Study on Predictive Biomarkers of Neoadjuvant Chemoradiotherapy for Rectal Cancer

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

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.

Study Overview

• Status: Unknown
• Conditions: Adenocarcinoma; Neoadjuvant Therapy; Chemoradiotherapy; Rectal Neoplasm Malignant Carcinoma; Predictive Biomarkers
• Intervention / Treatment: Radiation: Radiation; Drug: Capecitabine-Irinotecan Combination

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.

• Study Type: Observational
• Enrollment (Anticipated): 250

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Stage T3 or T4 and/or N+ rectal adenocarcinoma cancer eligible for neoadjuvant chemoradiation

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fudan University
• Collaborators: Harbin Medical University; Liaoning Tumor Hospital & Institute
• Investigators: Principal Investigator: Ji Zhu, MD, Fudan University

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2019
• Primary Completion (ANTICIPATED): December 31, 2020
• Study Completion (ANTICIPATED): December 31, 2021

Study Registration Dates

• First Submitted: December 30, 2019
• First Submitted That Met QC Criteria: January 11, 2020
• First Posted (ACTUAL): January 14, 2020

Study Record Updates

• Last Update Posted (ACTUAL): January 14, 2020
• Last Update Submitted That Met QC Criteria: January 11, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Irinotecan; Prediction Model; Toxicities; Neoadjuvant Chemoradiation; Treatment Response; Tissue RNA; Plasma exosome
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Capecitabine; Irinotecan
• Other Study ID Numbers: FDRT-011

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