Temozolomide and Irinotecan in Patients With MGMT Silenced Colorectal Cancer After Adjuvant Chemotherapy (ERASE-TMZ)
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|ClinicalTrials.gov Identifier: NCT05031975|
Recruitment Status : Not yet recruiting
First Posted : September 2, 2021
Last Update Posted : April 4, 2022
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).
|Condition or disease||Intervention/treatment||Phase|
|Colorectal Cancer||Drug: Irinotecan Drug: Temozolomide||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||35 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Temozolomide and Irinotecan Consolidation in Patients With MGMT Silenced, Microsatellite Stable Colorectal Cancer With Persistence of Minimal Residual Disease in Liquid Biopsy After Standard Adjuvant Chemotherapy: the ERASE-TMZ Study|
|Estimated Study Start Date :||June 1, 2022|
|Estimated Primary Completion Date :||June 1, 2024|
|Estimated Study Completion Date :||June 1, 2024|
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.
Irinotecan 100 mg/smq intravenous infusion every 14 days
Oral temozolomide 150 mg/sqm over days 1-5 every 28 days.
- 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 ]The activity of TEMIRI will be measured as the rate of patients with post-treatment seroreversion and disease-free at 2 years
- Disease-free survival (DFS) of patients treated with TEMIRI as consolidation regimen [ Time Frame: 36 months ]DFS is defined as the time from randomization to recurrence of tumor or death due to any cause, whichever occurs first. DFS will be censored on the date of the last evaluable on study tumour assessment documenting absence of disease relapse for patients who are alive and disease-free at the time of the analysis. Alive patients having no tumour assessments after baseline will have time to event censored on the data of enrolment
- Overall survival (OS) of patients treated with TEMIRI as consolidation regimen [ Time Frame: 36 months ]OS is defined as the time from enrolment to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.
- Safety profile of TEMIRI consolidation regimen [ Time Frame: 36 months ]Safety will be assessed by monitoring the frequency of adverse events
- Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: Assessed up to 24 months from enrollment ]EORTC QLQ-C30 administered every 12 weeks during treatment and at the date of first documented progression, assessed up to 24 months from enrollment
- Quality of life as assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Colorectal Cancer 29 (EORTC QLQ-CR29) [ Time Frame: Assessed up to 24 months from enrollment ]EORTC QLQ-CR29 administered every 12 weeks during treatment and at the date of first documented progression, assessed up to 24 months from enrollment
- Quality of life as assessed using the Euro Quality of Life 5 Dimensions Questionnaire (EQ-5D-5L) [ Time Frame: Assessed up to 24 months from enrollment ]EQ-5D-5L administered every 12 weeks during treatment and at the date of first documented progression, assessed up to 24 months from enrollment
- Identify a gene expression signature (name of mutated gene/genes) associated to temozolomide resistance/sensitivity [ Time Frame: 36 months ]To develop a gene expression signature (a single or combined group of genes) associated with temozolomide resistance/sensitivity by profiling tumor tissue blocks obtained prior to any treatment
- To assess the accuracy of ctDNA as disease recurrence biomarker [ Time Frame: 36 months ]To longitudinally monitor the disease recurrence thanks to serial liquid biopsies obtained during the follow-up phase. The outcome will be measured as the percentage of ctDNA negative patients with recurrence disease
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05031975
|Contact: Filippo Pietrantonio, MDemail@example.com|
|Contact: Federica Morano, MDfirstname.lastname@example.org|
|Principal Investigator:||Filippo Pietrantonio, MD||Fondazione IRCCS Istituto Nazionale dei Tumori, Milano|