Cetuximab/FOLFIRI With or Without Oxaliplatin and FOLFOXIRI With or Without Bevacizumab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases

NCT ID: NCT01802645

Last Updated: 2019-09-11

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 91 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-03-31
• Study Completion Date: 2020-12-31

Brief Summary

The aim of this study is to investigate the following schedules for efficacy with regard to response rate in neoadjuvant treatment of patients with non-resectable liver metastases:

• Cetuximab/FOLFOXIRI and cetuximab/FOLFIRI in patients with ras wild type tumours and
• Bevacizumab/FOLFOXIRI and FOLFOXIRI in patients with ras mutant tumours.

Detailed Description

Patients with liver metastases from colorectal and without known extrahepatic metastases will be screened for this study including ras status (b-raf status according to local standard).

Patients receive chemotherapy according to the allocation and are re-evaluated for resectability every 8 weeks for a maximum of 6 months. Resectable patients will be resected and receive an adjuvant treatment to complete 12 cycles.

In certain circumstances, a second resection is allowed within the study.

Patients will be randomized using a web-based computer system that allows randomization if the key basic characteristics are entered.

Patients with ras wild-type tumours will be randomized to receive:

• Cetuximab/FOLFIRI or
• Cetuximab/FOLFOXIRI

Patients with ras mutations will be randomized to receive:

• FOLFOXIRI or
• FOLFOXIRI/bevacizumab

Chemotherapy doses are adjusted to the risk of toxicity in all treatment arms.

Stratification will be performed according to:

• Number of metastases (< 5 vs. ≥ 5 metastases)
• Primary tumour in situ
• Centre

Treatment regimens For dose reductions and conditions to continue please refer to the full protocol.

All drugs are used within the label and approved doses.

B-raf mutations are determined according to local standard. If a b-raf mutation is known before randomization, the investigator can consider the patient as ras wildtype OR as ras mutant patient.

Cetuximab/FOLFIRI :

Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 180 mg/m², d-l Folinic acid 400 mg/m² (2 h), 5-FU 400 mg/m² (Bolus), 5-FU 2400 mg/m² (46 h) every 2 weeks

Cetuximab/FOLFOXIRI:

Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 125 mg/m² , Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks

FOLFOXIRI:

Irinotecan 165 mg/m², Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks

Bevacizumab/FOLFOXIRI:

Bevacizumab 5 mg/kg (90 - 30 min i.v.), Irinotecan 165 mg/m², Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks

Evaluation for response and resections Patients are evaluated for response by the same imaging technique as at baseline every 8 weeks. The findings will be discussed for resectability within two weeks after tumour assessment in a local multidisciplinary team.

Technically resectable patients should be offered liver resection. The treatment will continue until liver resection or for a maximum of six months (12 cycles).

Adjuvant treatment After liver resection, an adjuvant treatment is recommended with the same schedule as preoperatively, for a maximum combined pre- and postoperative treatment of 12 cycles. If less than three postoperative cycles remain, no postoperative treatment will be started (see chapter 9.10).

Follow up After resection, patients will be followed up for 5 years after randomization. This includes

• imaging and clinical investigation every three months for the first 2 years, then every six months (patients without tumour progression / recurrence)
• survival status and surgical/medical treatment every three months for the first 2 years and then every six months (all patients)

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cetuximab/FOLFIRI

Cetuximab 250 mg/m² (1 h) weekly Irinotecan 180 mg/m² (1 h)*, d-l Folinic acid 400 mg/m² (2 h), 5-FU 400 mg/m² (Bolus), 5-FU 2400 mg/m² (46 h) every 2 weeks

*reduced in UGT1A1 7/7 patients

Group Type: ACTIVE_COMPARATOR

Cetuximab

Intervention Type: DRUG

Irinotecan

Intervention Type: DRUG

5-FU

Intervention Type: DRUG

Folinic Acid

Intervention Type: DRUG

Cetuximab/FOLFOXIRI

Cetuximab 250 mg/m² (1 h) weekly Irinotecan 125 mg/m² (1 h),* Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks

*reduced in UGT1A1 7/7 patients

Group Type: EXPERIMENTAL

Cetuximab

Intervention Type: DRUG

Irinotecan

Intervention Type: DRUG

Oxaliplatin

Intervention Type: DRUG

5-FU

Intervention Type: DRUG

Folinic Acid

Intervention Type: DRUG

FOLFOXIRI

Irinotecan 165 mg/m² (1 h)*, Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks

*reduced in UGT1A1 7/7 patients

Group Type: ACTIVE_COMPARATOR

Irinotecan

Intervention Type: DRUG

Oxaliplatin

Intervention Type: DRUG

5-FU

Intervention Type: DRUG

Folinic Acid

Intervention Type: DRUG

Bevacizumab/FOLFOXIRI

Bevacizumab 5 mg/kg (30-90 min i.v.), Irinotecan 165 mg/m² (1 h),* Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks

*reduced in UGT1A1 7/7 patients

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Irinotecan

Intervention Type: DRUG

Oxaliplatin

Intervention Type: DRUG

5-FU

Intervention Type: DRUG

Folinic Acid

Intervention Type: DRUG

Interventions

Cetuximab

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Irinotecan

Intervention Type: DRUG

Oxaliplatin

Intervention Type: DRUG

5-FU

Intervention Type: DRUG

Folinic Acid

Intervention Type: DRUG

Other Intervention Names

Erbitux; Avastin; Campto; Eloxatin; 5-Fluorouracil; Leukovorin

Eligibility Criteria

Inclusion Criteria

1. if the primary tumour was resected at least 1 month prior to chemotherapy or

2. all of the following conditions apply:

i) the primary tumour is clearly resectable, ii) no radiation therapy is planned, iii) liver resection is planned before resection of the primary or at the same operation as the resection of the primary, iv) no two-stage liver resection is planned, and v) all efforts were made to exclude additional distant metastases.

4. WHO PS ≤ 1

5. Written informed consent

6. Adequate bone marrow function, liver function (neutrophils > 1.5 x 109/l; platelets > 100 x 109/l; haemoglobin > 5.0 mmol/l (8.0 g/dl); bilirubin ≤ ULN or ≤ 1.5 x ULN and not increasing more than 25 % within the last 4 weeks; SGOT and SGPT < 5 x UNL)

7. Age ≥ 18 years

Exclusion Criteria

1. Any evidence of extrahepatic metastases, distant lymph node metastases and primary tumour recurrence

2. (deleted)

3. Prior systemic anti-tumour therapy with anti- EGFR-, anti-angiogenetic drugs or with chemotherapy (except adjuvant chemotherapy with an interval of ≥ 6 months or in combination with radiation as radio sensitizer)

4. Radiotherapy or major abdominal or thoracic surgery (excluding diagnostic interventions or venous port implantation) ≤ 4 weeks before study entry

5. Renal insufficiency with serum creatinine ≥ 1.5 x UNL. If serum creatinine is between 1.0 and 1.5 x UNL, the creatinine clearance according to the Cockroft-Gault formula should be ≥ 60 ml/min

6. Hypertension with an arterial blood pressure > 150/90 mmHg

7. Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last 12 months, significant arrhythmias)

8. Known proteinuria > 1 g/day (to be tested if proteinuria more than 1+ in the urinary dipstick analysis)

9. Peripheral neuropathy > CTC grade I

10. Concurrent systemic immune therapy, chemotherapy, hormone therapy, or patients receiving immune suppressive treatment (i.e. for transplantation, severe rheumatologic disease)

11. Participation in clinical trials with investigational agents within 30 days before start of the treatment in study

12. Active treatment of

1. peptic ulcers or bleeding erosive esophagitis / gastritis within 3 months before study

2. pulmonary embolism, severe or unstable angina pectoris or myocardial infarction, stroke or transient ischemic attack within 12 months before study

3. deep vein thrombosis within 4 weeks before study

13. Inflammatory bowel disease

14. History of other malignancies, from which the patient is not 5 years disease free, with the exception of colorectal cancer, or adequately treated basal cell or squamous cell carcinoma of skin or in-situ cervical cancer within 5 years before study

15. History of brain metastases

16. History of severe psychiatric illness

17. Active drug- or alcohol abuse

18. Known hepatitis B or C or HIV infection

19. Breast- feeding or pregnant women

20. Lack of effective contraception (for male and female patients)

21. Known intolerance to one of the following drugs: cetuximab, bevacizumab, oxaliplatin, irinotecan, 5-FU, folinic acid

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Technische Universität Dresden

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gunnar Folprecht, PD Dr.

Role: PRINCIPAL_INVESTIGATOR

University hospital "Carl Gustav Carus" Dresden

Locations

Universitätsklinikum der RWTH Aachen

Aachen, , Germany

Charité Campus Virchow

Berlin, , Germany

Überörtliche Gemeinschaftspraxis Hämatologie/ Onkologie

Bocholt, , Germany

Klinikum Coburg GmbH

Coburg, , Germany

Onkologie Dülmen GbR

Coesfeld, , Germany

Universitätsklinikum Carl Gustav Carus

Dresden, , Germany

Klinikum der Johann Wolfgang Goethe Universität Frankfurt am Main

Frankfurt am Main, , Germany

Universitätsmedizin Göttingen

Göttingen, , Germany

Universitätsklinikum Hamburg-Eppendorf

Hamburg, , Germany

Klinikum Landshut gGmbH

Landshut, , Germany

University hospital Leipzig

Leipzig, , Germany

Johannes-Gutenberg-Universität

Mainz, , Germany

Klinikum Oldenburg GmbH

Oldenburg, , Germany

Rems-Murr-Klinikum Winnenden

Winnenden, , Germany

Universitätsklinikum Würzburg

Würzburg, , Germany

Countries

Germany

Other Identifiers

2011-003288-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

TUD-CELIM2-050

Identifier Type: -

Identifier Source: org_study_id