FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab 1st-line in BRAF-mutated mCRC (AIO-KRK-0116)

November 13, 2023 updated by: PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich

Randomised Study to Investigate FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab as First-line Treatment of BRAF-mutated Metastatic Colorectal Cancer

Once randomisation has been completed, the study treatment should be started preferably immediately; at the latest within one week following randomisation.

The patients will be randomised in a ratio of 1:2 to the following two treatment arms.

Patients in both treatment arms will receive standard chemotherapy with FOLFOXIRI as background treatment, which can be de-escalated to FOLFIRI in case of toxicity.

Standard arm A:

The patient will be treated with FOLFOXIRI plus bevacizumab for up to 12 cycles (24 weeks) or until progression (if the latter occurs before completing the 12 cycles). Within the 12 cycles, the FOLFOXIRI plus bevacizumab regimen may be de-escalated, owing to toxicity, to FOLFIRI and bevacizumab at the treating physician's discretion.

After 12 cycles of the study treatment, a switch to a maintenance regimen with a fluoropyrimidine (5-FU infusion or capecitabine) plus bevacizumab, administered until progression occurs, is recommended. The recommended maintenance phase of the study is not part of the study treatment. However, maintenance therapy will be counted as first-line therapy.

Experimental arm B:

The patient will be treated with FOLFOXIRI plus weekly administration of cetuximab for up to 12 cycles (24 weeks) or until progression (if the latter occurs before completing the 12 cycles). Within the 12 cycles, the FOLFOXIRI plus cetuximab regimen may be de-escalated owing to toxicity, to FOLFIRI and cetuximab at the treating physician's discretion.

After 12 cycles, a switch to a maintenance regimen with 5-FU and cetuximab or with irinotecan and cetuximab, administered until progression occurs, is recommended. The recommended maintenance phase of the study is not part of the study treatment. However, maintenance therapy will be counted as first-line therapy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
109

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Munich, Germany, 81377 München
        • Klinikum der Universitaet Muenchen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histologically confirmed UICC stage IV adenocarcinoma of the colon or rectum with metastases (metastatic colorectal cancer [mCRC]); metastases primarily non-resectable or surgery refused by the patient
  • RAS wild-type tumour status (KRAS and NRAS exons 2, 3, 4) (proven in the primary tumour or metastasis)
  • BRAF-mutant (V600E) tumour (proven in the primary tumour or metastasis)
  • Age ≥18 years
  • ECOG performance status 0-1
  • Patients suitable for chemotherapy administration
  • Patient's written declaration of consent obtained
  • Estimated life expectancy > 3 months
  • Presence of at least one measurable lesion according to the RECIST 1.1 - criteria (chest X-ray in two planes or chest CT and abdominal CT 4 weeks or less before randomisation)
  • Primary tumour tissue available and patient consents to storage and molecular and genetic profiling of the tumour material. Molecular profiling of blood samples is optionally performed.
  • Females of childbearing potential (FCBP) and men must agree to use effective contraceptive measures (Pearl index <1) for the duration of the study treatment and for at least 6 months after last administration of the study medication. A female subject will be considered to be of child-bearing potential unless she is ≥ 50 years of age as well as has had a natural menopause for at least 2 years or has been surgically sterilised.
  • Adequate bone marrow function:
  • Leukocytes ≥ 3.0 x 109/L with neutrophils ≥ 1.5 x 109/L
  • Thrombocytes ≥ 100 x 109/L,
  • Haemoglobin ≥ 5.6 mmol/L (equivalent to 9 g/dL)
  • Adequate hepatic function:
  • Serum bilirubin ≤ 1.5 x upper limit of normal (ULN),
  • ALAT and ASAT ≤ 2.5 x ULN (in case of hepatic metastasis, ALAT and ASAT ≤ 5 x ULN)
  • INR < 1.5 and aPTT < 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.
  • Adequate renal function:
  • Serum creatinine ≤ 1.5 x ULN or creatinine clearance (calculated according to Cockcroft and Gault) ≥ 50mL/min.
  • Adequate cardiac function: ECG and echocardiogram with a LVEF of ≥ 55%
  • No previous chemotherapy for metastatic disease (prior radiotherapy of metastasis/metastases without application of chemotherapy permitted provided that no irradiated metastasis is selected as target lesion)
  • Time interval since last administration of any previous neoadjuvant/adjuvant chemotherapy or radiochemotherapy ≥6 months
  • Any relevant toxicities of previous treatments must have subsided to grade 0

Exclusion Criteria:

  • Grade III or IV heart failure (NYHA classification)
  • Myocardial infarction, unstable angina pectoris, balloon angioplasty (PTCA) with or without stenting within the past 12 months before randomisation
  • Pregnancy (absence of pregnancy has to be ascertained by a beta hCG test) or breast feeding
  • Medical or psychological impairments associated with restricted ability to give consent or not allowing conduct of the study
  • Additional cancer treatment (chemotherapy, radiation, immune therapy or hormone treatment) during the study treatment. Treatments that are conducted as part of an anthroposophical or homeopathic treatment approach, e.g. mistletoe therapy, do not represent an exclusion criterion.
  • Previous chemotherapy for the colorectal cancer with exception of chemotherapy or radiochemotherapy given as neoadjuvant or adjuvant treatment with curative intent, completed ≥6 months before entering the study.
  • Participation in a clinical study or experimental drug treatment within 30 days prior to study inclusion or within a period of 5 half-lives of the substances administered in a clinical study or during an experimental drug treatment prior to inclusion in the study, depending on which period is longest, or simultaneous participation in another clinical study while taking part in the study
  • Known hypersensitivity or allergic reaction to any of the following substances: 5-fluorouracil, folinic acid, cetuximab, irinotecan, bevacizumab, oxaliplatin and chemically related substances and/or hypersensitivity to any of the excipients of any of the aforementioned substances
  • Known hypersensitivity to CHO (Chinese hamster ovary cells) - cell products or other recombinant human or humanised antibodies
  • Patients with confirmed cerebral metastases. In case of clinical suspicion of brain metastases, a cranial CT or MRI must be performed to rule out brain metastases before study inclusion.
  • History of acute or subacute intestinal occlusion or chronic inflammatory bowel disease or chronic diarrhoea.
  • Symptomatic peritoneal carcinosis
  • Severe, non-healing wounds, ulcers or bone fractures
  • Patients with active infection (including confirmed HIV and/or HBV/HCV infection). In case of clinical suspicion of the presence of HIV or HBV/HCV infection, the latter should be ruled out before study inclusion.
  • Requirement for immunisation with live vaccine during the study treatment.
  • Uncontrolled hypertension
  • Marked proteinuria (nephrotic syndrome)
  • Arterial thromboembolism or severe haemorrhage within 6 months prior to randomisation (with the exception of tumour bleeding before tumour resection surgery)
  • Haemorrhagic diathesis or tendency towards thrombosis
  • Known DPD deficiency (specific screening not required)
  • Known glucuronidation deficiency (Gilbert's syndrome) (specific screening not required)
  • History of a second malignancy during the 5 years before inclusion in the study or during participation in the study, with the exception of a basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ, if these were treated curatively.
  • Known history of alcohol or drug abuse
  • A significant concomitant disease, in particular chronic hepatic or renal disease, chronic inflammatory or autoimmune diseases, ruling out the patient's participation in the study according to investigator's judgement.
  • Absent or restricted legal capacity

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: FOLFOXIRI plus bevacizumab

One cycle (cycle duration 14 days) consists of:

  • Irinotecan 150 mg/m² iv, 30 - 90 min. day 1
  • Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1
  • Oxaliplatin 85mg/m² day 1
  • 5-FU 3000 mg/m² iv over 48 h days 1-2
  • Bevacizumab 5 mg/kg BW iv over 30 to 90* min day 1 *1st administration 90 min.; in case of good tolerability, second administration 60 min.; further administrations 30 min.

Repeat administration every 2 weeks for a maximum of 12 cycles

  • Dose adaptation at the treating physician's discretion.
  • Switch to the recommended maintenance treatment with fluoropyrimidine and bevacizumab after the 8th cycle (following 2nd staging after baseline) is possible at the treating physician's discretion if response according to RECIST 1.1 (CR or PR) has been achieved.
Drug: Bevacizumab
Bevacizumab 5 mg/kg BW iv over 30 to 90* min day 1
Drug: Irinotecan
Irinotecan 150 mg/m² iv, 30 - 90 min. day 1
Drug: Folinic acid
Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1
Drug: Oxaliplatin
Oxaliplatin 85mg/m² day 1
Drug: 5-FU
5-FU 3000 mg/m² iv over 48 h days 1-2
Experimental: FOLFOXIRI plus cetuximab

One cycle (cycle duration 14 days) consists of:

  • Irinotecan 150 mg/m² iv, 30 - 90 min. day 1
  • Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1
  • Oxaliplatin 85mg/m² day 1
  • 5-FU 3000 mg/m² iv over 48 h days 1-2
  • Cetuximab initially 400 mg/m² with infusion rate of ≤5 mg/min., subsequently 250 mg/m² iv with infusion rate of ≤10 mg/min. days 1+8

Repeat administration every two weeks up to a maximum of 12 cycles.

  • Dose adaptation at the treating physician's discretion.
  • Switch to the recommended maintenance treatment with 5-FU and cetuximab or irinotecan and cetuximab after the 8th cycle (following 2nd staging after baseline) is possible at the treating physician's discretion if response according to RECIST 1.1 (CR or PR) has been achieved.
Drug: Irinotecan
Irinotecan 150 mg/m² iv, 30 - 90 min. day 1
Drug: Folinic acid
Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1
Drug: Oxaliplatin
Oxaliplatin 85mg/m² day 1
Drug: 5-FU
5-FU 3000 mg/m² iv over 48 h days 1-2
Drug: Cetuximab
Cetuximab initially 400 mg/m² with infusion rate of ≤5 mg/min., subsequently 250 mg/m² iv with infusion rate of ≤10 mg/min. days 1+8

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Overall Response Rate (ORR)
Time Frame: up to 48 months
(overall response rate) measured in percentage of all treated patients according to RECIST 1.1 criteria
up to 48 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: up to 60 months
Investigation of progression-free survival (PFS) from randomisation
up to 60 months
Overall Survival (OS)
Time Frame: up to 60 months
Investigation of overall survival (OS) from randomisation
up to 60 months
Investigation of Early Tumour Shrinkage (ETS) as early-on-Treatment predictor for treatment
Time Frame: up to 48 months
Investigation of early tumour shrinkage (ETS)
up to 48 months
Investigation of Depth of Response (DpR) to define nadir for tumour response.
Time Frame: up to 48 months
Investigation of depth of response (DpR)
up to 48 months
Investigation of Molecular Biomarkers for Prediction of an Anti-EGFR Treatment
Time Frame: up to 48 months
Investigation of molecular biomarkers for prediction of sensitivity and secondary resistance of an anti-EGFR treatment with cetuximab (including tumour biopsies and liquid biopsies from blood samples)
up to 48 months
Prospective Analysis of Tumour Marker Level Evolution (CEA and CA 19-9)
Time Frame: up to 48 months
Investigation of prospective analysis of tumour marker level evolution (CEA and CA 19-9)
up to 48 months
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame: up to 48 months
Recording of the safety and tolerability (NCI-CTCAE version 4.03 criteria) of the treatment
up to 48 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Ludwig-Maximilians - University of Munich

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Volker Heinemann, Prof. Dr., Medizinische Klinik Iii

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 25, 2016

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 1, 2023

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 22, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 24, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 26, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
November 14, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
November 13, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • FIRE-4.5

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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