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Preoperative Chemoradiotherapy With CApecitabine and Temozolomide in MGMT Silenced, MSS, Locally Advanced RecTal Cancer

NCT05136326 · Status: RECRUITING · Phase: PHASE2 · Type: INTERVENTIONAL · Enrollment: 21

Last updated 2023-03-01

No results posted yet for this study

Summary

In patients with locally advanced rectal cancer (LARC), preoperative chemo-radiotherapy (CTRT) is considered the standard of care. Preoperative CTRT approach often results in a significant tumor downstaging and local control, with evidence of complete pathological response (pCR) rate of about 15% in high volume institutions. In high-risk LARC a new strategy called total neoadjuvant therapy (TNT) has emerged, in which systemic chemotherapy with fluorouracil and oxaliplatin (RAPIDO trial) or with the triplet FOLFIRINOX (as was used in the PRODIGE 23 study) is incorporated before or after the administration of short-course RT or neoadjuvant CTRT and prior to surgery. However, given the fact that TNT may represent an overtreatment for a subset of patients, additional therapeutic strategies are warranted to improve the outcomes also in patients with lower risk that are not good candidate for a TNT.

In the era of personalized medicine, tumor molecular profiling may lead to the identification of therapeutic targets for pharmacological intervention potentially useful to enhance treatment outcomes.

O(6)-methylguanine-DNA-methyltransferase (MGMT) repairs DNA damage induced by alkylating agents and MGMT inactivation due to promoter methylation confers enhanced sensitivity to alkylating agents such as temozolomide (TMZ).

TMZ has modest activity in patients with MGMT-methylated pretreated metastatic colorectal cancer and responses are restricted to tumors with complete MGMT loss by immunohistochemistry (IHC) and microsatellite stable (MSS) status.

Both capecitabine and temozolomide induces deoxythymidine triphosphate thymidine pool depletion might induce deoxyribonucleic acid (DNA)-double strand breaks and eventually apoptosis in rapidly dividing cells. On the basis of such evidences, there is a strong biological and clinical rationale for testing the addition of TMZ to capecitabine-based CTRT in patients with MGMT silenced and MSS technically resectable LARC.

The aim of this trial is investigating whether the addition of TMZ to standard concurrent capecitabine-based long-course chemoradiation may increase pCR rate as compared to historical control in patients with locally advanced rectal cancer not candidate to TNT and molecularly selected for the presence of MGMT silencing and microsatellite stable status.

Conditions

Interventions

RADIATION

External-beam radiation

External-beam radiation 50.4 GY (45 Gy in 25 fractions + Boost 5.4 Gy in 3 fractions over 5 weeks)

DRUG

Capecitabine

825 mg/sqm/bid per os (p.o.) 5 days/week for 5 weeks;

DRUG

Temozolomide

75 mg/sqm p.o. 5 days/week for 5 weeks

Sponsors & Collaborators

  • Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

    lead OTHER

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2021-12-01
Primary Completion
2023-12-31
Completion
2026-12-31

Countries

  • Italy

Study Locations

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Entities

Drugs
Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT05136326 on ClinicalTrials.gov