Study on Predictive Biomarkers of Neoadjuvant Chemoradiotherapy for Rectal Cancer

Study Overview
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Brief Summary
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Backgrounds: A multicenter randomized phase III trial (NCT02605265) proved that adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. Purposes: This study aims to identify the predictive biomarkers (from patients' tumor biopsy samples and peripheral blood samples before neoadjuvant therapy) for predicting the response and toxicities to neoadjuvant therapy to stratify patients and optimize treatment strategy.

Detailed Description
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OBJECTIVES: Primary: Establish a predictive model for response based on tissue RNA and plasma exosome RNA Establish a predictive model for toxicities based on tissue RNA and plasma exosome RNA Secondary: Internal validation of the established predictive models External validation of the established predictive models OUTLINE: -Treatment: Patients receive neoadjuvant therapy and surgery per the protocol. Samples collection Tumor tissue and peripheral blood will be collected prior to neoadjuvant therapy. -Grouping: Response: Patients will be dichotomized into two groups based on the TRG. TRG of 0-1 is defined as good response. TRG of 2-3 is defined as poor response. Toxicities: Patients will be dichotomized into two groups based on the grade of AEs. No grade 3-4 toxicities occurs during neoadjuvant therapy is defined as light toxicities. Grade 3-4 toxicities occur during neoadjuvant therapy is defined as heavy toxicities. -Predictive Model Construction: Using RNA sequencing method to obtain the whole genome transcription profiles of the tumor tissue and plasm exosome RNA. Compare the gene expression differences between the two response groups and the two toxicity groups. Predictive models of response and toxicities are constructed. -Internal Validation: Patients treated at Fudan University Shanghai Cancer Center (N=50) per the protocol will be enrolled as the internal validation cohort. Samples of tissue and plasm will be collected and analyzed. The performance of the model will be evaluated by the correlation of the predicted response/toxicities and the actual response/toxicities. -External Validation: Patients treated at Liao'ning Cancer Hospital & Institute (N=50) and Harbin Medical University Cancer Hospital (N=50) per the protocol will be enrolled as two external validation cohorts. Samples of tissue and plasm will be collected and analyzed. The performance of the model will be evaluated by the correlation of the predicted response/toxicities and the actual response/toxicities.

Official Title
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A Prospective, Observational, Multicenter Study on Biomarkers for Predicting the Efficacy and Toxicities of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer Based on Tissue and Plasma Exosome RNA

Conditions
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Rectal Neoplasm Malignant Carcinoma, Chemoradiotherapy, Neoadjuvant Therapy, Predictive Biomarkers, Adenocarcinoma

Intervention / Treatment
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* Radiation: Radiation
* Drug: Capecitabine-Irinotecan Combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathological confirmed adenocarcinoma Clinical stage T3-4 andor N+ The distance from anal verge less than 12 cm No suspicious metastatic disease (M1) ECOG PS 0-1 UGT1A1*28 6/6 or 6/7 No previous anti-cancer therapy Exclusion Criteria: Pregnancy or breast-feeding women Serious medical illness Baseline blood and biochemical indicators do not meet the following criteria: neutrophils≥1.5×10^9/L, Hb≥90g/L, PLT≥100×10^9/L, ALT/AST ≤2.5 ULN, Cr≤ 1 ULN DPD deficiency UGT1A1*28 7/7

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Good response<br>TRG of 0-1 is defined as good response. | Radiation: Radiation<br>* Neoadjuvant radiotherapy consisted of 50 Gy in 25 fractions using intensity-modulated radiotherapy to the primary tumor and to mesorectal, presacral, and internal iliac lymph nodes.<br>Drug: Capecitabine-Irinotecan Combination<br>* The concurrent chemotherapy consists of capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI.<br>|
| Poor response<br>TRG of 2-3 is defined as poor response. | Radiation: Radiation<br>* Neoadjuvant radiotherapy consisted of 50 Gy in 25 fractions using intensity-modulated radiotherapy to the primary tumor and to mesorectal, presacral, and internal iliac lymph nodes.<br>Drug: Capecitabine-Irinotecan Combination<br>* The concurrent chemotherapy consists of capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI.<br>|
| Light toxicity<br>No grade 3-4 toxicities occur during neoadjuvant therapy. | Radiation: Radiation<br>* Neoadjuvant radiotherapy consisted of 50 Gy in 25 fractions using intensity-modulated radiotherapy to the primary tumor and to mesorectal, presacral, and internal iliac lymph nodes.<br>Drug: Capecitabine-Irinotecan Combination<br>* The concurrent chemotherapy consists of capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI.<br>|
| Heavy toxicity<br>Grade 3-4 toxicities occur during neoadjuvant therapy. | Radiation: Radiation<br>* Neoadjuvant radiotherapy consisted of 50 Gy in 25 fractions using intensity-modulated radiotherapy to the primary tumor and to mesorectal, presacral, and internal iliac lymph nodes.<br>Drug: Capecitabine-Irinotecan Combination<br>* The concurrent chemotherapy consists of capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TRG | Tumor regression grade | Surgery scheduled 6-8 weeks after the end of neoadjuvant therapy | 
| Toxicities | Number of participants with chemoradiation-related adverse events as assessed by CTCAE v4.0 | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The total survival time of the participants from joining the group to the death | 3 years | 
| Progression-free Survival | The time period that from participants joining the groups to the progression of disease (recurrence or metastasis) or death of any cause. | 3 years | 
| Local Control rate | The time period that from participants joining the groups to the date of first documented pelvic failure. | 3 years | 
| pCR | Pathologic Complete Response | Surgery scheduled 6-8 weeks after the end of neoadjuvant therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Chemoradiation, Prediction Model, Treatment Response, Toxicities, Irinotecan, Tissue RNA, Plasma exosome