Study on Predictive Biomarkers of Neoadjuvant Chemoradiotherapy for Rectal Cancer

• Conditions: Rectal Neoplasm Malignant Carcinoma; Chemoradiotherapy; Predictive Biomarkers; Adenocarcinoma; Neoadjuvant Therapy
• Interventions: Radiation: Radiation; Drug: Capecitabine-Irinotecan Combination

• Registration Number: NCT04227886
• Lead Sponsor: Fudan University

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2019-12-01
• Study First Submitted: 2019-12-30
• Status Verified: 2020-01
• Study First Submitted QC: 2020-01-11
• Last Update Submitted: 2020-01-11
• Study First Posted: 2020-01-14
• Last Update Posted: 2020-01-14
• Primary Completion: 2020-12-31
• Study Completion: 2021-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 250

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

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Good response	Radiation	TRG of 0-1 is defined as good response.
Heavy toxicity	Capecitabine-Irinotecan Combination	Grade 3-4 toxicities occur during neoadjuvant therapy.
Poor response	Radiation	TRG of 2-3 is defined as poor response.
Good response	Capecitabine-Irinotecan Combination	TRG of 0-1 is defined as good response.
Poor response	Capecitabine-Irinotecan Combination	TRG of 2-3 is defined as poor response.
Light toxicity	Capecitabine-Irinotecan Combination	No grade 3-4 toxicities occur during neoadjuvant therapy.
Light toxicity	Radiation	No grade 3-4 toxicities occur during neoadjuvant therapy.
Heavy toxicity	Radiation	Grade 3-4 toxicities occur during neoadjuvant therapy.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Fudan University Shanghai Cancer Center; 🇨🇳 Shanghai, Shanghai, China