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

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Adenocarcinoma of the Rectum; Adenocarcinoma of the Colon
• Intervention / Treatment: Drug: Cetuximab; Other: FOLFIRI

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Bochum, Germany
    • Universitätsklinikum Knappschaftskrankenhaus
  • Dachau, Germany
    • Onkologisches Zentrum (Dachau II)
  • Essen, Germany
    • Kliniken-Essen-Mitte Evang. Huyssens-Stiftung
  • Hamm, Germany
    • Evangelisches Krankenhaus Hamm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 97 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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)]	Drug: Cetuximab; Patients in Arm A will receive FOLFIRI +cetuximab.; Other: FOLFIRI; Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)
Other: FOLFIRI; Patients in Arm B will continue therapy with FOLFIRI until PD, unacceptable toxicity, withdrawal of informed consent or death, whatever occurs first.	Other: FOLFIRI; Irinotecan, Folinic acid (racemic), Fluorouracil (5-FU)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: TheraOp

Publications and helpful links

General Publications

• Klein-Scory S, Wahner I, Maslova M, Al-Sewaidi Y, Pohl M, Mika T, Ladigan S, Schroers R, Baraniskin A. Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer. Front Oncol. 2020 Jul 16;10:1115. doi: 10.3389/fonc.2020.01115. eCollection 2020.

Helpful Links

• Evolution of RAS Mutational Status in Liquid Biopsies During First-Line Chemotherapy for Metastatic Colorectal Cancer.

Study record dates

Study Major Dates

• Study Start (Actual): December 29, 2020
• Primary Completion (Estimated): July 22, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: September 7, 2020
• First Submitted That Met QC Criteria: September 14, 2020
• First Posted (Actual): September 18, 2020

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Left sided Adenocarcinoma of the Colon; RAS mutated
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: 4213000

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No