Clinical trial NCT01508000: Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab in Patients With Resectable Liver Metastases
Official title: Randomized Phase II Trial Evaluating the Efficacy of FOLFOX Alone, FOLFOX Plus Bevacizumab and FOLFOX Plus Panitumumab as Perioperative Treatment in Patients With Resectable Liver Metastases From Wild Type KRAS/NRAS Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Colorectal Cancer Metastatic
Liver Metastases
KRAS Wild Type Colorectal Cancer
Keywords: Liver metastases
Colorectal Cancer
KRAS wild type
FOLFOX
Bevacizumab
Panitumumab
Randomized
Phase II
Perioperative treatment
Adjuvant
Neo-adjuvant
Surgery
Progression Free Survival
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Amgen
name: Roche Pharma AG
First posted: 2012-01-11
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


Eligibility criteria: 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.

Primary outcomes:
measure: Progression free survival
timeFrame: 1 year
Secondary outcomes:
measure: Pathological response rate
timeFrame: 4 years
measure: Resection rate
timeFrame: 4 years
measure: Overall survival
timeFrame: 8 years
measure: Safety
timeFrame: 4 years
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien
city: Brussels
country: Belgium
facility: Hopital Universitaire Brugmann
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk - Campus Kennedylaan
city: Turnhout
country: Belgium
facility: AZ Turnhout - Campus Sint Elisabeth
city: Verviers
country: Belgium
facility: Centre Hospitalier Peltzer-La Tourelle
city: Avignon
country: France
facility: Institut Sainte Catherine
city: Bordeaux
country: France
facility: Institut Bergonie
city: Boulogne Billancourt
country: France
facility: CHU Ambroise Pare
city: Le Kremlin Bicetre
country: France
facility: Assistance Publique - Hôpitaux de Paris - Hopital De Bicetre AP-HP
city: Lyon
country: France
facility: Centre Hospitalier Saint Joseph Saint Luc
city: Lyon
country: France
facility: Centre Leon Berard
city: Lyon
country: France
facility: Hopital Prive Jean Mermoz
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Europeen Georges Pompidou
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses Croix Saint-Simon - Site Reuilly
city: Pierre-Benite (lyon)
country: France
facility: CHU de Lyon - Centre Hospitalier Lyon Sud
city: Reims
country: France
facility: CHU de Reims - Hôpital Robert Debré
city: Rouen
country: France
facility: Hopital Charles Nicolle
city: Saint Priest en Jarez
country: France
facility: CHU Saint-Etienne - CHU de Saint-Etienne - Hopital Nord
city: Saint-Gregoire
country: France
facility: Centre Hospitalier Privé Saint-Grégoire
city: Salouel
country: France
facility: CHU d'Amiens - CHU Amiens - Hopital Sud
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
city: Barcelona
country: Spain
facility: Hospital General Vall D'Hebron
city: Geneve
country: Switzerland
facility: Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie
Study officials:
affiliation: C.H.U. AMBROISE PARE AP-HP, Boulogne-Billancourt, France
name: Bernard Nordlinger, Pr.
role: STUDY_CHAIR
affiliation: HOPITAL DE BICETRE AP-HP, Le Kremlin Bicetre, France
name: Stephane Benoist, Pr.
role: STUDY_CHAIR
References: