Evaluation of Temozolomide and Irinotecan Consolidation in MGMT-Silenced, Microsatellite Stable Colorectal Cancer with Persistent Minimal Residual Disease

The primary objective of the study is to assess the activity in terms of **seroreversion** of the temozolomide and irinotecan (TEMIRI) consolidation regimen. This regimen is administered to patients with high-risk stage II (pT4) or III microsatellite stable, MGMT silenced colorectal cancer (CRC) who have positive post-adjuvant circulating tumor DNA (ctDNA) following standard oxaliplatin-based adjuvant chemotherapy. The clinical relevance of this objective lies in its potential to improve treatment outcomes by targeting residual disease, thereby reducing the risk of cancer recurrence.

Secondary objectives include:

• Estimating the disease-free survival (DFS) of patients treated with the TEMIRI regimen and comparing DFS based on seroreversion status, specifically ctDNA clearance versus persistence.
• Estimating overall survival (OS) of patients treated with the TEMIRI regimen and comparing OS according to seroreversion status.
• Evaluating the safety profile and adverse events associated with the TEMIRI consolidation regimen.
• Assessing the quality of life of patients during the TEMIRI consolidation regimen.

The clinical trial involves participants diagnosed with **Stage II (pT4) or III colorectal cancer** who exhibit positive circulating tumor DNA (ctDNA) following oxaliplatin-based adjuvant chemotherapy. The study population includes both male and female subjects, aged 18 years and older, with a histologically confirmed diagnosis of stage III or T4N0 stage II colon cancer or locally-advanced resectable rectal cancer. Participants must have completed radical surgery and at least three months of oxaliplatin-based adjuvant chemotherapy. The trial does not include a vulnerable population. Participants are required to have adequate organ function, a carcinoembryonic antigen (CEA) level of 10 ng/ml or less, and no evidence of metastatic disease as confirmed by CT scans. The trial population was selected based on the presence of ctDNA in liquid biopsies collected 2-6 weeks after the last dose of standard adjuvant chemotherapy, absent MGMT expression, and an ECOG performance status of 0-1. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed to evaluate the efficacy of a **temozolomide** and **irinotecan** consolidation regimen in patients with high-risk stage II (pT4) or III microsatellite stable colorectal cancer (CRC) who exhibit positive circulating tumor DNA (ctDNA) following standard oxaliplatin-based adjuvant chemotherapy. This is a randomized, double-blind, controlled trial with an estimated duration from March 2021 to October 2024. The primary objective is to assess the seroreversion rate and disease-free status at two years post-treatment. Secondary endpoints include disease-free survival, overall survival, safety assessments, and the development of a gene expression signature related to temozolomide resistance or sensitivity.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate organ function, absence of metastatic disease, and completion of prior chemotherapy. Follow-up visits will be scheduled to monitor treatment response, adverse events, and ctDNA levels. The end-of-study visit will evaluate the long-term outcomes and collect final data for analysis. The expected length of participant involvement is approximately six months, with conditions for early termination including significant adverse events or withdrawal of consent.

Inclusion criteria require participants to be at least 18 years old, have a histologically confirmed diagnosis of stage III or T4N0 stage II colon cancer, and have completed radical surgery and adjuvant chemotherapy. Exclusion criteria are not explicitly detailed in the provided data. The trial will utilize both oral and injection routes for drug administration, with a maximum daily dose of 150 mg for temozolomide and 100 mg for irinotecan. The trial is categorized as a therapeutic exploratory phase II study, focusing on the potential benefits of the consolidation regimen in this specific patient population.

The clinical trial involves the administration of **irinotecan hydrochloride**, an antineoplastic agent, as part of the experimental treatment regimen. **Irinotecan** is provided in a pharmaceutical form identified as PHF00230MIG and is administered via **injection**. The dosage is calculated based on body surface area, with a maximum daily dose of 100 mg/m². The treatment period is limited to a maximum of six cycles, with each cycle corresponding to a specific time unit code of 3. The chemical origin of the active substance is confirmed, and the product is not formulated for pediatric use. Monitoring of participant compliance with the dosing schedule is integral to the study protocol.

Additionally, the trial includes the use of **temozolomide**, another antineoplastic agent, which is administered orally. The pharmaceutical form of **temozolomide** is designated as PHF00005MIG. The dosage is also determined based on body surface area, with a maximum daily dose of 150 mg/m² and a total maximum dose of 300 mg. Similar to **irinotecan**, the treatment period for **temozolomide** is capped at six cycles. The chemical nature of the active substance is verified, and it is not intended for pediatric patients. The study protocol includes measures to ensure adherence to the oral dosing regimen by participants.

Both **irinotecan hydrochloride** and **temozolomide** are utilized in this trial to evaluate their combined efficacy in patients with microsatellite stable colorectal cancer, specifically those with MGMT silenced tumors and minimal residual disease post-standard adjuvant chemotherapy. The trial aims to assess the seroreversion activity of this consolidation regimen. No placebo or comparator treatment is employed in this study, and the focus remains on the experimental combination of these two chemotherapeutic agents.

Efficacy in the clinical trial titled "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" will be assessed using several endpoints. The primary endpoint is the activity of the TEMIRI regimen, measured by the rate of patients achieving post-treatment **seroreversion** and remaining disease-free at two years. Secondary endpoints include disease-free survival (DFS), defined as the time from enrolment to the first documentation of objective disease relapse or death from any cause, and overall survival (OS), defined as the time from enrolment to death from any cause, with censoring for patients alive at the time of analysis.

Additional secondary endpoints involve safety assessments through monitoring the frequency, duration, and severity of adverse events (AEs) via physical examinations and clinical laboratory evaluations. Patient-reported outcomes (PROs) will be analyzed using the EORTC QLQ-C30, EORTC QLQ-CR29, and EuroQol EQ-5D questionnaires, with scoring conducted according to the EORTC Scoring and Reference Values Manual. Furthermore, the trial aims to develop a gene expression signature associated with temozolomide resistance or sensitivity by profiling tumor tissue blocks obtained prior to treatment. The accuracy of liquid biopsies collected during follow-up to predict recurrence will also be assessed.