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

Colorectal Neoplasms Clinical Trial

Official title: Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status

Status Active, not recruiting

Clinical Trial 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.

Clinical Trial Description

Arethusa consists of three different phases - SCREENING Phase, PRIMING phase, and TRIAL Phase.

• SCREENING PHASE: MMR-Deficient (MMR-D) patients will proceed directly to TRIAL Phase (cohort D) to be treated with pembrolizumab. RAS mutant MMR-Proficient (MMR-P) patients, instead, are further tested for O6-methylguanine-DNA methyltransferase gene expression (MGMT) status in tissue (MGMT protein IHC and MGMT promoter methylation). MGMT IHC negative and promoter methylated patients will proceed to PRIMING phase.

• PRIMING PHASE: MMR-P patients showing negative MGMT protein and high levels of MGMT promoter methylation in tissues will receive TMZ therapy until progression. Two tumor biopsies will be taken prior to starting therapy and at progression to determine the mutational load. Patients with a mutational load < 20 mutations/megabase will go off-study. Patients with a mutational load >20 mutations/megabase, will proceed to trial phase no longer than week 5 post TMZ-ML.

• TRIAL PHASE: Eligible patients, i.e. MMRD patients (cohort D) and patients with a TMZ-ML > 20 mutations per megabase at TMZ-ML (cohort P), will be treated with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. ;

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Microsatellite Instability

• NCT number: NCT03519412
• Study type: Interventional
• Source: IFOM ETS - The AIRC Institute of Molecular Oncology
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 23, 2019
• Completion date: December 2024