Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy

Sponsor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Study ID
NCT05031975
Phase
PHASE2
Status
Unknown

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - N/A
Healthy Volunteers
Not accepted

Interventions

  • Irinotecan — DRUG
    Irinotecan 100 mg/smq intravenous infusion every 14 days
  • Temozolomide — DRUG
    Oral temozolomide 150 mg/sqm over days 1-5 every 28 days.

Study Details

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).

Key Dates

Start date
May 2, 2022
Status verified
Aug 2022
Primary completion
Jun 1, 2024
Completion
Jun 1, 2024

Study Design

Enrollment
35 participants (estimated)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: TEMIRI
    Irinotecan intravenous infusion (IV) given every 14 days in combination with oral (PO) temozolomide over days 1-5 every 28 days. The treatment will consist of six 28-days cycles of TEMIRI.

Primary Outcome Measure

To assess the activity in terms of seroreversion of TEMIRI consolidation regimen administered to patients with high-risk stage II (pT4) or III MSS, MGMT silenced CRC and positive post-adjuvant ctDNA after standard oxaliplatin-based adjuvant chemotherapy. [ Time Frame: 2 years from randomization ]

Central Contacts

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