Ignite Creation Date:
2024-05-06 @ 11:26 AM
Last Modification Date:
2024-10-26 @ 12:45 PM
Study NCT ID:
NCT03519412
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-09-28
First Post:
2018-04-26
Brief Title:
Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Hypermutation Status
Sponsor:
IFOM ETS - The AIRC Institute of Molecular Oncology
Organization:
IFOM ETS - The AIRC Institute of Molecular Oncology
Study Overview
Official Title:
Pembrolizumab in MMR-Proficient Metastatic Colorectal Cancer Pharmacologically Primed to Trigger Dynamic Hypermutation Status
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ARETHUSA
Brief 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 mutationsMb The primary study hypothesis is that tumors with acquired resistance to temozolomide become hypermutated and are sensitive to pembrolizumab
Detailed 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 mutationsmegabase will go off-study Patients with a mutational load 20 mutationsmegabase will proceed to trial phase no longer than week 5 post TMZ-ML
TRIAL PHASE Eligible patients ie 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
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 mutationsmegabase will go off-study Patients with a mutational load 20 mutationsmegabase will proceed to trial phase no longer than week 5 post TMZ-ML
TRIAL PHASE Eligible patients ie 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2018-001441-14 | EUDRACT_NUMBER | None | None |