Study Evaluating Biomarkers in Patients With Colorectal Cancer and Native KRAS Treated With Chemotherapy + Cetuximab

Phase 2

Completed

Conditions: Colorectal Cancer

Interventions: Drug: FOLFIRI (m)
Drug: FOLFOX-6 (m)
Drug: Cetuximab

Registration Number: NCT01276379

Lead Sponsor: Grupo Espanol Multidisciplinario del Cancer Digestivo

Brief Summary: Advanced colorectal cancer (ACRC) is a heterogeneous disease and classification of patients is nowadays inefficient. Roughly twenty per cent of patients present with favorable figures (less than 4 liver nodules and less than 5 cm) and are suitable for local treatments (surgery or local-ablative therapies). Additionally, 10-15% of patients have poor performance status (PS \>2) or are severe disabled due to geriatric syndromes or/and co-morbid diseases that preclude any treatment strategies than best supportive care alone. The rest of patients (fit patients not suitable for radical treatments) constitute the population of patients treated with palliative therapies. Despite of it not all these patients have the same prognosis. Patients with PS 0,1 and levels of LDH \<ULN (Intermediate-risk patients) have better PFS and OS irrespective of therapy in all randomized clinical trials (de Gramont et al, JCO 2000; Douillard et al, Lancet 2000; Koopman et al, 2007).

CRYSTAL trial shows a benefit in PFS (1.5 months) in RASWT of FOLFIRI plus cetuximab compared with FOLFIRI alone. Nowadays the selection of patients for cetuximab treatment is based on mutational status of KRAS, which allow to select those patients who will not respond to therapy. Other surrogate markers of activity should be also evaluated. Our hypothesis is that the suggested biomarkers will allow the selection of the patients who will benefit the most from the biweekly cetuximab treatment.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 221

Inclusion Criteria

Male or female, age ≥ 18 years
Able to sign an informed consent form
Advanced and/or metastatic colorectal cancer
Colorectal cancer with KRAS wild type genotype
At least one unidimensionally measurable lesion according to RECIST criteria (1.1 revised) (to be assessed ≤ 28 days prior to the study treatment)
All patients with the following features will be included:
1. Progression free survival > 6 months after adjuvant treatment +/- radiotherapy
2. "De novo" diagnosis of the disease
Performance ECOG status of 0-2
Life expectancy ≥ 3 months
Adequate bone marrow function: neutrophils ≥1,5 x 10^9/L; platelets ≥ 100 x 10^9/L; hemoglobin ≥9 g/dL.
Adequate liver, renal and hematological function as follows:
1. Adequate liver function: SGOT and SGPT 2.5 x ULN (5 x ULN in case of hepatic metastasis). Total bilirubin < 1,5 x ULN. Alkaline phosphatase 2,5 x LSN (5 x ULN if hepatic metastasis or 10 x ULN if bone metastasis)
2. Creatinine clearance or creatinine clearance during 24 hours ≥ 50 mL/min
3. Magnesium ≥ LLN, calcium ≥ LLN

Exclusion Criteria

PS > 2 or elderly patients with fragility criteria
Previous surgery for metastasis
Previous systemic treatment for the metastatic colorectal cancer
Previous treatment with antibodies anti-EGFR or treatment with small-molecule EGFR tyrosine kinase inhibitors or EGFR signal transduction inhibitors. Subjects who suspend their first dose due to a reaction to the infusion can participate
Central nervous system metastasis (except: treated subjects with asymptomatic CNS metastasis who have not received steroids within the 30 days prior to inclusion)
Prior malignant tumor in the last 5 years, except: basal cell carcinoma of the skin or pre-invasive cervical cancer
Unresolved toxicities from a prior systemic treatment which do not qualify the patient for inclusion
Presence of peripheral neuropathy (degree > 1 in the ctc version 3.0) and serious nonhealing wound, ulcer, or bone fracture
Hormonal treatment, immunotherapy or experimental or approved antibodies/proteins ≤ 30 days before the inclusion
Uncontrolled serious cardiovascular disease or: congestive cardiac failure NYHA lll or lV, unstable angina pectoris, myocardial infarction precedents in the past 12 months, significant arrhythmias
Interstitial pneumonitis or pulmonary fibrosis precedents, or interstitial pneumonitis or pulmonary fibrosis signs on the thoracic CT-scan
Treatment for systemic infection within the 14 days prior to treatment
Acute/subacute intestinal occlusion and/or active inflammatory bowel disease or any other bowel disease producing chronic diarrhea
Precedent of Gilbert's syndrome or dihydropyrimidine dehydrogenase deficiency
Precedent of any disease which can increase the risks associated to the participation in the study or interfere in the study results
Known positive test for the following infections: HIV, Hepatitis C + abnormal liver enzymes values, active chronic Hepatitis B (except Hepatitis C seropositive with normal liver enzymes)
All concurrent diseases which can increase the toxicity risk
The individual presents a disorder of any kind which jeopardizes their ability to give their written consent form and/or fulfill the study procedures
Any investigational agent within 30 days before enrolment
Pregnant or breastfeeding woman, or planning to get pregnant within the 6 months after treatment
Surgery (excluding the diagnostic biopsy or placing of a central venous catheter)
Woman or man of childbearing potential not consenting to use adequate contraceptive precautions during the study and 6 months after de last administration for women, and 1 month for men
Unability to fulfill the study requirements by the patients
Psychological, family, sociological or geographical conditions that may interfere with the fulfillment of the study protocol and the follow-up calendar

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
FOLFIRI (m) or FOLFOX-6 (m) + cetuximab	FOLFOX-6 (m)	FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.
FOLFIRI (m) or FOLFOX-6 (m) + cetuximab	Cetuximab	FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.
FOLFIRI (m) or FOLFOX-6 (m) + cetuximab	FOLFIRI (m)	FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.

Primary Outcome Measures

Name	Time	Method
Progression Free Survival	4 years	Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Two groups will be defined based on the score built from the proposed clinical variables and biomarkers. Instead of a binomial distribution, a Log-rank method has been used to calculate the sample size in order to include all the incidents during the follow-up. Expecting a minimum 20% difference (60 vs. 40%) on PFS at 12 months between groups and with the following assumptions: Alpha error (bilateral): 5% Beta error: 20% Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.

Secondary Outcome Measures

Name	Time	Method
Frequency of Adverse Events	4 years	Frequency and type of adverse events (AEs). AEs were coded according to NCI CTCAE V3.0 and classified by frequency, relatedness to study treatment (related/not related) and severity (Grade). Severity ranges from grade 1 (low intensity) to Grade 5 (max. intensity, death)
Secondary Biomarkers Analysis	4 years	The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance.
Overall Survival	4 years	Measured as time in months from start of study treatment to death or lost to follow up. Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Response Duration	4 years	Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors)
Tumoral Response	4 years	Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.

Trial Locations

Locations (27): Complejo Hospitalario Universitario de Albacete
🇪🇸
Albacete, Spain
Hospital Sant Jaume de Calella
🇪🇸
Calella, Spain
Hospital Provincial de Castellón
🇪🇸
Castelló de la Plana, Castellón, Spain
Hospital Son Espases
🇪🇸
Palma, Malllorca, Spain
Hospital Son Llàtzer
🇪🇸
Palma, Mallorca, Spain
Hospital Sant Joan de Reus
🇪🇸
Reus, Tarragona, Spain
Hospital Infanta Cristina de Badajoz
🇪🇸
Badajoz, Spain
Hospital de Barbastro
🇪🇸
Barbastro, Spain
Hospital General Yagüe
🇪🇸
Burgos, Spain
Hospital Clínic de Barcelona
🇪🇸
Barcelona, Spain
Hospital San Pedro de Alcántara
🇪🇸
Cáceres, Spain
Hospital General Universitario de Elche
🇪🇸
Elche, Spain
Hospital Universitari Arnau de Vilanova de Lleida
🇪🇸
Lleida, Spain
Hospital de Jaén
🇪🇸
Jaén, Spain
Hospital Universitario de Gran Canaria Dr. Negrín
🇪🇸
Las Palmas de Gran Canaria, Spain
Fundación Jimenez Díaz
🇪🇸
Madrid, Spain
Hospital de Móstoles
🇪🇸
Madrid, Spain
Hospital Universitario la Paz
🇪🇸
Madrid, Spain
Hospital de Mataró
🇪🇸
Mataró, Spain
Clínica Universitaria de Navarra
🇪🇸
Pamplona, Spain
Hospital de Sagunto
🇪🇸
Sagunto, Spain
Mutua de Terrassa
🇪🇸
Terrassa, Spain
Hospital Virgen de la Salud
🇪🇸
Toledo, Spain
Hospital Clínico Universitario Lozano Blesa
🇪🇸
Zaragoza, Spain
Instituto Valenciano de Oncología
🇪🇸
Valencia, Spain
Hospital de Navarra
🇪🇸
Pamplona, Spain
Hospital Miguel Servet
🇪🇸
Zaragoza, Spain