Clinical trial NCT01442649: Efficacy of Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab
Official title: Phase II, Multicentric Randomized Trial, Evaluating the Efficacy of Fluoropyrimidine-based Standard Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: Adenocarcinoma
Metastatic
Second-line treatment
Progressive disease after first-line treatment with bevacizumab
Non-mutated (wild-type) KRAS.
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2011-09-28
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective is to evaluate progression-free survival (PFS) at 4 months.

The secondary objectives are to evaluate the objective response rate (OR) (= complete responses (CR) and partial responses (PR)) according to the RECIST v1.1 criteria, the progression-free survival (PFS), the overall survival (OS), the overall survival from the date of the first-line chemotherapy used on the metastatic disease, the treatment tolerance (NCI CTC AE V4 criteria, except for peripheral neurological toxicity (Lévi Scale)), the quality of life according to the EORTC QLQ-C30 criteria.

The objectives of the biological study are to evaluate potentially predictive anti-EGFR and anti-VEGF response factors and CEC rates as predictive biomarkers for the efficacy of bevacizumab associated with chemotherapy in mCRC treatment.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically proven adenocarcinoma of the colon expressing non-mutated (wild-type) KRAS.
* Progressive metastatic disease after first-line treatment with chemotherapy alone: based on 5-FU (iv or per os) with irinotecan or oxaliplatin associated to bevacizumab.
* Prior adjuvant chemotherapy (of the primary tumor) with fluoropyrimidine and oxaliplatin is allowed if the time interval between the end of this chemotherapy and the beginning of the first-line metastatic treatment is ≥ 6 months.
* Measurable disease (at least one measurable metastatic lesion) according to the RECIST V1.1 criteria (the lesion should not be located in a previous field of radiation).
* Previous radiotherapy is authorized if discontinued ≥ 15 days prior to randomization and if the measurable metastatic lesions are outside the radiation area.
* Sites of disease evaluated within 28 days prior to randomization with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI plus Chest Xray)
* Age ≥18 years
* Patient with ECOG 0 or 1
* Life Expectancy ≥ 3 months
* Hematologic function (polynuclear neutrophiles ≥ 1.5.109/L ; platelets ≥ 100.109/L ; hemoglobin ≥ 9 g/dL
* Hepatic transaminases ≤ 2.5 times upper limit of normal (ULN) (≤ 5 ULN in case of hepatic metastases), alkaline phosphatases ≤ 2.5 ULN (≤ 5 ULN in case of hepatic metastases), total bilirubinemia ≤ 1.5 ULN
* Renal function (creatinemia ≤1.5 ULN; creatine clearance ≥ 50 mL/mn (Cockcroft and Gault) ; urine test strip \< 2+. If proteinuria is ≥ +2 at inclusion, the serum urea test must be redone and show proteinuria ≤ 1 g/L within 24 h)
* Completion of the EORTC QLQ-C30 quality of life form
* Negative pregnancy test for women of child-bearing age
* Information given to the patient and signed informed consent
* Public Health insurance coverage

Exclusion Criteria:

* Known meningeal or brain metastases
* Pre-treatment with anti-EGFR
* Specific contraindication or known hypersensitivity to one treatment product
* Patient with known allergy or hypersensitivity to monoclonal antibodies (bevacizumab, cetuximab
* Clinically significant affection of the coronaries or myocardial infarction within 6 months prior to inclusion.
* Peripheral neuropathy of grade \> 1 (CTCAE scale version 4.0).
* Known depletion of the dihydropyrimidine dehydrogenase (DPD).
* Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis.
* Uncontrolled Arterial hypertension (systolic pressure \> 150 mmHg and/or diastolic pressure \> 100 mmHg with and without antihypertensive medication. Patients with high hypertension are eligible if antihypertensive medication lowers their arterial pressure to the level of acceptability specified by the inclusion criteria.
* History of hypertensive crisis or hypertensive encephalopathy
* Other concomitant malignancy or history cancer (except carcinoma in situ of the cervix, or non melanoma skin cancer, with curative intent treatment, when considered in complete remission for at least 5 years before randomization.
* Any treatment including an experimental drug, or participation in another clinical trial within 28 days preceding inclusion.
* Persons deprived of liberty or under guardianship.
* Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Primary outcomes:
measure: Progression-free survival (PFS) at 4 months
timeFrame: 4 months
Secondary outcomes:
measure: Objective response rate (OR)
timeFrame: 12 months
measure: Progression-free survival (PFS)
timeFrame: 4 months
measure: Overall survival (OS)
timeFrame: until death or progression (24 months)
measure: Overall survival from the date of the first-line chemotherapy used on the metastatic disease
timeFrame: until death or progression (24 months)
measure: Treatment tolerance
timeFrame: Every 2 weeks, during the treatment.
measure: Quality of life
timeFrame: every 6 weeks
Other outcomes:
Locations:
city: Saint-herblain
country: France
facility: Centre rené Gauducheau
Study officials:
affiliation: Centre René Gauducheau
name: Jaafar BENNOUNA, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Jean Minjoz-BESANCON
name: Christophe BORG, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Paul Strauss-STRASBOURG
name: Christian BOREL, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Claudius Regaud-TOULOUSE
name: Jean-Pierre DELORD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier du Mittan-MONTBELIARD
name: Christophe BORG, Pr.
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Timone-MARSEILLE
name: Jean-François SEITZ, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Alexis Vautrin-VANDOEUVRE LES NANCY
name: Thierry CONROY, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHD Vendée-LA ROCHE SUR YON
name: Roger FAROUX, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Antoine Lacassagne-NICE
name: Eric FRANCOIS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Bocage-DIJON
name: Alice GAGNAIRE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Oscar Lambret-LILLE
name: Antoine ADENIS, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Polyclinique Bordeaux Nord Aquitaine-BORDEAUX
name: Cédric LECAILLE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Groupe hospitalier St Joseph-PARIS
name: Gaël DEPLANQUE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Privé Jean Mermoz-LYON
name: Pascal ARTRU, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier du Mans-LE MANS
name: Oana COJOCARASU, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHP Saint Grégoire-SAINT GREGOIRE
name: Laurent MIGLIANICO, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Robert Debré - CHU Reims
name: Olivier BOUCHE, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier de Cholet
name: You-Heng LAM, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Poitiers-POITIERS
name: David TOUGERON, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHR d'Orléans - Hôpital la Source
name: Barbara DAUVOIS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Claude Bernard, Albi
name: Philippe HOUYAU, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bennouna J, Hiret S, Bertaut A, Bouche O, Deplanque G, Borel C, Francois E, Conroy T, Ghiringhelli F, des Guetz G, Seitz JF, Artru P, Hebbar M, Stanbury T, Denis MG, Adenis A, Borg C. Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer: The UNICANCER PRODIGE18 Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):83-90. doi: 10.1001/jamaoncol.2018.4465.