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Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status

NCT03519412 · Status: COMPLETED · Phase: PHASE2 · Type: INTERVENTIONAL · Enrollment: 107

Last updated 2026-03-03

Study results available
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Summary

In this study, MMRd metastatic colorectal cancer (mCRC) patients who failed standard therapies will undergo treatment with pembrolizumab, while RAS-extended mutated MMR-proficient mCRC patients will be tested for o6-methylguanine-DNA-methyltransferase (MGMT) expression (IHC) and then for MGMT promoter methylation. MGMT IHC-negative, promoter methylation positive patients will be treated with temozolomide (TMZ). Patients progressing under temozolomide will be tested for tumor mutational burden (TMB) and proceed to pembrolizumab if TMB is \> 20 mutations/Mb. The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab.

Conditions

  • Colorectal Neoplasms
  • Microsatellite Instability

Interventions

DRUG

temozolomide (induction),

temozolomide is administered to MGMT promoter methylation-positive MMRp patients orally, once daily, at the dose of 150-200 mg/m2/day for 5 consecutive days of each treatment cycle A treatment cycle will comprise 5 days of temozolomide administration (Day 1 to 5) followed by 23 days of rest for a total of 28 days (4 weeks) period (dose-schedule: 150 mg/m2 day 1-5 q28),until disease progression or unacceptable toxicity whichever comes first.

BIOLOGICAL

pembrolizumab (treatment)

pembrolizumab is administered to MGMT-IHC-negative, MGMT promoter methylation-positive MMRp patients with TMB\>20 Mut/Mb after Temozolomide treatment, and to MMRd. Patients receive pembrolizumab IV , 200 mg Q3W, Day 1 of each 3 week cycle for maximum 35 cycles, until disease progression or unacceptable toxicity whichever comes first.

Sponsors & Collaborators

  • IFOM ETS - The AIRC Institute of Molecular Oncology

    lead OTHER

Principal Investigators

  • Salvatore Siena, MD · Grande ospedale metropolitano Niguarda

  • Silvia Marsoni, MD · IFOM (Istituto FIRC di Oncologia Molecolare)

  • Andrea Sartore bianchi, MD · Grande ospedale metropolitano Niguarda

Study Design

Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Model
PARALLEL

Eligibility

Min Age
18 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2019-01-23
Primary Completion
2025-01-08
Completion
2025-01-08

Countries

  • Italy

Study Locations

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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 NCT03519412 on ClinicalTrials.gov