Assessment of Efficacy and Safety of PD-1 Monoclonal Antibody Combined With IL-2 and CapeOX in Neoadjuvant Therapy for Locally Advanced Rectal Cancer Prior to Surgery: A Prospective, Multi-center, Randomized Controlled Study (PICM)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 130
- 试验地点
- 4
- 主要终点
- Pathological Complete Response rate (pCR)
研究概览
简要总结
The objective is to evaluate whether the neoadjuvant combination of tislelizumab (a PD-1 inhibitor) with interleukin-2 (IL-2) chemotherapy can significantly increase the Objective Response Rate (ORR) and the Pathological Complete Response rate (pCR) in patients with locally advanced rectal cancer who have Microsatellite Stable/Proficient Mismatch Repair (MSS/pMMR) status.
详细描述
Colorectal cancer (CRC) stands as a prominent global health concern, ranking among the most prevalent malignancies worldwide. Its incidence exhibits striking geographical variations, with higher rates observed in developed countries. Age is a significant risk factor, predominantly affecting individuals aged 50 and above, although a concerning trend of increasing incidence in younger adults has been noted in recent years. There exists a gender disparity, with slightly higher prevalence in males. Notably, lifestyle factors, including dietary choices, sedentary habits, smoking, and obesity, play crucial roles in its etiology. These epidemiological patterns underscore the urgency for implementing effective prevention strategies and advancing early detection methods to mitigate the disease's impact.
In recent years, substantial advancements have reshaped the landscape of CRC treatment, offering new hope and improved outcomes for affected individuals. Surgical intervention remains the cornerstone of curative therapy, guided by tumor stage, location, and patient's overall health status. Adjuvant therapies, including chemotherapy and radiotherapy, have been pivotal in reducing recurrence rates and enhancing overall survival. Targeted treatments, such as anti-EGFR and anti-VEGF drugs, have ushered in an era of precision medicine, selectively targeting critical molecular pathways. Meanwhile, immunotherapy, particularly immune checkpoint inhibitors, has emerged as a promising frontier, offering personalized treatment options for CRC patients.
In CRC, the PD-1 inhibition pathway plays a central role in regulating immune cell exhaustion; however, the response to PD-1 monotherapy is limited in a majority of colorectal cancer patients, suggesting that combining PD-1 blockade with other immunostimulatory agents holds promise. Currently, several combination therapies have shown progress in animal models and are being explored in clinical studies. Among these, interleukin-2 (IL-2) emerges as a candidate drug, synergizing with PD-1 blockade to potentiate antitumor effects. This study aims to investigate the combination of IL-2 with PD-1 inhibitors, seeking to overcome the limitations of single-agent immunotherapy through multifaceted immunomodulation. By modulating the immune microenvironment to enhance immune cell infiltration and break down the physical and immunosuppressive barriers of the tumor, this approach seeks to augment the efficacy of immunotherapy, particularly for immunologically cold CRC patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males and females aged between 18 and 75 years;
- •An Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
- •Histologically confirmed rectal adenocarcinoma;
- •Clinical stage T3-T4 or any T with node-positive (N+) disease: locally advanced;
- •Microsatellite stable (MSS) status;
- •Adequate hematological, hepatic, and renal functions.
排除标准
- •Patients with metastatic disease (Stage IV); recurrent colorectal cancer with active bleeding, perforation, or complex conditions requiring urgent surgery; or concurrent non-colorectal cancer malignancies.
- •Patients who have previously received systemic anticancer therapy for colorectal cancer; or have been treated with PD-1, PD-L1, or CTLA-4 antibodies.
- •Patients with any active autoimmune disease; known or tested positive for Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS); or a history requiring steroid or immunosuppressive drug treatment.
- •Patients with interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases (such as diabetes, hypertension, pulmonary fibrosis, and acute pneumonia).
- •Patients who experienced any Grade 2 or higher toxicities due to prior treatments (as classified by the Common Terminology Criteria for Adverse Events [CTCAE] version 5), which have not resolved (excluding anemia, alopecia, and skin pigmentation changes); known or suspected history of hypersensitivity to any of the drugs used in the trial.
- •Pregnant or breastfeeding women.
研究组 & 干预措施
PD-1+IL-2+CapeOX group
Patients in the PICM group received 21-day cycles of tislelizumab 200 mg intravenously on day 1, oxaliplatin 130 mg/m² intravenously on day 1, capecitabine 1000 mg/m² orally twice daily on days 1-14, and recombinant human IL-2 1 million IU subcutaneously on Monday, Wednesday, and Friday during days 1-14, for six doses per cycle. Rectal MRI was done after two cycles. Patients with tumor regression greater than 20% continued to six cycles; those with regression less than 20%, local progression, or distant metastasis discontinued protocol treatment and received subsequent treatment at the investigator's discretion.
干预措施: Oxaliplatin (Drug)
PD-1+IL-2+CapeOX group
Patients in the PICM group received 21-day cycles of tislelizumab 200 mg intravenously on day 1, oxaliplatin 130 mg/m² intravenously on day 1, capecitabine 1000 mg/m² orally twice daily on days 1-14, and recombinant human IL-2 1 million IU subcutaneously on Monday, Wednesday, and Friday during days 1-14, for six doses per cycle. Rectal MRI was done after two cycles. Patients with tumor regression greater than 20% continued to six cycles; those with regression less than 20%, local progression, or distant metastasis discontinued protocol treatment and received subsequent treatment at the investigator's discretion.
干预措施: Interleukin-2 (Drug)
Conventional Neoadjuvant Group
Patients in the CRT group received long-course radiotherapy to a total dose of 50.4 Gy in 28 fractions of 1.8 Gy, delivered 5 days per week with three-dimensional conformal radiotherapy, VMAT, or IMRT. Concurrent capecitabine was given orally at 825 mg/m² twice daily on days 1-5 each week for 5 weeks. After radiotherapy, patients received four cycles of CapeOX: oxaliplatin 130 mg/m² intravenously on day 1 and capecitabine 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle
干预措施: Oxaliplatin (Drug)
Conventional Neoadjuvant Group
Patients in the CRT group received long-course radiotherapy to a total dose of 50.4 Gy in 28 fractions of 1.8 Gy, delivered 5 days per week with three-dimensional conformal radiotherapy, VMAT, or IMRT. Concurrent capecitabine was given orally at 825 mg/m² twice daily on days 1-5 each week for 5 weeks. After radiotherapy, patients received four cycles of CapeOX: oxaliplatin 130 mg/m² intravenously on day 1 and capecitabine 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle
干预措施: Capecitabine (Drug)
Conventional Neoadjuvant Group
Patients in the CRT group received long-course radiotherapy to a total dose of 50.4 Gy in 28 fractions of 1.8 Gy, delivered 5 days per week with three-dimensional conformal radiotherapy, VMAT, or IMRT. Concurrent capecitabine was given orally at 825 mg/m² twice daily on days 1-5 each week for 5 weeks. After radiotherapy, patients received four cycles of CapeOX: oxaliplatin 130 mg/m² intravenously on day 1 and capecitabine 1000 mg/m² orally twice daily on days 1-14 of each 21-day cycle
干预措施: Radiotherapy (Radiation)
PD-1+IL-2+CapeOX group
Patients in the PICM group received 21-day cycles of tislelizumab 200 mg intravenously on day 1, oxaliplatin 130 mg/m² intravenously on day 1, capecitabine 1000 mg/m² orally twice daily on days 1-14, and recombinant human IL-2 1 million IU subcutaneously on Monday, Wednesday, and Friday during days 1-14, for six doses per cycle. Rectal MRI was done after two cycles. Patients with tumor regression greater than 20% continued to six cycles; those with regression less than 20%, local progression, or distant metastasis discontinued protocol treatment and received subsequent treatment at the investigator's discretion.
干预措施: Tislelizumab (Drug)
PD-1+IL-2+CapeOX group
Patients in the PICM group received 21-day cycles of tislelizumab 200 mg intravenously on day 1, oxaliplatin 130 mg/m² intravenously on day 1, capecitabine 1000 mg/m² orally twice daily on days 1-14, and recombinant human IL-2 1 million IU subcutaneously on Monday, Wednesday, and Friday during days 1-14, for six doses per cycle. Rectal MRI was done after two cycles. Patients with tumor regression greater than 20% continued to six cycles; those with regression less than 20%, local progression, or distant metastasis discontinued protocol treatment and received subsequent treatment at the investigator's discretion.
干预措施: Capecitabine (Drug)
结局指标
主要结局
Pathological Complete Response rate (pCR)
时间窗: 1 year
Objective Response Rate (ORR)
时间窗: 1 years
Pathological Complete Response rate (pCR)
时间窗: 1 year
Clinical complete response (cCR)
时间窗: 1 years
near cCR
时间窗: 1 years
次要结局
- Safety and Tolerability(1 month)
- Overall survival(3 years)
- Disease free survival (DFS)(3 years)
- MPR(1 year)
- R0 resection rate(1 year)