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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04034459
Recruitment Status : Active, not recruiting
First Posted : July 26, 2019
Last Update Posted : December 3, 2021
Sponsor:
Information provided by (Responsible Party):
PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich

Tracking Information
First Submitted Date  ICMJE December 22, 2017
First Posted Date  ICMJE July 26, 2019
Last Update Posted Date December 3, 2021
Actual Study Start Date  ICMJE November 25, 2016
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 24, 2019)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2019)
  • Progression Free Survival (PFS) [ Time Frame: up to 60 months ]
    Investigation of progression-free survival (PFS) from randomisation
  • Overall Survival (OS) [ Time Frame: up to 60 months ]
    Investigation of overall survival (OS) from randomisation
  • 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)
  • Investigation of Depth of Response (DpR) to define nadir for tumour response. [ Time Frame: up to 48 months ]
    Investigation of depth of response (DpR)
  • 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)
  • 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)
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab 1st-line in BRAF-mutated mCRC
Official Title  ICMJE Randomised Study to Investigate FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab as First-line Treatment of BRAF-mutated Metastatic Colorectal Cancer
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Colorectal Cancer
Intervention  ICMJE
  • 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
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Bevacizumab
    • Drug: Irinotecan
    • Drug: Folinic acid
    • Drug: Oxaliplatin
    • Drug: 5-FU
  • 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.
    Interventions:
    • Drug: Irinotecan
    • Drug: Folinic acid
    • Drug: Oxaliplatin
    • Drug: 5-FU
    • Drug: Cetuximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 2, 2021)
109
Original Estimated Enrollment  ICMJE
 (submitted: July 24, 2019)
99
Estimated Study Completion Date  ICMJE December 31, 2023
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04034459
Other Study ID Numbers  ICMJE FIRE-4.5
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party PD Dr. med. Volker Heinemann, Ludwig-Maximilians - University of Munich
Study Sponsor  ICMJE Ludwig-Maximilians - University of Munich
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Volker Heinemann, Prof. Dr. Medizinische Klinik III
PRS Account Ludwig-Maximilians - University of Munich
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP