Study Evaluating Biomarkers in Patients With Colorectal Cancer and Native KRAS Treated With Chemotherapy + Cetuximab
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: FOLFIRI (m); FOLFOX-6 (m); Cetuximab
Intervention description: 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.; 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.; - 500 mg/m2 i.v. Every 2 weeks.
Intervention MeSH terms: Leucovorin; Folic Acid; Fluorouracil; Oxaliplatin; Irinotecan; Cetuximab; Levoleucovorin
Phase: Phase 2
Study type: Interventional
Primary purpose: Screening
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 221.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colorectal cancer; advanced; metastatic; KRAS; biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN); cetuximab

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.
    

Eligibility criteria:

        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