Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy
Status:
Not yet recruiting
Trial end date:
2024-11-01
Target enrollment:
Participant gender:
Summary
Surgical resection is curative for 75% of stage II and 50% of stage III colon cancer
patients. The magnitude of benefit of adjuvant chemotherapy in terms of disease-free (DFS)
and overall survival (OS) varies according to TNM stage and microsatellite status. Standard
adjuvant chemotherapy includes fluoropyrimidine and oxaliplatin regimens for up to six
months.
Circulating tumor DNA (ctDNA) detected after surgical resection reflects the presence of
micrometastatic disease and pivotal observational studies addressed the prognostic value of
ctDNA in the post-surgical setting. Adjuvant chemotherapy can promote the clearance of ctDNA,
and ctDNA clearance after adjuvant chemotherapy is prognostic for better DFS in patients with
stage III resected cancers and post-operative positive ctDNA.
ctDNA may be investigated as a potential real-time surrogate biomarker of the efficacy of
adjuvant therapy, but suggest that patients with ctDNA persistence after standard
chemotherapy might be "molecularly metastatic" and may benefit from additional
"consolidation" non-cross resistant strategies aimed at clearing micrometastatic disease.
Temozolomide has modest but non-negligible activity (about 10%) in chemo-refractory patients
with MGMT methylated mCRC. The response rate to temozolomide-based therapy in pretreated
patients is increased to up to 20% when restricting the focus on those with MGMT
IHC-negative/MGMT methylated and MSS cancers Significant activity (ORR 26%) and favorable
safety profile were reported by the combination of temozolomide and irinotecan (TEMIRI
regimen) in patients with pretreated MGMT methylated/MSS mCRC, thus suggesting that the two
agents may have synergist activity in line with preclinical data.
Based on all these considerations, there is a strong rationale for investigating TEMIRI
regimen as consolidation non-cross resistant therapy in a liquid-biopsy driven interventional
trial.
Eligible patients with MGMT-silenced, MSS, radically resected CRC and detectable ctDNA after
standard chemotherapy will be enrolled and will receive 6-month post-adjuvant/consolidation
TEMIRI (given for up to 6 monthly cycles).
Phase:
Phase 2
Details
Lead Sponsor:
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano