Induction Chemoterapy With Folfoxiri Plus Cetuxumab in Unresectable Colorectal Cancer Patient (MACBETH)

Gruppo Oncologico del Nord-Ovest

Status and phase: Completed; Phase 2

Conditions: Metastatic Colorectal Cancer

Treatments: Other: folfoxiri+cetuximab+surgery+cetuximab; Other: folfoxiri+cetuximab+surgery+bevacizumab

Study type: Interventional

Funder types: Other

Identifiers

NCT02295930

2011-000840-70 (EudraCT Number)

3306

Details and patient eligibility

About

This is a phase II randomized study of 4-months induction first-line chemotherapy with FOLFOXIRI + cetuximab followed by maintenance with cetuximab or bevacizumab in patients affected by KRAS wild type (wt) mCRC.

Full description

The aim of the study is to obtain a rapid disease control with the therapy and the maximum tumoral shrinkage, and than to treat patient with less intensive maintenance to inhibit tumoral regrowth.

Enrollment: 143 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Histologically confirmed colorectal adenocarcinoma;
• Availability of formalin-fixed paraffin embedded tumor block from primary and/or metastasis;
• KRAS wild-type status of primary colorectal cancer or related metastasis;
• Unresectable and measurable metastatic disease according to RECIST criteria;
• Male or female, aged > 18 years and < 75 years;
• ECOG PS < 2 if aged < 71 years, ECOG PS = 0 if aged 71-75 years;
• Life expectancy of more than 3 months;
• Adequate haematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL;
• Adequate liver and renal function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN); serum creatinine ≤ 1.5 x ULN;
• Previous adjuvant chemotherapy containing oxaliplatin is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse;
• Previous adjuvant chemotherapy with fluoropyrimidine monotherapy is allowed if more than 6 months have elapsed between the end of adjuvant and first relapse;
• At least 6 weeks from prior extended radiotherapy and 4 weeks from surgery;
• Written informed consent to experimental treatment and KRAS analysis.

Exclusion criteria

• Prior palliative chemotherapy;
• Prior treatment with EGFR or VEGF inhibitors;
• Symptomatic peripheral neuropathy > 2 grade NCIC-CTG criteria;
• Presence or history of CNS metastasis;
• Active uncontrolled infections; active disseminated intravascular coagulation;
• Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix;
• Clinically significant cardiovascular disease: cerebrovascular accidents or myocardial infarction ≤ 12 months before treatment start, unstable angina, NYHA ≥ grade 2 chronic heart failure, uncontrolled arrhythmia, uncontrolled hypertension;
• Serious, non-healing wound, ulcer, or bone fracture;
• Evidence of bleeding diathesis or coagulopathy;
• Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start;
• Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes or chronic, daily treatment with high-dose aspirin (>325 mg/day);
• Subtotal colectomy, malabsorption syndrome and chronic inflammatory bowel disease (i.e. ulcerative colitis, Chron syndrome);
• Fertile women (<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
• Psychiatric disorder precluding understanding of information on trial related topics,
• Serious underlying medical condition (judged by the investigator) which could impair the ability of the patient to participate in the trial (e.g. uncontrolled diabetes mellitus, active autoimmune disease)
• Concurrent treatment with other experimental drugs or other anti-cancer therapy; treatment in a clinical trial within 30 days prior to trial entry
• Definite contraindications for the use of corticosteroids and antihistamines as premedication
• Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs
• Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies
• Pregnancy
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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143 participants in 2 patient groups

folfoxiri+cetuximab+surgery+cetuximab

Experimental group

Description:

Induction FOLFOXIRI plus cetuximab will consist of: * CETUXIMAB 500 mg/sqm IV over 1-h\* , day 1 followed by * IRINOTECAN 130 mg/sqm IV over 1-h, day 1 followed by * OXALIPLATIN 85 mg/sqm IV over 2-h, day 1 concomitantly with * l-LV 200 mg/sqm IV over 2-h, day 1 followed by * 5-FLUOROURACIL 2400 mg/sqm IV 48-h continuous infusion, starting on day 1 repeated every 2 weeks for 8 cycles. Surgical revaluation will be performed after the induction phase (8 cycles). Patients deemed unsuitable for surgery will received maintenance treatment as follows: •CETUXIMAB 500 mg/sqm IV over 60-min, day 1 repeated every 2 weeks until PD, patient's refusal, unacceptable toxicity or consent withdrawal.

Treatment:

Other: folfoxiri+cetuximab+surgery+cetuximab

folfoxiri+cetuximab+surgery+bevacizumab

Experimental group

Description:

Induction FOLFOXIRI plus cetuximab will consist of: * CETUXIMAB 500 mg/sqm IV over 1-h\* , day 1 followed by * IRINOTECAN 130 mg/sqm IV over 1-h, day 1 followed by * OXALIPLATIN 85 mg/sqm IV over 2-h, day 1 concomitantly with * l-LV 200 mg/sqm IV over 2-h, day 1 followed by * 5-FLUOROURACIL 2400 mg/sqm IV 48-h continuous infusion, starting on day 1 repeated every 2 weeks for 8 cycles. Surgical revaluation will be performed after the induction phase (8 cycles). Patients deemed unsuitable for surgery will received maintenance treatment as follows: •BEVACIZUMAB 5 mg/kg IV over 30-min, day 1 repeated every 2 weeks until PD, patient's refusal, unacceptable toxicity or consent withdrawal.

Treatment:

Other: folfoxiri+cetuximab+surgery+bevacizumab