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)
Overview
- Phase
- Phase 2
- Intervention
- Cetuximab
- Conditions
- Adenocarcinoma of the Colon
- Sponsor
- TheraOp
- Enrollment
- 6
- Locations
- 4
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Completed
- Last Updated
- 10 months ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
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)
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
Arms & Interventions
FOLFIRI + cetuximab
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. \[FOLFIRI = Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)\]
Intervention: Cetuximab
FOLFIRI + cetuximab
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. \[FOLFIRI = Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)\]
Intervention: FOLFIRI
FOLFIRI
Patients in Arm B will continue therapy with FOLFIRI until PD, unacceptable toxicity, withdrawal of informed consent or death, whatever occurs first.
Intervention: FOLFIRI
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: From date of randomization up to 24 months
Evaluation of efficacy in terms of progression free survival (PFS)
Secondary Outcomes
- Overall Survival (OS)(From date of randomization up to 24 months.)
- Time to Failure of Treatment Strategy (TFTS)(After randomization up to 24 months.)
- PFS (Progression Free Survival) Rate(1 year after date of randomization)
- Depth of Response(From the start of the first line treatment in the study up to 24 months.)
- Metastasis Resections.(From the start of the first line treatment in the study up to 24 months.)
- Objective Response Rate (ORR)(From the start of the first line treatment in the study up to 24 months.)
- Safety Profile(From the date of signature of Informed Consent to 24 months.)
- Identification of Driver Mutations.(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)(From the start of the first line treatment in the study up to 24 months.)