FOLFOXIRI Plus Cetuximab vs. FOLFOXIRI Plus Bevacizumab 1st-line in BRAF-mutated mCRC

NCT04034459 | Unknown Phase 2

• 1 other identifier: FIRE-4.5
• Study Type: interventional
• Target: 109
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Colorectal Cancer

Keywords

FIRE; mCRC; AIO; BRAF; FOLFOXIRI; Cetuximab; Bevacizumab

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR)

  (overall response rate) measured in percentage of all treated patients according to RECIST 1.1 criteria

  up to 48 months

Secondary Outcomes (7)

• Progression Free Survival (PFS)

  up to 60 months

• Overall Survival (OS)

  up to 60 months

• Investigation of Early Tumour Shrinkage (ETS) as early-on-Treatment predictor for treatment

  up to 48 months

• Investigation of Depth of Response (DpR) to define nadir for tumour response.

  up to 48 months

• Investigation of Molecular Biomarkers for Prediction of an Anti-EGFR Treatment

  up to 48 months

Study Arms (2)

FOLFOXIRI plus bevacizumab

ACTIVE COMPARATOR

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; Drug: Irinotecan; Drug: Folinic acid; Drug: Oxaliplatin; Drug: 5-FU

FOLFOXIRI plus cetuximab

EXPERIMENTAL

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; Drug: Folinic acid; Drug: Oxaliplatin; Drug: 5-FU; Drug: Cetuximab

Interventions

Bevacizumab DRUG

Bevacizumab 5 mg/kg BW iv over 30 to 90\* min day 1

FOLFOXIRI plus bevacizumab

Irinotecan DRUG

Irinotecan 150 mg/m² iv, 30 - 90 min. day 1

FOLFOXIRI plus bevacizumab; FOLFOXIRI plus cetuximab

Folinic acid DRUG

Folinic acid (racemic) 400 mg/m² iv, 120 min. day 1

FOLFOXIRI plus bevacizumab; FOLFOXIRI plus cetuximab

Oxaliplatin DRUG

Oxaliplatin 85mg/m² day 1

FOLFOXIRI plus bevacizumab; FOLFOXIRI plus cetuximab

5-FU DRUG

5-FU 3000 mg/m² iv over 48 h days 1-2

FOLFOXIRI plus bevacizumab; FOLFOXIRI plus cetuximab

Cetuximab DRUG

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

FOLFOXIRI plus cetuximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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
• 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.
• 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
• 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
• 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

Sponsors & Collaborators

• Ludwig-Maximilians - University of Munich: lead

Study Sites (1)

Klinikum der Universitaet Muenchen

Munich, 81377 München, Germany

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab; Irinotecan; Leucovorin; Oxaliplatin; Fluorouracil; Cetuximab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Camptothecin; Alkaloids; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Volker Heinemann, Prof. Dr.

  Medizinische Klinik III

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director Comprehensive cancer center

Study Record Dates

• First Submitted: December 22, 2017
• First Posted: July 26, 2019
• Study Start: November 25, 2016
• Primary Completion: November 1, 2023
• Study Completion: December 31, 2023
• Last Updated: November 14, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)