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.
Arethusa consists of three different phases - SCREENING Phase, PRIMING phase, and TRIAL
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
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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