Vecchione et al showed that suppression of RANBP2 results in mitotic defects only in BRAF-like colon cancer (CC) cells, which leads to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. Vinorelbine mimics RANPB2 silencing in BRAF-like and BRAFV600E CC cell lines.

These preclinical data represent a strong rationale to also explore the anti-tumor activity of vinorelbine in patients with advanced BRAF-like (both BRAFm and BRAF wild type) CC. Tumors having this gene signature are referred to as "BRAF-like" and have a similar poor prognosis irrespective of the presence of BRAF(V600E) mutation. Since vinorelbine is standard of care in advanced breast and NSCLC, there is ample experience with the dose and schedule as well as with the safety profile and supportive measures required to prevent side-effects.

Inclusion Criteria:

1. Written informed consent for this clinical trial (+ TR (translational research)) must be given according to ICH/GCP and national/local regulations

2. Written documentation of BRAF-like signature CC, including BRAFm and BRAFwt, as determined by the validated assay of Agendia

3. Written documentation of KRAS and BRAF mutational status.

4. Age > 18 years

5. Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon not in a previously irradiated area, treated with at least one or two lines of standard of care therapy, including BRAF inhibitors, for advanced disease

6. WHO performance status of 0-1

7. Able and willing to undergo blood sampling for pharmacodynamic (PD) analysis;

8. Able and willing to undergo tumor biopsy prior to, during and upon treatment;

9. Life expectancy > 3 months allowing adequate follow up of toxicity evaluation and antitumor activity

10. Minimal acceptable safety laboratory values:

    1. ANC > 1.5 x 109 /L
    2. Platelet count > 100 x 109 /L
    3. Hemoglobin > 6.0 mmol/L
    4. Hepatic function as defined by serum bilirubin < 1.5 x ULN, ALAT and ASAT < 2.5 x ULN, or ALAT and ASAT < 5 x ULN in patients with liver metastases
    5. Renal function as defined by serum creatinine < 1.5 x ULN
    6. creatinine clearance > 50 ml/min (by Cockcroft-Gault formula)

11. Negative urine or serum pregnancy test (serum or urine) for female patients with childbearing potential

Exclusion Criteria:

1. Any treatment with investigational drugs, including BRAF inhibitors, within 28 days prior to receiving the first dose of investigational treatment
2. Symptomatic or untreated leptomeningeal disease
3. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anticonvulsant therapy (for at least 4 weeks) are allowed to enroll. Radiotherapy for brain metastasis must have been completed at least 6 weeks prior to start of study treatment. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening (<21 days before start of treatment) demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids.
4. Impairment of gastrointestinal (GI) function or GI disease (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, any condition inducing malabsorption, small bowel resection)
5. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection
6. Known allergy or any other adverse reaction to any of the drugs or to any related compound
7. Women who are pregnant or breast feeding
8. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms) 9. Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment. Palliative radiation (1x 8Gy) is allowed

10. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery 11. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients 12. Patients with a known history of hepatitis B or C 13. Patients with cardiac comorbidities (myocardial infarct within 6 months of study start, NYHA class ≥ III, congestive heart failure or instable angina pectoris), uncontrolled hypertension (systolic blood pressure > 150 mm Hg and/or diastolic pressure > 90 mm Hg) or prolonged QT-interval (> 440 ms for men, > 460 ms for women) 14. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study 15. Known hypersensitivity to study drug or excipients