MSS

To explore the efficacy and safety of short-course radiotherapy combined with mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) in High-Risk pMMR/MSS Rectal Adenocarcinoma through a prospective study, providing high-level evidence-based medical evidence for the use in the treatment of high-risk rectal cancer.

To explore the efficacy and safety of an intensified treatment regimen consisting of short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with precise targeted therapy (based on RAS/BRAF status: cetuximab for wild-type, bevacizumab for mutant) and a PD-1 monoclonal antibody, compared with short-course radiotherapy followed by mFOLFOX6 chemotherapy alone, in high-risk locally advanced pMMR/MSS rectal adenocarcinoma through a prospective, randomized controlled phase III clinical study, providing high-level evidence-based medical evidence to establish a superior neoadjuvant treatment strategy for this population.

Background and Significance: Colorectal cancer (CRC) ranks as the third most common cancer and the second leading cause of cancer-related deaths globally. Despite improved early screening rates, a significant proportion of newly diagnosed CRC patients present with synchronous metastases, predominantly liver metastases. The concept of oligometastases, introduced by Hellman and Weichselbaum in 1995, describes a transitional state between localized disease and widespread metastases, characterized by limited metastatic lesions (typically 1-5) confined to 1-2 organs. Current Treatment Landscape: The management of oligometastatic disease combines local therapeutic approaches (surgery, radiotherapy, radiofrequency ablation) with systemic treatments, aiming to achieve No Evidence of Disease (NED) status. The ESMO guidelines officially categorized metastatic CRC into oligometastatic and widespread metastatic states in 2016, emphasizing the importance of integrated local and systemic treatments for oligometastatic colorectal liver metastases (CRLM). Treatment Evolution and Challenges: While the EPOC study established CAPEOX neoadjuvant chemotherapy followed by R0 resection as the standard treatment for initially resectable CRLM, patients with synchronous rectal cancer oligometastases present unique challenges due to complex local anatomy and high local recurrence risks. Although various neoadjuvant approaches, including Total Neoadjuvant Therapy (TNT), have been studied, they have not demonstrated significant long-term survival benefits, primarily because distant metastases impact survival more significantly than local recurrence. Innovative Approach: Recent success with Immunotherapy-Based Total Neoadjuvant Therapy (iTNT) in microsatellite stable/proficient mismatch repair (MSS/pMMR) locally advanced rectal cancer has shown promising results. Short-course radiotherapy (SCRT) combined with chemotherapy and immunotherapy has demonstrated superior efficacy trends, attributed to radiation's immune-activating effects on both local and distant tumor microenvironments. Research Objective: This project aims to evaluate the effectiveness of iTNT combined with SCRT in MSS/pMMR rectal cancer patients with synchronous oligometastases. The novel approach integrates SCRT with CAPEOX chemotherapy and Serplulimab, potentially improving complete response rates, organ preservation opportunities, and overall treatment efficacy while reducing recurrence risks. This pioneering study represents the first investigation of iTNT in synchronous rectal cancer oligometastases, offering a potentially transformative treatment strategy for this challenging patient population. Research Innovation: The study uniquely combines SCRT, CAPEOX chemotherapy, and Serplulimab in a neoadjuvant setting for MSS/pMMR synchronous rectal cancer oligometastases, addressing an unmet clinical need and potentially establishing a new treatment paradigm in this field.

Colorectal cancer of Mismatch Repair-proficient (pMMR)/ Microsatellite Stability (MSS) accounts for approximately 85% of all colorectal cancer patients, which might be insensitive to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy, such as CAPEOX regimen, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Celecoxib, a COX-2 inhibitor, can improve the immune microenvironment and have a potential to synergy with immunotherapy. Chemotherapy can improve the immunogenicity of cancer cells that might enhance the efficacy of immunotherapy. The aim of this study is to explore whether chemotherapy and cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could improve efficacy for resectable colorectal cancer patient with the pMMR/MSS phenotype.

This research study aims to evaluate the safety and determine the optimal dose of a new experimental drug, vvDD-hIL2 (vaccinia virus double-deleted human interleukin 2), in patients with advanced abdominal cancer. The study will involve three dose levels, with three to six patients enrolled at each level. vvDD-hIL2 is a genetically modified vaccinia virus, derived from the virus previously used for smallpox vaccination. The modification is intended to target and destroy tumors while minimizing harm to healthy tissues by stimulating the body's immune response. Participants will receive an injection of vvDD-hIL2 directly into their abdominal tumors at AHN West Penn. The study team will monitor for side effects and assess tumor response to the treatment. Active participation will last up to two months, involving seven clinic visits and approximately four lab visits at AHN West Penn Hospital. Visits will include standard of care procedures as well as study-specific tests and exams. Most visits will last one to two hours, with some extending to two to three hours. The drug administration day will require a twelve-hour visit. Effectiveness and side effects will be evaluated through blood draws, oral swabs, urinalysis and tissue biopsies. Tissue samples will be used for genomic analysis and stored for potential future research. Data collected may also be used for future research purposes. Previous human trials of vvDD-hIL2 have reported side effects such as pain, rash or inflammation at the injection site, low-grade fevers, flu-like symptoms, and fatigue. There is a rare risk of rash transmission to close contacts with skin openings, and information on limiting contact and managing rash development will be provided.

This is a prospective, single-arm, single-center Phase II clinical study. In this study, participants will receive Ivosidenib in combination with CapeOX chemotherapy and radiotherapy. The treatment regimen is as follows: participants will first receive Ivosidenib in combination with CapeOX chemotherapy during the first cycle, followed by radiotherapy starting 2 weeks after medication. Depending on the dose limits of normal tissue radiation, Stereotactic Ablative Radiotherapy (SABR), large fraction radiotherapy, or high-dose combined with low-dose radiotherapy will be administered to primary and metastatic lesions. One week after completing radiotherapy, participants will continue to receive Ivosidenib in combination with CapeOX systemic treatment. If extensive primary and metastatic lesions cannot be treated with radiotherapy initially, participants will continue to receive Ivosidenib in combination with CapeOX systemic treatment until the lesions shrink, at which point radiotherapy may be considered. Assessments will be conducted every 2 treatment cycles after treatment initiation, with multidisciplinary team (MDT) discussions to determine if No Evidence of Disease (NED) is achieved. Patients achieving NED may undergo surgery or local treatment, while those with stable or partial responses will continue combination therapy. Patients with disease progression will discontinue study treatment. Patients ineligible for surgical treatment will continue combination therapy until disease progression or until they exit the study for surgical treatment. During the study period, participants will undergo safety monitoring. The safety follow-up period is defined as 90 days after the last dose of Ivosidenib. Safety data will be collected from the time of informed consent signing until the end of the safety follow-up period or initiation of new anti-tumor treatment (whichever occurs first).

This is a non-profit phase II, open, clinical study of the combination of irinotecan plus cetuximab and envafolimab as a rechallenge regimen, in pre-treated RAS/BRAF wild type metastatic colorectal cancer patients (according to liquid biopsy at baseline). Patients have been treated in front lines with irinotecan and cetuximab and had a clinical benefit (complete or partial response) from both of them, no matter whether they had treated by any PD-1 inhibitor before.

This is a single arm, open-label, prospective clinical trial to evaluate the combination of neoadjuvant short-course radiotherapy and toripalimab (PD-1 antibody) for locally advanced rectal cancer (LARC) patients with high risk factors. A total of 53patients will be enrolled in this trial to receive 5\*5Gy short-course radiotherapy, followed by 4 cycles of CAPOX chemotherapy and PD-1 antibody. Then they will receive the TME surgery and another 2 cycles of CAPOX chemotherapy. The primary end point is the rate of pathological complete response (pCR). The long-term prognosis and adverse effects will also be evaluated and analyzed.