Preoperative CRT With Capecitabine ± Temozolomide in Patients With LARC

Advanced Rectal Cancer Clinical Trial

Official title: Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer; A Prospective Randomised Phase 2 Study Stratified by MGMT (O6-methylguanine DNA Methyltransferase) Status

Status Completed

Clinical Trial Summary

This is a prospective biomarker-stratified, randomised phase II study of preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer.

The primary endpoint is pathologic complete response rates defined as total regression of the primary tumor.

For each cohort of MGMT hypermethylated versus MGMT unmethylated, patients will be randomised (ratio 1:1 for each arm) into preoperative CRT with capecitabine or preoperative CRT with temozolomide plus capecitabine arms. According to the prior phase I results, MGMT hypermethylated arm is estimated as 70% of total patients and the target pathologic complete response rate was assumed as 35% in this population when treated with preoperative CRT with temozolomide and capecitabine (15% in the standard treatment arm or those with unmethylated MGMT). Investigator would like to demonstrate the superiority in terms of pathologic complete responses when treated with preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer, and to validate the predictive role of MGMT status

Clinical Trial Description

Preoperative chemoradiation (CRT) with fluoropyrimidine (5-fluorouracil or capecitabine) is now regarded as a standard treatment option in patients with locally advanced resectable rectal cancer and pathologic response rates and tumor regression grades after preoperative CRT have been proved to be important prognostic factors for survival outcomes.

Several studies of preoperative CRT with fluoropyrimidines plus other agents, such as oxaliplatin, irinotecan, cetuximab, and bevacizumab, have been performed to improve pathologic response rates; however, they have failed to show improved results compared to those with fluoropyrimidine alone.

Thus fluoropyrimidine alone is a standard chemotherapeutic strategy in patients with locally advanced resectable rectal cancer who will be treated with preoperative CRT at present.

Temozolomide is an oral alkylating agent, and has been proved to be effective in patients with glioblastoma or high grade anaplastic glioma when administered with concurrent radiotherapy either as adjuvant or recurrent settings.

Temozolomide has been known to deplete O6-methylguanine DNA methyltransferase (MGMT), which is one of the DNA repair enzymes, and recent studies have shown that MGMT gene silencing (lower expression by immunohistochemistry or hypermethylation by methylation-specific PCR) played a predictive marker of better responses to CRT with temozolomide in patient with glioblastoma and high grade anaplastic glioma.

Silencing of MGMT by promoter hypermethylation has been known to involve colorectal carcinogenesis pathway by the association with KRAS mutation and low-CIMP (CpG island methylation phenotype), and microsatellite instability. There have been suggestions that MGMT promoter hypermethylation played a role as a predictive factor of low recurrence in colorectal cancer patients with adjuvant oral fluoropyrimidine chemotherapy after curative surgery, and also as a predictive factor for treatment response from temozolomide in patients with metastatic colorectal cancer.

Therefore, combination chemotherapy of temozolomide plus capecitabine for rectal cancer patients when treated with preoperative CRT is worthy of investigated especially in those harbouring silenced MGMT gene as following reasons;

1. the role of temozolomide has been well established,

2. MGMT gene silencing is associated with colorectal carcinogenesis and might act as a predictive biomarker; and

3. the addition of temozolomide can be synergistic during preoperative CRT with capecitabine for rectal cancer patients.

Investigator have performed a phase I study of preoperative CRT with temozolomide plus capecitabine in patient with locally advanced rectal cancer, and the results of this study has been published The recommended dose of temozolomide was determined as 75 mg/m2 once daily when combined with standard preoperative CRT with capecitabine, there was no grade 4 adverse events and the treatment was generally well tolerated. MGMT hypermethylation was found in 72% of rectal cancer patients (16/22), and the pathologic complete responses rates were 37.5% (6/16) in patient harbouring hypermethylated MGMT versus 16.7% in those with unmethylated MGMT.

On the basis of prior trial results, Investigator concluded that preoperative CRT with temozolomide plus capecitabine is well tolerated without any notable adverse event, and is worthy of investigation especially in those harbouring MGMT gene silencing.

Investigator planned a prospective, biomarker-stratified, randomised phase II study of preoperative CRT with temozolomide plus capecitabine in patients with locally advanced rectal cancer to demonstrate the addition of temozolomide in the conventional preoperative CRT might enhance the pathologic responses in those harbouring hypermethylated MGMT. ;

Related Conditions & MeSH terms

• Advanced Rectal Cancer
• Rectal Neoplasms

• NCT number: NCT03156036
• Study type: Interventional
• Source: Asan Medical Center
• Status: Completed
• Phase: Phase 2
• Start date: November 30, 2017
• Completion date: February 2, 2021