MoLiMoR - A Study With FOLFIRI-based First-line Therapy With or Without Intermittent Cetuximab

Study Overview
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Brief Summary
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This is an open-label, prospective, randomized, multicenter phase II trial that will evaluate the efficacy and safety of intermittent addition of cetuximab to a FOLFIRI-based first line therapy to patients with RAS (Rat sarcoma)-mutant mCRC (Metastatic colorectal cancer) diagnosis who convert to RAS wild-type using monitoring of the RAS mutation status by liquid biopsy.

Official Title
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Modulation of the FOLFIRI-based Standard First-line Therapy With Cetuximab, Controlled by Monitoring the RAS (Rat Sarcoma) Mutation Load by Liquid Biopsy in RAS-mutated mCRC (Metastatic Colorectal Cancer): A Randomized Phase II Study With FOLFIRI-based First-line Therapy With or Without Intermittent Cetuximab (MoLiMoR)

Conditions
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Adenocarcinoma of the Colon, Adenocarcinoma of the Rectum

Intervention / Treatment
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* Drug: Cetuximab
* Other: FOLFIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, UICC stage IV adenocarcinoma of the left-sided colon or rectum with metastases (metastatic colorectal cancer), primarily non-resectable, confirmed RAS mutations proven in the primary tumor or metastasis (KRAS ans NRAS exon 2, 3, 4) Age ≥ 18 years on day of signing informed consent No previous chemotherapy for metastatic disease (1- 2 cycles FOLFIRI or mFOLFIRI are permitted before enrolment until RAS status is determined) Patients suitable for chemotherapy administration ECOG (Eastern Cooperative Oncology Group) status 0-1 Consent to liquid biopsy and mutation analysis Estimated life expectancy > 3 months Presence of at least one measurable reference lesion according to the RECIST 1.1 criteria (chest CT and abdominal CT 4 weeks or less before enrollment) Adequate bone marrow function defined as: Leukocytes 3.0 x 10 9/L with neutrophils 1.5 x 10 9/L, Thrombocytes 100 x 10 9/L, Hemoglobin 9 g/dL Adequate hepatic function defined as: Serum bilirubin 1.5 x ULN (Upper limit of normal), ALAT (Alanine-aminotransferase (= SGPT = serum glutamate pyruvate transaminase) and ASAT (aspartate-aminotransferase (= SGOT = serum glutamate oxalacetate transaminase) 2.5 x ULN (Upper limit of normal) (in the presence of hepatic metastases, ALAT and ASAT 5 x ULN) Adequate renal function: Creatinine clearance ≥ 50 mL/min Adequate cardiac function defined as Normal ECG and echocardiogram with a left ventricular ejection fraction (LVEF) of 55% INR (International normalized ratio) < 1.5 and aPTT (activated Partial thromboplastin time) < 1.5 x ULN (patients without anticoagulation). Therapeutic anticoagulation is allowed if INR and aPTT have remained stable within the therapeutic range for at least 2 weeks. Time interval of at least 6 months since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy of the primary tumor in curative treatment intention to start of 1st line treatment Any relevant toxicities of prior treatments must have resolved to grade ≤ 1 according to the CTCAE (version 5), except alopecia Women of childbearing potential (WOCBP) should have a negative urine pregnancy test within 72 hours prior to receiving the first dose of study medication. Highly effective contraception for both male and female patients throughout the study and for at least 3 months after last dose of study medication administration if the risk of conception exists. Highly effective contraception has to be in line with the definition of the CTFG (Clinical Trial Facilitation Group) recommendation Signed written informed consent and capacity of understanding the informed consent Exclusion Criteria: Right sided mCRC Primarily resectable metastases Previous chemotherapy for the colorectal cancer with the exception of adjuvant treatment, completed at least 6 months before entering the study (1- 2 cycles FOLFIRI or mFOLFIRI are permitted before enrolment) Patients with known brain metastases Symptomatic peritoneal carcinosis Progressive disease before randomization History of acute or subacute intestinal occlusion, inflammatory bowel disease, immune colitis or chronic diarrhea Grade II heart failure (NYHA classification), Myocardial infarction, balloon angioplasty (PTCA) with or without stenting, and cerebral vascular accident/stroke within the past 12 months before enrollment, unstable angina pectoris, serious cardiac arrhythmia according to investigator's judgment requiring medication Active infection with hepatitis B or C Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study Additional cancer; Exceptions include adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy without evidence of recurrence Uncontrolled hypertension Marked proteinuria (nephrotic syndrome) Arterial thromboembolism or severe hemorrhage within 6 months prior to randomization (with the exception of tumor bleeding before tumor resection surgery) Hemorrhagic diathesis or tendency towards thrombosis Participation in a clinical study or experimental drug treatment within 30 days prior to study Known hypersensitivity or allergic reaction to any of the study medications Severe, non-healing wounds, ulcers, bone fractures or an infection requiring systemic therapy Known history of alcohol or drug abuse Complete dihydropyrimidine dehydrogenase (DPD) deficiency (phenotype and/or genotype test) (Patients with partial DPD deficiency may be included in this clinical trial at the discretion of the investigator and should receive a reduced starting 5-FU dose) Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required) Absent or restricted legal capacity For female patients only: Pregnancy (absence to be confirmed by ß-HCG test) or lactating

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFIRI + cetuximab<br>Patients in Arm A will receive FOLFIRI + cetuximab until progressive disease (PD), unacceptable toxicity, withdrawal of informed consent or death, whatever occurs first. The recurrence of RAS-mutation without PD to switch back to FOLFIRI. In case of repeated conversion to RAS wild-type without PD, treatment will shift to FOLFIRI + cetuximab again, and so on. Switches of treatment will proceed until progressive disease (PD), unacceptable toxicity, withdrawal of informed consent or death, whatever occurs first. [FOLFIRI = Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)] | Drug: Cetuximab<br>* Patients in Arm A will receive FOLFIRI +cetuximab.<br>Other: FOLFIRI<br>* Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)<br>|
| Other: FOLFIRI<br>Patients in Arm B will continue therapy with FOLFIRI until PD, unacceptable toxicity, withdrawal of informed consent or death, whatever occurs first. | Other: FOLFIRI<br>* Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Evaluation of efficacy in terms of progression free survival (PFS) | From date of randomization up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | In experimental and control arms | From date of randomization up to 24 months. | 
| Time to failure of treatment strategy (TFTS) | In experimental and control arms | After randomization up to 24 months. | 
| PFS (progression free survival) rate | In experimental and control arms | 1 year after date of randomization | 
| Depth of response | In terms of reduction of tumor mass in experimental and control arms | From the start of the first line treatment in the study up to 24 months. | 
| Metastasis resections. | In experimental and control arms. | From the start of the first line treatment in the study up to 24 months. | 
| Objective response rate (ORR) | Defined as patients with partial or complete response (CR or PR) in experimental and control arms | From the start of the first line treatment in the study up to 24 months. | 
| Safety profile | According to CTCAE (Common Terminology Criteria of Adverse Events), Version 5.0 criteria in experimental and control arms. | From the date of signature of Informed Consent to 24 months. | 
| Identification of driver mutations. | In patients with progressive disease (PD) under cetuximab therapy who remain RAS (Rat sarcoma) wild-type in liquid biopsy. | From the start of the first line treatment in the study up to 24 months. | 
| Comparison the efficacy in terms of progression free survival (PFS) | In patients with conversion to RAS (RAt sarcoma) wild-type in both ddPCR (Droplet Digital PCR) BEAMing with those patients showing conversion to RAS wild-type in ddPCR but not in BEAMing. | From the start of the first line treatment in the study up to 24 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Left sided Adenocarcinoma of the Colon, RAS mutated