At a glance
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Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status
In Brief
A Phase 2 clinical trial evaluating temozolomide (induction), and pembrolizumab (treatment) for Colorectal Neoplasms and Microsatellite Instability. Completed, enrolled 107 participants across 4 sites.
Detailed 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.
Study Details
Timeline
Interventions
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.
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.