Phase II Multicenter Study on Efficacy and Safety of Cetuximab and Irinotecan Rechallenge Versus Investigator's Choice in Metastatic Colorectal Cancer

Trial ID: 2024-518728-59-00
Sponsor: Associacio Per A La Recerca Oncologica

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Diseases & Conditions

Colorectal cancer metastatic

Objectives

The primary objective of this study is to evaluate the **efficacy**, in terms of overall response rate (ORR), of a rechallenge strategy with **cetuximab** and **irinotecan** compared to the investigator's choice of treatment, excluding anti-EGFR therapy, as third-line treatment in patients with RAS, BRAF, and EGFR-ECD wild-type metastatic colorectal cancer (mCRC) genomically selected by liquid biopsy. This is clinically relevant as it aims to determine the potential benefit of reintroducing cetuximab and irinotecan in a specific patient population, potentially offering a more effective treatment option in the third-line setting.

Secondary objectives include:

Evaluating the efficacy in terms of disease control rate (DCR) of cetuximab plus irinotecan rechallenge compared to the investigator's choice of treatment in the third-line setting.
Assessing the duration of disease control (DDC) with cetuximab plus irinotecan rechallenge versus the investigator's choice of treatment.
Determining the time to treatment failure (TTF) with cetuximab plus irinotecan rechallenge compared to the investigator's choice of treatment.
Evaluating the efficacy in terms of progression-free survival (PFS) and overall survival (OS) of cetuximab plus irinotecan rechallenge versus the investigator's choice of treatment.
Assessing the safety profile of cetuximab plus irinotecan treatment and the investigator's choice of treatment in the third-line setting in patients previously treated with a non-anti-EGFR therapy as second-line treatment after cetuximab-based first-line treatment.
Evaluating the emergence/expression levels of additional potential biomarkers related to treatment resistance in circulating tumor DNA (ctDNA) and tissue.

Participants

The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have adequate bone marrow, renal, and hepatic function, and a life expectancy of more than 12 weeks. They should have histologically confirmed metastatic colorectal cancer with RAS wild-type status, as determined by a local assay before starting first-line treatment. The trial population was selected based on their previous treatment history, requiring that they have received two prior regimens of standard chemotherapy for metastatic colorectal cancer and have shown acquired resistance to anti-EGFR monoclonal antibodies. The sponsor has not provided information regarding the total number of participants in the study.

Plans and Procedures

The clinical trial is a multicenter, open-label, randomized, two-arm, phase II study designed to evaluate the efficacy and safety of a **cetuximab** plus **irinotecan** rechallenge compared to the investigator's choice of therapy in patients with metastatic colorectal cancer. The trial aims to assess the overall response rate (ORR) as the primary endpoint, with secondary endpoints including disease control rate (DCR), duration of disease control (DDC), time to treatment failure (TTF), progression-free survival (PFS), and overall survival (OS). The study will also monitor the safety profile of the treatments and explore potential biomarkers related to treatment resistance.

The trial is expected to run from November 2020 to June 2026. Participants will be randomly assigned to one of the two treatment arms. The study includes a screening visit to confirm eligibility based on criteria such as histologically confirmed metastatic colorectal cancer, RAS wild-type status, and previous treatment history. Participants must have received two prior regimens of standard chemotherapy and must be refractory to or have failed these regimens. The inclusion criteria also require adequate bone marrow, renal, and hepatic function, and a life expectancy of more than 12 weeks.

Study visits will follow a structured sequence, beginning with the inclusion visit for screening and baseline assessments. Follow-up visits will occur at regular intervals to monitor treatment response and safety, with assessments including physical examinations, laboratory tests, and imaging studies. The end-of-study visit will conclude the participant's involvement, with final evaluations to determine the overall treatment outcome.

Participant involvement is expected to last up to 60 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring that all procedures are performed with the utmost care and scientific rigor.

Treatment

The clinical trial involves the administration of **IRINOTECAN**, a cytostatic agent classified as a Topoisomerase I inhibitor. **IRINOTECAN** is provided in the pharmaceutical form of a concentrate for solution for infusion. The active substance is of chemical origin. The maximum daily dose is 180 mg/m², with a total maximum dose of 21,600 mg/m² over a treatment period of up to 60 days. The route of administration is via solution for infusion, and the dosing schedule is determined based on the patient's body surface area in milligrams per square meter.

**CETUXIMAB** is also utilized in this study, categorized under antineoplastic agents and monoclonal antibodies. It is administered as a solution for intravenous infusion. The maximum daily dose for **CETUXIMAB** is 500 mg/m², with a total maximum dose of 60,000 mg/m² over a treatment period of up to 60 days. The administration is conducted through intravenous infusion, and dosing is similarly calculated based on the patient's body surface area in milligrams per square meter.

The trial compares the efficacy and safety of a rechallenge strategy with **CETUXIMAB** and **IRINOTECAN** against the investigator's choice of therapy, excluding anti-EGFR therapy, in patients with metastatic colorectal cancer. The study ensures participant compliance through monitoring of dosing schedules and adherence to the treatment protocol. No additional non-experimental treatments, such as placebo or comparator treatments, are specified in the trial documentation.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **Overall Response Rate (ORR)**, which is defined as the percentage of patients achieving a Complete Response (CR) or Partial Response (PR) as the best overall response. This assessment will be conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, from the time of randomization to disease progression, death, or premature withdrawal from study treatment due to any reason, including unacceptable toxicity, whichever occurs first, in both study arms.

Secondary endpoints include the Disease Control Rate (DCR), Duration of Disease Control (DDC), Time to Treatment Failure (TTF), Progression-Free Survival (PFS), and Overall Survival (OS). DCR is defined as the percentage of patients achieving CR, PR, or Stable Disease (SD) as the best overall response. DDC measures the time from first CR, PR, or SD to first observed progression or death. TTF is the time from randomization to the end date of study treatment for any reason or date of progressive disease. PFS is the time from randomization to the date of first observed progression or death. OS is the time from randomization to the date of death due to any cause.

The safety profile of the treatments will be evaluated based on all adverse events (AEs), both serious and non-serious, experienced since randomization. These will be classified and graded according to NCICTCAE version 5.0. Additionally, any abnormal findings on physical examination, vital signs, laboratory results, electrocardiogram (ECG), and imaging tests will be monitored throughout the study.

Biomarker analysis will also be conducted to assess the emergence or expression level of potential biomarkers related to treatment resistance, including MAPKs pathway mutations, alternative receptor activation, and PIK3CA mutations in circulating tumor DNA (ctDNA). Immunologic characteristics in peripheral blood and tumor tissue will be evaluated during the screening period, at week 8 after randomization, and at the end-of-treatment visit in both study arms.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent before any study procedure is performed.
Men and women aged 18 years or older.
Histologically confirmed mCRC.
RAS wild-type (KRAS and NRAS exon 2,3,4) status in a tissue-based test determined by a local assay before starting first-line treatment.
Patients must have received two prior regimens of standard chemotherapy for mCRC and must have been refractory to or failed (includes intolerance) to those regimens. ▪ Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must have included all of the following agents: ▪ AntiEGFR monoclonal antibodies (cetuximab or panitumumab) in the firstline setting ▪ Fluoropyrimidines, irinotecan and oxaliplatin (+/- an anti-VEGF pathway inhibitor approved for treatment of mCRC). Reintroduction of a chemotherapeutic regimen will not be considered as a new line of treatment.
Patients with “acquired” resistance to antiEGFR monoclonal antibodies (cetuximab or panitumumab), defined as: ▪ Response to first-line antiEGFR-based treatment (defined as CR, PR or SD lasting ≥16 weeks). ▪ Documented progression to first-line antiEGFR-based treatment within 4 weeks after the last administration of cetuximab or panitumumab.
Recovery of any toxicity related to second-line treatment to grade ≤1 according to NCICTCAE version 5.0 at screening, with the exception of grade 2 alopecia or grade 2 neuropathy.
Triple negative mutation status defined as no detection of clonal mutations in extended RAS (KRAS and NRAS exon 2,3,4), BRAF V600E and EGFR-ECD (V441, S464, G465 and S492) as assessed in liquid biopsy testing for screening before third-line treatment initiation assessed by the central laboratory. Note: A centralized genomic analysis will be performed. For this purpose, peripheral blood will be collected and sent to the central laboratory for detecting RAS, BRAF V600E, and EGFR-ECD mutations on ctDNA by Oncomine CRC NGS analysis.
At least one measurable lesion, defined as one or more target lesions according to RECIST, version 1.1.
ECOG performance status of 0-1
Adequate bone marrow (hemoglobin ≥9.0 g/dL, neutrophil count > 1.0 x 109/L and platelet > 50 x 109/L), renal (serum creatinine <2 x upper limit of normal [ULN] and/or bilirubin <2.5 x UNL) and hepatic function (ALT and AST < 2.5 x ULN, ≤ 5 x ULN if liver metastases are present).
Absence of any psychological, familial, sociological or geographical circumstance potentially hampering compliance with the study protocol.
Life expectancy >12 weeks, as determined by the investigator.

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Exclusion Criteria

Patients who decline or are unable to understand, provide or are unwilling to sign an informed consent form.
Failure to perform screening examinations.
Second-line treatment with anti-EGFR therapy.
Pregnant or nursing (lactating) women; women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause) who have not undergone surgical sterilization and who are sexually active that are unwilling to use adequate contraception (such as oral contraceptives, intrauterine contraceptive device or barrier method with spermicide or surgical sterilization) during the study and until 3 months after last dose of study treatment administration.
Previous or concurrent second malignancy with exception of basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other solid tumors with no evidence of recurrence in the last 5 years.
Patients with known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression; patients with any of these metastases not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.
Patients with MSI-high (MSI-H) tumors.
Suspected or known allergy or intolerance to any components of the study treatment.
History of grade 3/4 infusion reactions to cetuximab or panitumumab monoclonal antibodies.
Unable or unwilling to complete all required screening and/or follow-up assessments.
Patients under ongoing treatment with an investigational medication or medical device or participation in another investigational study within the previous 4 weeks.
Patients with active alcohol or drug addiction or any other condition that, in the investigator's opinion, would interfere with their ability to comply with the study requirements.
Patients with any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.