Treating Locally Advanced Rectal Cancer With TAS-102 Chemotherapy Plus Neoadjuvant Radiotherapy

Study Overview
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Brief Summary
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The goal of this Phase 2 trial is to evaluate a neoadjuvant treatment mode for locally advanced rectal cancer (LARC), consisting of radiotherapy and concurrent Trifluridine/Tipiracil (TAS-102). The main questions it aims to answer are: (i) whether TAS-102 is effective in treating LARC, when combined with radiotherapy; (ii) whether TAS-102 is safe in combination with radiotherapy. Participants will receive one cycle of TAS-102 chemotherapy and neoadjuvant radiotherapy based on intensity-modulated technique. Then the ones with a possibility of R0 resection will receive radical surgery followed by 6 cycles of adjuvant XELOX (capecitabine plus oxaliplatin) chemotherapy.

Detailed Description
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The standard management recommended by the National Comprehensive Cancer Network for locally advanced rectal cancer (LARC) is neoadjuvant chemo-radiotherapy followed by surgery plus adjuvant chemotherapy or not. Currently, the regimens of neoadjuvant chemotherapy are based on fluorouracil or capecitabine. The therapeutic effects of these regimens are satisfactory, with a pathological complete response (pCR) and 3-year disease-free survival (DFS) rate of 14% and 68%. Addition of oxaliplatin has been proven to further improve the pCR and DFS rates, by the CAO/ARO/AIO-04, FOWARC and ADORE trials. However, the acute toxicities of fluorouracil and capecitabine remain as a concern. It was reported that the incidence of the grade 3/4 symptomatic toxicities brought by these two agents was nearly 15%. When combined with oxaliplatin, the incidence could rise to 25%. A special toxicity, hand-foot syndrome, was seen in 43-71% of the patients receiving capecitabine. It included blister, ulceration, numbness, pain and paresthesia, and seriously influenced the daily work and life of the patients. Trifluridine/Tipiracil (TAS-102) is a new generation of cytotoxic agent whose therapeutic effects in metastatic colorectal cancer have been confirmed by a series of large-scale, multicenter, randomized controlled trials. And the latest TASCO1 trial reported that TAS-102 exhibited a trend to improve overall survival, compared to capecitabine. Moreover, it could be well tolerated, with an incidence of grade 3/4 symptomatic toxicities of merely 1.5%. Until now, there was few study focusing on combination of TAS-102 and radiotherapy. This phase 2 trial intended to evaluate the therapeutic and adverse effects of TAS-102 concurrently with neoadjuvant radiotherapy, in a small patient cohort with LARC. The results might provide an effective and low-toxic choice which improves patients' experience of chemo-radiotherapy.

Official Title
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A Single-arm, Phase II Clinical Trial to Treat Locally Advanced, pMMR Rectal Cancer With Single-agent Trifluridine/Tipiracil Chemotherapy Plus Neoadjuvant Intensity-modulated Radiotherapy

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Trifluridine/Tipiracil
* Radiation: intensity-modulated radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically diagnosed rectal adenocarcinoma via biopsy Pretreatment clinical TNM stage as T3-4N0M0 or T1-4N1-2M0 (UICC TNM staging classification, version 8) Tumor with proficient DNA mismatch repair confirmed by immunohistochemical analysis Age between 18 and 70 years old Karnofsky performance score ≥ 70 Distance from tumor lower margin to anal verge < 12 cm Exclusion Criteria: Inguinal lymph node metastasis Multiple primary colorectal cancer Complete obstruction or perforation Uncontrolled tuberculosis, AIDS or mental diseases Severe cardiac, renal, hepatic or hematopoietic dysfunctions unsuitable for chemotherapy or radiotherapy Prior history of other malignancies with 5 years, except cured cervical carcinoma in situ and skin basal cell carcinoma Prior history of rectal surgery, pelvic radiotherapy or chemotherapy Pregnant or lactating women Other situations for which the investigators consider a patient inappropriate to participate

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This study adopts the Simon's optimal two-stage design and uses the objective response rate (ORR) as the primary endpoint. The first stage will enroll 19 eligible patients. If the observed ORR > 70%, the study will enter the second stage and continue to enroll 40 eligible patients. The final sample size is 65 when a drop-out rate of 10% is considered.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant chemo-radiotherapy with TAS-102<br>The patients in this group will all receive neoadjuvant treatment consisting of intensity-modulated radiotherapy and concurrent Trifluridine/Tipiracil (TAS-102). Then the ones evaluated to have a possibility of R0 resection will receive radical surgery, followed by 6 cycles of adjuvant XELOX (capecitabine plus oxaliplatin) chemotherapy. | Drug: Trifluridine/Tipiracil<br>* TAS-102 is given in a dose of 35 mg/m2, twice daily on the 1st to 5th and 8th to 12th days of the period of neoadjuvant radiotherapy.<br>* Other names: TAS-102;Radiation: intensity-modulated radiotherapy<br>* intensity-modulated radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | The percentage of the patients complete R0 resection and attain a tumor regression grade of 1-4 (Mandard's 5-tier standard) in postsurgical pathologic examination | One week after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate | The percentage of the patients complete R0 resection and attain a complete remission of both primary tumor and regional lymph nodes in postsurgical pathologic examination | One week after surgery | 
| The incidence of grade 3/4 toxicities | The percentage of the patients undergo any grade 3/4 toxicity during neoadjuvant treatment, based on the Common Terminology Criteria for Adverse Events | Once a week during the period of neoadjuvant treatment | 
| The incidence of grade 3/4 complications | The percentage of the patients undergo any grade 3/4 surgery-related complication, based on the Clavien-Dindo classification. | The period from the date of radical surgery to the 90th day after surgery | 
| Disease-free survival | The percentage of the patients survive without local recurrence or distant metastasis after a time period, from pathological diagnosis | When all the patients are followed-up for 1, 2 and 5 years | 
| Overall survival | The percentage of the patients survive after a time period, from pathological diagnosis | When all the patients are followed-up for 1, 2 and 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, Trifluridine/Tipiracil, radiotherapy