Neoadjuvant Radiotherapy for Rectal Adenocarcinoma With Capecitabine Versus TAS-102 (Neo-REACT): A Multi-center, Randomized, Phase III Trial

Neoadjuvant fluoropyrimidine-based chemoradiotherapy followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer (LARC); however, pathologic complete response (pCR) rates are low. Trifluridine/tipiracil (TAS-102) is a new oral anti-tumor oral formulation of nucleoside analogue, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI). Previous studies have shown that TAS-102 has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Also, a phase 2 trials conducted by our team have demonstrated that neoaduvant TAS-102 concurrent with long-course radiotherapy could lead to a high pCR rate of 32% with acceptable toxicity for LARC patients. Herein, we will conduct this multicenter, randomized controlled, phase III trial to explore the safety and efficacy benefit of TAS-102 concurrent with long-course radiotherapy for LARC.

Study Overview

• Status: Recruiting
• Conditions: Rectal Cancer; Rectal Cancer Patients
• Intervention / Treatment: Combination product: TAS-102; Combination product: Capecitabine

Detailed Description

Neoadjuvant fluoropyrimidine-based chemoradiotherapy (nCRT) followed by TME is the standard care for LARC. However, the tumor responses to nCRT cover a wide spectrum and the complete pathologic response rate varies from 8% to 20%. The low rate of pCR after neoadjuvant therapy could not satisfy patients with distal rectal cancer who want to keep anal function. Therefore, currently, the addition of other agents to 5-FU or capecitabine as components of the multimodality treatment for LARC outside of clinical trials is not recommended in clinical practice. TAS-102 is a new oral anti-tumor oral formulation of nucleoside analogue, FTD, and a thymidine phosphorylase inhibitor, TPI. TPI improves the bioavailability and ensures sufficient blood concentrations of FDT. Previous studies have shown that TAS-102 has shown clinically relevant activity after fluoropyrimidine failure in colorectal cancer and may thus be of increased efficacy compared with current standard capecitabine chemoradiation. Also, a phase 2 trials conducted by our team have demonstrated that neoaduvant TAS-102 concurrent with long-course radiotherapy could lead to a high pCR rate of 32% with acceptable toxicity for LARC patients. Herein, we will conduct this multicenter, randomized controlled, phase III trial to explore the safety and efficacy benefit of TAS-102 concurrent with long-course radiotherapy for LARC.

• Study Type: Interventional
• Enrollment (Estimated): 210
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jinbo Yue, Docter; Phone Number: 0531-67626442; Email: jbyue@sdfmu.edu.cn

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China
      • Recruiting
      • Shandong Cancer Hospital and Institute
      • Contact: Jinbo Yue, Doctor; Phone Number: 0531-67626442; Email: jbyue@sdfmu.ed

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients aged between 18 and 75 years of either sex.

2. Histologically confirmed rectal adenocarcinoma with the following conditions:

   1. Clinical stage II (T3-4, N-) or III (any T, N+) as determined by MRI.
   2. The tumor is located within 12 cm from the anal margin, with at least one high-risk factors (ie, extramural vascular invasion [EMVI+], mesorectal fascia involved [MRF+], cT4, cN2, lateral lymph nodes, tumor deposit, or tumor located in the lower rectum [≤5 cm from the anal verge]).
3. No other types of rectal cancer (e.g., sarcoma, lymphoma, carcinoid, squamous cell carcinoma) or synchronous colon cancer.
4. Presence of measurable lesions that meet RECIST v1.1 criteria for evaluation.
5. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
6. Estimated life expectancy > 6 months.

Exclusion Criteria:

1. Patients of dMMR or MSI-H status.
2. Unexplained myelosuppression.
3. Evidence of distant metastasis and inguinal lymph node metastasis based on comprehensive chest and abdominal CT or whole-body PET-CT scans. Retroperitoneal lymph nodes above the iliac vessel bifurcation are considered distant metastasis.
4. Active autoimmune disease or history of autoimmune disease.
5. Uncontrolled cardiac symptoms or diseases.
6. History of other malignancies, except for cured basal cell carcinoma of the skin and cervical carcinoma in situ.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAS-102 group; Neoadjuvant long-course radiotherapy combined with TAS-102	Combination product: TAS-102; Radiotherapy: Radiotherapy Technique: Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), or volume modulated arc therapy (VMAT);; Radiotherapy Dose and Fractionation Schedule: Conventional fractionation with external beam irradiation at a dose of 50 Gy delivered in 25 fractions over 5 weeks. Synchronous Chemotherapy: Concurrent administration of TAS-102 at a dose of 35 mg/m² twice daily at the 1st, 3rd and 5th week of radiotherapy. Intermittent Consolidation Chemotherapy: Oxaliplatin at 85 mg/m² on day 1 combined with TAS-102 at 35 mg/m² twice daily from day 1 to day 5, repeated every 14 days for a total of 6 cycles. Surgery: The operation follows the principle of TME. The type of surgery depends on the location and extent of the primary tumor. Postoperative adjuvant therapy: Two cycles of CapeOX (Oxaliplatin 130 mg/m2 on day 1+ capecitabine 1000 mg/m2 twice a day on days 1-14, q3w).
Active Comparator: Capecitabine group; Neoadjuvant long-course radiotherapy combined with capecitabine	Combination product: Capecitabine; Radiotherapy: Radiotherapy Technique: Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), or volume modulated arc therapy (VMAT);; Radiotherapy Dose and Fractionation Schedule: Conventional fractionation with external beam irradiation at a dose of 50 Gy delivered in 25 fractions over 5 weeks. Synchronous Chemotherapy: Capecitabine administered orally at a dose of 825 mg/m² twice daily on days of radiotherapy. Intermittent Consolidation Chemotherapy: Oxaliplatin at 130 mg/m² on day 1 combined with capecitabine at 1000 mg/m² twice daily from day 1 to day 14, repeated every 21 days for a total of 4 cycles. Surgery: The operation follows the principle of TME. The type of surgery depends on the location and extent of the primary tumor. Postoperative adjuvant therapy: Two cycles of CapeOX (Oxaliplatin 130 mg/m2 on day 1+ capecitabine 1000 mg/m2 twice a day on days 1-14, q3w)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response (CR) rate	The primary outcomes is CR rate, which is the sum of the number of patients with a pCR who undergo surgery plus the number of patients with a cCR who undergo watch-and-wait divided by the total number of evaluable patients.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence of 3-4 grade adverse reactions	The adverse reactions are graded and recorded according to the National Cancer Institute General Terminology for Adverse Events (CTCAE) Version 5.0.	1 year
3-year recurrence-free survival (RFS)	3-year RFS is measured from randomization to the first occurrence of recurrence or last follow-up.	3 year
3-year overall survival (OS)	3-year OS is measured from randomization to death due to any cause or last follow-up.	3 year

Collaborators and Investigators

• Sponsor: Shandong Cancer Hospital and Institute
• Investigators: Principal Investigator: Jinbo Yue, Docter, Shandong Cancer Hospital and Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2025
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: February 19, 2025
• First Submitted That Met QC Criteria: February 24, 2025
• First Posted (Actual): February 27, 2025

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: June 1, 2025

More Information

Terms related to this study

• 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; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Uracil; Pyrimidinones; Deoxyribonucleosides; Fluorouracil; Capecitabine; trifluridine tipiracil drug combination
• Other Study ID Numbers: SDZLEC2025-026-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No