expression of one or more of the four proteins MSH1, MSH2, MSH6, and PMS2; or genetic testing indicating MSI-H

Exclusion criteria

• Has distant metastatic disease.
• Has received prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy), radiation therapy or surgery for management of colon cancer
• Has undergone any major surgical procedure, open biopsy, or experienced significant traumatic injury within 28 days prior to randomization
• Is receiving any other anticancer or experimental therapy. No other experimental therapies (including but not limited to chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, or other experimental drugs) of any kind are permitted while the participant is receiving study intervention
• There is a history of illness or evidence of disease, treatment, or abnormal laboratory test values that could potentially interfere with the trial results or hinder the subject's full participation in the study, or any other conditions deemed unsuitable for inclusion by the investigator.
• The investigator believes there are other potential risks that make the subject unsuitable for participation in this 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

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital of Zhengzhou University — Zheng'zhou

Identifiers

NCT: NCT06698757 · 2024-KY-1330-003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗