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

Liver Metastases Clinical Trial

— BOS2  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01508000
• Other study ID #: EORTC-40091
• Secondary ID: 2010-019238-29
• Status: Terminated
• Phase: Phase 2
• First received: January 9, 2012
• Last updated: October 11, 2016
• Start date: June 2013
• Est. completion date: September 2016

Study information

• Verified date: October 2016
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Agency for Health and Food SafetyBelgium: Federal Agency for Medicinal Products and Health ProductsFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Paul-Ehrlich-InstitutNorway: Norwegian Medicines AgencyPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSpain: Agencia Española de Medicamentos y Productos SanitariosSweden: Medical Products AgencySwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 44
• Est. completion date: September 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms
• KRAS Wild Type Colorectal Cancer
• Liver Metastases
• Liver Neoplasms
• Neoplasm Metastasis
• Neoplasms, Second Primary

Intervention

Drug:
• FOLFOX6
5-FU, folinic acid, oxaliplatin

Biological:
• Bevacizumab
Targeted therapy
• Panitumumab
Targeted therapy

Procedure:
• Surgery

Locations

Country	Name	City	State
Austria	Allgemeines Krankenhaus der Stadt Wien	Vienna
Belgium	Hopital Universitaire Brugmann	Brussels
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	AZ Groeninge Kortrijk - Campus Kennedylaan	Kortrijk
Belgium	AZ Turnhout - Campus Sint Elisabeth	Turnhout
Belgium	Centre Hospitalier Peltzer-La Tourelle	Verviers
France	Institut Sainte Catherine	Avignon
France	Institut Bergonie	Bordeaux
France	CHU Ambroise Pare	Boulogne Billancourt
France	Assistance Publique - Hôpitaux de Paris - Hopital De Bicetre AP-HP	Le Kremlin Bicetre
France	Centre Hospitalier Saint Joseph Saint Luc	Lyon
France	Centre Leon Berard	Lyon
France	Hopital Prive Jean Mermoz	Lyon
France	Centre Antoine Lacassagne	Nice
France	Groupe Hospitalier Diaconesses Croix Saint-Simon - Site Reuilly	Paris
France	Hopital Europeen Georges Pompidou	Paris
France	CHU de Lyon - Centre Hospitalier Lyon Sud	Pierre-Benite (lyon)
France	CHU de Reims - Hôpital Robert Debré	Reims
France	Hopital Charles Nicolle	Rouen
France	CHU Saint-Etienne - CHU de Saint-Etienne - Hopital Nord	Saint Priest en Jarez
France	Centre Hospitalier Privé Saint-Grégoire	Saint-Gregoire
France	CHU d'Amiens - CHU Amiens - Hopital Sud	Salouel
Netherlands	The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis	Amsterdam
Spain	Hospital General Vall D'Hebron	Barcelona
Switzerland	Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie	Geneve

Sponsors (3)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Amgen, Roche Pharma AG

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Netherlands,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival	Increase in progression free survival rate at 1 year in each experimental arm (mFOLFOX6 + bevacizumab or panitumumab) compared to mFOLFOX6 alone arm.	1 year	No
Secondary	Pathological response rate	Increase in major pathological response rate between mFOLFOX6 alone arm and each experimental arm.	4 years	No
Secondary	Resection rate	Compare the percentage of patients with total resection with these three treatments.	4 years	No
Secondary	Overall survival	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.	8 years	No
Secondary	Safety	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.	4 years	Yes