Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab in Patients With Resectable Liver Metastases

Phase 2

Terminated

• Conditions: Colorectal Cancer Metastatic; Liver Metastases; KRAS Wild Type Colorectal Cancer
• Interventions: Drug: FOLFOX6; Procedure: Surgery; Biological: Bevacizumab; Biological: Panitumumab

• Registration Number: NCT01508000
• Lead Sponsor: European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary

Patients presenting with multiple innumerable liver metastases will probably never come to resection, however, for all others, including patients with numerous multiple metastases or large metastases,resection should be considered after limited chemotherapy.

There is consensus for a backbone chemotherapy consisting of fluoropyrimidine + oxaliplatin. FOLFOX was used in the previous EORTC study and is again recommended.

The addition of targeted agents to standard chemotherapy in the perioperative strategy for mCRC might increase the ORR and R0 resectability, without significant increase in toxicity, therefore translating to a better outcome.

It was therefore decided to design an open label, randomized, multi-center, 3-arm late phase II study.

Arm A: (standard) mFOLFOX6 + Surgery Arm B: (experimental) mFOLFOX6 + Bevacizumab + Surgery Arm C: (experimental) mFOLFOX6 + Panitumumab + Surgery

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2012-01-09
• Study First Submitted QC: 2012-01-10
• Study First Posted: 2012-01-11
• Study Start: 2013-06
• Primary Completion: 2016-09
• Study Completion: 2016-09
• Status Verified: 2016-10
• Last Update Submitted: 2016-10-11
• Last Update Posted: 2016-10-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 44

Inclusion Criteria

• Histologically proven CRC with 1 to 8 metachronous or synchronous liver metastases considered to be completely resectable.
• Primary tumor (or liver metastasis) of CRC must be KRAS and NRAS status "wild type".
• Patients must have undergone complete resection (R0) of the primary tumor at least 4 weeks before randomization. Or for patients with synchronous metastases the primary tumor can be resected (R0) at the same time as the liver metastases if: the patient has a non-obstructive primary tumor and is able to receive preoperative chemotherapy (3-4 months) before surgery.
• Measurable hepatic disease by RECIST version 1.1.
• Patients must be 18 years old or older.
• A WHO performance status of 0 or 1. Radiotherapy alone is allowed if given pre or post protocol treatment.
• Previous adjuvant chemotherapy for primary CRC is allowed if completed at least 12 months before inclusion in this study.
• All the following tests should be done within 4 weeks prior to randomization:
• Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9 g/dL and white blood cell count (WBC) ≥ 3 x 109/L.
• Serum creatinine ≤ 1.5 times the upper limit of normal (ULN) (to exclude severe renal impairment); no significant proteinuria (urine protein < 1g/24 hours urine collection) OR urine protein/creatinine ratio < 1.0 OR 1+ proteinuria on urine dipstick.
• Absence of major hepatic insufficiency (bilirubin ≤ 1.5 x ULN and aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 5 x ULN).
• Magnesium ≥ lower limit of normal (LLN)
• Patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry are acceptable. This will not apply for Renal Function, including Creatinine.
• Women of child bearing potential (WOCBP) must have a negative serum (or urine) pregnancy test within 14 days prior to the first dose of study treatment.
• Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria

• Evidence of extra-hepatic metastasis (of CRC).
• Previous chemotherapy for metastatic disease or surgical treatment (e.g. surgical resection or radiofrequency ablation) for liver metastasis.
• Previous exposure to EGFR or VEGF/VEGFR targeting therapy within the last 12 months.
• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to randomization.
• Regular use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
• Bleeding diathesis (e.g. hemoptysis of ≥ 1/2 teaspoon or 2.5mL), coagulopathy, or need for administration of full-dose anti-coagulant(s).
• Clinically significant cardiovascular disease, including: uncontrolled hypertension, New York Heart Association (NYHA) class II-IV heart failure, myocardial infarction or unstable angina pectoris, cerebrovascular accident or transient ischemic attack within the past 12 months, peripheral vascular disease ≥ grade 2, serious cardiac arrhythmia requiring medication and other clinically significant cardiovascular disease.
• Peripheral neuropathy > grade 1 (Common Terminology Criteria for Adverse Events, v4.0) serious wound complications, ulcers, or bone fractures.
• Symptomatic diverticulitis or active or uncontrolled gastroduodenal ulceration.
• History or evidence of interstitial lung disease (e.g. pneumonitis, pulmonary fibrosis)
• Significant disease that, in the investigator's opinion, would exclude the patient from the study. Including known allergy or any other adverse reaction to any of the study drugs (including any of the excipients) or to any related compound, including hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanized antibodies.
• Presence of 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.
• Participation in another clinical study (except sub studies of this protocol) within the 30 days before randomization and during this study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: modified FOLFOX6 and Surgery	FOLFOX6	6 cycles before and 6 cycles after surgery consisting in: Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm A: modified FOLFOX6 and Surgery	Surgery	6 cycles before and 6 cycles after surgery consisting in: Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm B: modified FOLFOX6 + Bevacizumab and Surgery	FOLFOX6	6 cycles before and 6 cycles after surgery consisting in: Hour 0: Oxaliplatin 85 mg/m2 2-h infusion Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion\*. Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm B: modified FOLFOX6 + Bevacizumab and Surgery	Bevacizumab	6 cycles before and 6 cycles after surgery consisting in: Hour 0: Oxaliplatin 85 mg/m2 2-h infusion Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion\*. Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm B: modified FOLFOX6 + Bevacizumab and Surgery	Surgery	6 cycles before and 6 cycles after surgery consisting in: Hour 0: Oxaliplatin 85 mg/m2 2-h infusion Hour 0: Folinic Acid 400 mg/m2 (DL form) or 200 mg/m2 (L form) 2-h infusion Hour 2 (before 5-FU bolus): Bevacizumab 5 mg/kg IV over 90 minutes infusion\*. Hour 3.5: 5-FU bolus 400 mg/m2 IV bolus over 2-4 minutes Hour 3.5: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm C: modified FOLFOX6 + Panitumumab and Surgery	FOLFOX6	Experimental: Arm B: modified FOLFOX6 + Bevacizumab and Surgery 6 cycles before and 6 cycles after surgery consisting in: Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (\> 1000 mg) +/- 15 min. infusion\*. Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm C: modified FOLFOX6 + Panitumumab and Surgery	Panitumumab	Experimental: Arm B: modified FOLFOX6 + Bevacizumab and Surgery 6 cycles before and 6 cycles after surgery consisting in: Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (\> 1000 mg) +/- 15 min. infusion\*. Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle
Arm C: modified FOLFOX6 + Panitumumab and Surgery	Surgery	Experimental: Arm B: modified FOLFOX6 + Bevacizumab and Surgery 6 cycles before and 6 cycles after surgery consisting in: Hour - 1 (pre chemotherapy): Panitumumab 6 mg/kg IV over 60 minutes (≤ 1000 mg) or 90 minutes (\> 1000 mg) +/- 15 min. infusion\*. Hour 0: Oxaliplatin 85 mg/m² IV 2-h infusion Hour 0: Folinic Acid 400 mg/m² (DL form) or 200 mg/m2 (L form) IV 2-h infusion Hour 2: 5-FU 400 mg/m² IV bolus over 2-4 minutes Hour 2: 5-FU 2400 mg/m² given as a continuous infusion over 46h. On day 1 of a 14 day cycle

Primary Outcome Measures

Name	Time	Method
Progression free survival	1 year	Increase in progression free survival rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) compared to mFOLFOX6 alone arm.

Secondary Outcome Measures

Name	Time	Method
Pathological response rate	4 years	Increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm.
Resection rate	4 years	Compare the percentage of patients with total resection with these three treatments.
Overall survival	8 years	Overall survival is defined as the time interval between the date of randomization and the date of death. Patients who are still alive when last traced will be censored at the date of last follow-up.
Safety	4 years	All adverse events will be recorded; the investigator will assess whether those events are drug related (reasonable possibility, no reasonable possibility) and this assessment will be recorded in the database for all adverse events.

Trial Locations

Locations (25)

AZ Groeninge Kortrijk - Campus Kennedylaan; 🇧🇪 Kortrijk, Belgium

Universitair Ziekenhuis Gent; 🇧🇪 Gent, Belgium

CHU Ambroise Pare; 🇫🇷 Boulogne Billancourt, France

Hopital Universitaire Brugmann; 🇧🇪 Brussels, Belgium

Allgemeines Krankenhaus der Stadt Wien; 🇦🇹 Vienna, Austria

Institut Sainte Catherine; 🇫🇷 Avignon, France

Institut Bergonie; 🇫🇷 Bordeaux, France

Assistance Publique - Hôpitaux de Paris - Hopital De Bicetre AP-HP; 🇫🇷 Le Kremlin Bicetre, France

Hopital Charles Nicolle; 🇫🇷 Rouen, France

Centre Hospitalier Saint Joseph Saint Luc; 🇫🇷 Lyon, France

Hopital Prive Jean Mermoz; 🇫🇷 Lyon, France

Hospital General Vall D'Hebron; 🇪🇸 Barcelona, Spain

The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis; 🇳🇱 Amsterdam, Netherlands

CHU d'Amiens - CHU Amiens - Hopital Sud; 🇫🇷 Salouel, France

Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie; 🇨🇭 Geneve, Switzerland

Centre Antoine Lacassagne; 🇫🇷 Nice, France

Centre Hospitalier Privé Saint-Grégoire; 🇫🇷 Saint-Gregoire, France

CHU de Lyon - Centre Hospitalier Lyon Sud; 🇫🇷 Pierre-Benite (lyon), France

Hopital Europeen Georges Pompidou; 🇫🇷 Paris, France

Centre Leon Berard; 🇫🇷 Lyon, France

Groupe Hospitalier Diaconesses Croix Saint-Simon - Site Reuilly; 🇫🇷 Paris, France

CHU de Reims - Hôpital Robert Debré; 🇫🇷 Reims, France

CHU Saint-Etienne - CHU de Saint-Etienne - Hopital Nord; 🇫🇷 Saint Priest en Jarez, France

AZ Turnhout - Campus Sint Elisabeth; 🇧🇪 Turnhout, Belgium

Centre Hospitalier Peltzer-La Tourelle; 🇧🇪 Verviers, Belgium