Induction and Consolidation Chemotherapy in Patients With Locally Advanced CRM-positive Rectal Cancer (RuCorT-03)

Induction and Consolidation Chemotherapy in Locally Advanced Rectal Cancer Patients With Circumferential Resection Margin Involvement: a Multicenter Prospective Randomized Phase III Clinical Trial

The purpose of this study is to determine whether the addition of 2 cycles of induction CapOx chemotherapy and 2 cycles of consolidation CapOx chemotherapy to standard chemoradiation improves 3-year disease-free survival in patients with locally advanced CRM"+" mid and low rectal cancer.

Study Overview

• Status: Enrolling by invitation
• Conditions: Rectal Cancer; Rectum Carcinoma; Rectal Neoplasms Malignant
• Intervention / Treatment: Drug: Capecitabine; Drug: Oxaliplatin; Drug: Capecitabine; Radiation: Radiotherapy; Procedure: Rectal cancer surgery

Detailed Description

This trial aims to investigate the efficacy of adding neoadjuvant induction and consolidation chemotherapy compared to standard chemoradiotherapy in locally advanced rectal cancer patients with circumferential resection margin involvement. This is a prospective multicenter open-label randomized phase III clinical trial. Patients will be randomized using an online randomization system to receive either 2 cycles of induction CapOx (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 per os bid days 1-14) chemotherapy, followed by chemoradiotherapy (54 Gy in 2 Gy fractions with concomitant capecitabine 825 mg/m2 per os bid on radiation days), then 2 cycles of consolidation CapOx chemotherapy, surgery (10-12 weeks following chemoradiotherapy) and 2 cycles of adjuvant CapOx chemotherapy OR chemoradiotherapy (54 Gy in 2 Gy fractions with concomitant capecitabine 825 mg/m2 per os bid on radiation days), surgery (10-12 weeks following chemoradiotherapy) and 6 cycles of adjuvant CapOx chemotherapy. A stratification will be performed based on N stage, tumor location in the middle or low rectum and clinical center. Patients with middle or low rectal cancer without distant metastases, with involved circumferential resection margin (based on pretreatment MRI) will be included.

The target accrual is 270 patients in each treatment arm (including 10% potential data loss) based on potential benefit of 12% 3-yr disease-free survival (60% vs 72%), α=0,05, power 80% in the experimental arm. An interim analysis is planned after 50% of the patients will reach a 3-year followup. Pelvic Magnetic Resonance Imaging (MRI) is performed in all patients for staging before and after neoadjuvant chemotherapy and before surgery. Pelvic MRI is subject to central review. Conduction of this study and data collection are controlled by a local institutional board.

• Study Type: Interventional
• Enrollment (Anticipated): 540
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 115478
    • N.N.Blokhin Russian Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent
• Histologically verified colon rectal adenocarcinoma 0-10 cm above the anal verge
• No distant metastases
• Circumferential resection margin (CRM) involvement (based on pelvic MRI)
• Eastern Cooperative Oncology Group (ECOG) status 0-2
• Haemoglobin (HGB) > 90 g/L
• Platelet Count (PLT) > 120x10*9/L
• Serum creatinine < 150 µmol/L
• Total bilirubin < 25 µmol/L

Exclusion Criteria:

• inability to obtain informed consent
• distant metastases
• cT2N0M0 rectal cancer
• synchronous or metachronous tumors
• previous chemotherapy or radiotherapy
• clinically significant cardiovascular disorders (myocardial infarction < 6 months before visit, stroke < < 6 months before visit, instable angina < 3 months before visit, arrhythmia, uncontrolled hypertension > 160/100 mm hg
• clinically significant neurological disorders
• previous neuropathy 2 or higher
• current infection or heavy systemic disease
• pregnancy, breastfeeding
• ulcerative colitis
• individual intolerance to treatment components
• proven dihydropyrimidine dehydrogenase (DPD) deficiency
• participation in other clinical trials
• psychiatric disorders, which render patient unable to follow instructions or understand his/her condition
• technical inability to perform pelvic MRI
• inability of long-term followup of the patient
• HIV

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: Neoadjuvant chemotherapy; Patients receive 2 cycles of induction CapOx (oxaliplatin 130 mg/m2 iv day 1, capecitabine 2000 mg/m2 per os bid days 1-14) chemotherapy, followed by chemoradiotherapy (54 Gy in 2 Gy fractions with concomitant capecitabine 825 mg/m2 per os bid on radiation days), then 2 cycles of consolidation CapOx chemotherapy, surgery (10-12 weeks following chemoradiotherapy) and 2 cycles of adjuvant CapOx chemotherapy	Drug: Capecitabine; 2000 mg/m2, bid, per os, days 1-14; Other Names: Xeloda; Drug: Oxaliplatin; 130 mg/m2 iv day 1; Drug: Capecitabine; 825 mg/m2, bid, per os, only on days of radiation (Monday through Friday); Other Names: Xeloda; Radiation: Radiotherapy; Pelvic radiotherapy dose: 44 Gy on regional nodes, 54 Gy on primary tumor in 2 Gy fractions; Procedure: Rectal cancer surgery; Laparoscopic or open total mesorectal excision or extralevator abdominoperineal resection
Active Comparator: Chemoradiotherpy; Patients receive 54 Gy pelvic chemoradiotherapy in 2 Gy fractions with capecitabine 825 mg/m2 bid per os on radiation days and then surgery following 10-12 weeks. After surgery patients receive 6 cycles of adjuvant CapOx chemotherapy.	Drug: Capecitabine; 2000 mg/m2, bid, per os, days 1-14; Other Names: Xeloda; Drug: Oxaliplatin; 130 mg/m2 iv day 1; Drug: Capecitabine; 825 mg/m2, bid, per os, only on days of radiation (Monday through Friday); Other Names: Xeloda; Radiation: Radiotherapy; Pelvic radiotherapy dose: 44 Gy on regional nodes, 54 Gy on primary tumor in 2 Gy fractions; Procedure: Rectal cancer surgery; Laparoscopic or open total mesorectal excision or extralevator abdominoperineal resection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
3-year disease-free survival	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year overall survival		3 years
Adjuvant chemotherapy compliance	Proportion of patients who receive a complete course of adjuvant chemotherapy	6 months
Acute chemotherapy toxicity	Toxicity measured according to NCI-CTCAE v.5.0	6 months
pathologic complete response rate (pCR)		1 month
local recurrence rate		3 years
Operative morbidity	Morbidity measured according to Clavien-Dindo classification	30 days
Preoperative tumor-associated complications rate	The rate of tumor-associated complications (bowel obstruction, bleeding etc) during neoadjuvant chemotherapy	6 months
Sphincter preservation rate		1 month

Collaborators and Investigators

• Sponsor: Blokhin's Russian Cancer Research Center
• Investigators: Principal Investigator: Zaman Z Mamedli, PhD, N.N.Blokhin Russian Cancer Research Center

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2019
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): October 1, 2024

Study Registration Dates

• First Submitted: October 20, 2019
• First Submitted That Met QC Criteria: October 20, 2019
• First Posted (Actual): October 22, 2019

Study Record Updates

• Last Update Posted (Actual): February 9, 2021
• Last Update Submitted That Met QC Criteria: February 7, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: rectal cancer; neoadjuvant chemotherapy; induction chemotherapy; consolidation chemotherapy
• 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; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Oxaliplatin
• Other Study ID Numbers: RuCorT-03

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