Neoadjuvant Short-Course Radiotherapy Followed by CAPOX Plus PD-1 Antibody and IL-2 in Locally Advanced Rectal Cancer (PRIDE01)

A Single-Center, Single-Arm Study of Neoadjuvant Short-Course Radiotherapy Followed by Sequential Immunotherapy With CAPOX Combined With PD-1 Antibody and IL-2 for Locally Advanced Rectal Cancer

A Single-Center, Single-Arm Study of Neoadjuvant Short-Course Radiotherapy Followed by Sequential Immunotherapy with CAPOX Combined with PD-1 antibody and IL-2 for Locally Advanced Rectal Cancer

Study Overview

• Status: Active, not recruiting
• Conditions: Rectal Cancer; Advanced Solid Tumor
• Intervention / Treatment: Drug: Sintilimab + IL-2 Combined with CAPOX; Radiation: Short-course radiotherapy

Detailed Description

Globally, there are around 732,000 new cases of rectal cancer annually, with locally advanced rectal cancer (T3-4 or N+) comprising a significant proportion. The current NCCN guidelines recommend neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) and adjuvant chemotherapy, which has significantly reduced local recurrence rates from over 30% to less than 10%. However, challenges such as low rates of functional sphincter preservation, high incidence of distant metastasis, and limited long-term survival benefits persist. In response, total neoadjuvant therapy (TNT)-completing all chemotherapy and radiotherapy before surgery-has emerged as a strategy to improve outcomes. Yet, TNT may not be suitable for all patients due to the risk of overtreatment and associated toxicities.

Immunotherapy, including adoptive cell transfer (ACT) and immune checkpoint blockade (ICB), offers new therapeutic avenues for locally advanced rectal cancer. However, most colorectal cancer patients show limited responses to immunotherapy. For example, ACT has shown suboptimal results due to poor T-cell infiltration in tumors, and only a small subset of patients benefit from immune checkpoint inhibitors (ICIs). While PD-1/PD-L1 inhibitors are effective in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer, MSI-H tumors account for less than 5% of rectal cancer cases. Consequently, most patients with microsatellite-stable (MSS) tumors gain minimal benefit from monotherapy.

Immunotherapy resistance in MSS colorectal cancer is attributed to low tumor mutational burden, poor T-cell infiltration, and an immunosuppressive tumor microenvironment (iTME). Strategies to enhance local immune cell infiltration and reverse the iTME are crucial for improving immunotherapy efficacy in these cases. For instance, radiotherapy can synergize with immunotherapy by releasing tumor antigens and reshaping the immune environment to boost antitumor responses. Studies like UNION and TORCH have shown promising results by combining neoadjuvant chemoradiotherapy with anti-PD-1 immunotherapy in pMMR/MSS locally advanced rectal cancer patients.

Interleukin-2 (IL-2) plays a critical role in immune regulation, promoting T-cell growth and differentiation and enhancing cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity. High-dose IL-2 therapy has been used to treat malignant melanoma and renal cell carcinoma, leading to long-term survival in about 15% of patients. However, this approach is limited by severe side effects, such as hypotension and capillary leak syndrome. Current research focuses on improving IL-2 efficacy at low doses, including developing IL-2 variants with enhanced selectivity to avoid regulatory T cell (Treg) activation. Additionally, combining IL-2 with other treatments has shown significant clinical benefits. For example, in chronic lymphocytic choriomeningitis virus infection (LCMV), PD-1 and IL-2 combination therapy demonstrated superior efficacy compared to monotherapy. Preclinical studies in tumors also showed that PD-1/IL-2 combination therapy reversed terminal T-cell exhaustion, generating effector CD8+ T cells with enhanced profiles.

Based on these findings, combining IL-2 with anti-PD-1 therapy provides a strong foundation for clinical trials in locally advanced rectal cancer, specifically using neoadjuvant short-course radiotherapy, followed by CAPOX, PD-1 monoclonal antibodies, and IL-2.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Jiangsu Province Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18 to 70 years at enrollment.
• Histologically confirmed rectal adenocarcinoma with the inferior tumor border within 12 cm of the anal verge.
• Pelvic MRI stage T3-T4, or any T stage with regional lymph-node involvement.
• Absolute neutrophil count >=1.5 x 10^9/L and platelet count >=75 x 10^9/L.
• Total bilirubin <=1.5 x the upper limit of normal; aspartate aminotransferase and alanine aminotransferase <=2.5 x the upper limit of normal.
• Serum creatinine <=1.5 x the upper limit of normal.
• Eastern Cooperative Oncology Group performance status 0 or 1.
• Ability and willingness to provide written informed consent.

Exclusion Criteria:

• Distant metastatic disease.
• Recurrent rectal cancer.
• Tumor-related bleeding or perforation, or another condition requiring emergency surgery.
• Previous systemic anticancer treatment for rectal cancer.
• A concurrent malignancy other than colorectal cancer.
• Active autoimmune disease, or a history of autoimmune disease requiring systemic corticosteroids or other immunosuppressive therapy.
• Interstitial lung disease, non-infectious pneumonitis, or another uncontrolled systemic disease.
• Unresolved toxicity of grade 2 or higher from previous treatment, except anemia, alopecia or pigmentation changes.
• Previous treatment targeting PD-1, PD-L1 or CTLA-4.
• Pregnancy or breastfeeding.
• Human immunodeficiency virus infection or acquired immunodeficiency syndrome.
• Known hypersensitivity to any protocol treatment component.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental group; Experimental arm	Drug: Sintilimab + IL-2 Combined with CAPOX; Sintilimab + IL-2 Combined with Capox; Radiation: Short-course radiotherapy; Short-course radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate (pCR or cCR)	The proportion of enrolled participants who achieved either a pathological complete response (pCR) or a clinical complete response (cCR).	Up to approximately 6 months after treatment initiation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response (pCR) rate	Proportion of participants with no viable carcinoma in the resected primary tumor and in all regional lymph nodes (ypT0N0). Reported in all enrolled participants and, separately, in participants undergoing radical resection.	Up to 6 months after initiation of short-course radiotherapy
Clinical complete response (cCR) rate	Proportion of participants with multidisciplinary-team-confirmed clinical complete response, defined by concordant digital rectal examination, endoscopy and high-resolution pelvic MRI criteria at post-treatment response assessment.	Up to 6 months after initiation of short-course radiotherapy
R0 resection rate	Proportion of participants with microscopically margin-negative (R0) resection.	Up to 6 months after initiation of short-course radiotherapy
Major pathological response (MPR) rate	Proportion of participants with 10% or less residual viable tumor in the primary tumor bed, assessed in evaluable radical-resection specimens.	Up to 6 months after initiation of short-course radiotherapy
Tumor regression grade (TRG) distribution	Distribution of tumor regression grade 0-3	Up to 6 months after initiation of short-course radiotherapy
3-year event-free survival (EFS)	Time from initiation of short-course radiotherapy to disease progression, local regrowth or recurrence, distant metastasis, or death from any cause. Participants without an event are censored at the last disease assessment. Reported as the 3-year Kaplan-Meier landmark estimate with 95% confidence interval.	From initiation of short-course radiotherapy up to 3 years
3-year disease-free survival (DFS)	Assessed in participants who undergo radical resection. Time from surgery to local or distant recurrence or death from any cause. Reported as the 3-year Kaplan-Meier landmark estimate with 95% confidence interval.	From surgery up to 3 years
3-year overall survival (OS)	Time from initiation of short-course radiotherapy to death from any cause. Reported as the 3-year Kaplan-Meier landmark estimate with 95% confidence interval.	From initiation of short-course radiotherapy up to 3 years

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): October 9, 2024
• Primary Completion (Actual): June 10, 2026
• Study Completion (Estimated): January 15, 2029

Study Registration Dates

• First Submitted: August 27, 2024
• First Submitted That Met QC Criteria: August 27, 2024
• First Posted (Actual): August 29, 2024

Study Record Updates

• Last Update Posted (Actual): August 10, 2026
• Last Update Submitted That Met QC Criteria: August 5, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; IL-2; Short-course radiotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Rectal Diseases; Rectal Neoplasms; sintilimab
• Other Study ID Numbers: PRSYM20240827

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data underlying the published results, with a data dictionary.
• IPD Sharing Time Frame: From publication of the primary results for 5 years.
• IPD Sharing Access Criteria: Written proposal approved by the principal investigator and the institutional ethics committee, and a signed data access agreement. Requests to the corresponding author at pengwen@njmu.edu.cn. Transfer outside China is subject to Chinese regulatory requirements.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No