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

• Overall survival [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
• Response duration [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
  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)
• Toxicity [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: Yes ]
• Secondary biomarkers analysis [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
  The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance.
• Tumoral response [ Time Frame: anticipated: 4 years ] [ Designated as safety issue: No ]
  Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan.

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.

• Drug: FOLFIRI (m)

  FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:

  • Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
  • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.
  • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
  • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
  Other Name: folinic acid, fluorouracil and irinotecan.
• Drug: FOLFOX-6 (m)

  FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:

  • Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
  • l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1.
  • One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
  • 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
  Other Name: folinic acid, fluorouracil and oxaliplatin.
• Drug: Cetuximab
  - 500 mg/m2 i.v. Every 2 weeks.
  Other Name: erbitux

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