Inclusion Criteria:

          -  I1.Adult men and women ≥ 18 years at time of inform consent form signature.

          -  I2. Patients with histologically confirmed locally advanced or metastatic CRC bearing
             RAS (may be KRAS or NRAS or HRAS) or BRAF mutation, and TP53 wild type Note : TP53 wt
             status has to be determined by NGS sequencing of the full coding sequence using a
             tumor sample collected no longer than 36 months before inclusion.

        Note: BRAF translocation are eligible.

          -  I3. Previously treated by at least one prior chemotherapy line of treatment in the
             advanced/metastatic setting.

          -  I4. Documented progressive disease and presence of at least one measurable lesion
             according to RECIST 1.1 based on screening tumor assessment.

          -  I5.Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology
             Group (ECOG) scale.

          -  I6. Adequate organ function defined according to the following lab tests performed
             within 7 days before C1D1:

        Bone marrow (without transfusion within 7 days) :Absolute neutrophil count (ANC) ≥ 1.5 x
        109/L, Hemoglobin ≥ 9 g/ dL, Platelet count ≥ 100 x 109/L.

        Coagulation: INR ≤ 1.5, aPTT ≤ 1.5 ULN. Note: patients receiving therapeutic
        anticoagulation should be on a stable dose for at least 7 days prior to C1D1.

        Liver function: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤3 ULN
        (or ≤ 5.0 ULN in case of liver metastasis or hepatic infiltration), Serum bilirubin ≤ 1.5
        ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3 ULN is
        acceptable). Renal function:

        Calculated creatinine clearance ≥ 50 mL/ min/1.73m2 or serum creatinine ≤1.5ULN. Chronic
        Kidney Disease Epidemiology Collaboration (CKD-EPI), formulae will be used for creatinine
        clearance calculation. Proteinuria ≤ +1 on dipstick or ≤ 1 g/24 hours.

          -  I7.Adequate cardiovascular function QTcF ≤470ms, Resting blood pressure systolic
             <160mmHg and diastolic<100mmHg, LVEF ≥50% as determined by transthoracic
             echocardiogram.

          -  I8.Presence of at least one biopsable lesion i.e. at least one lesion with a diameter
             ≥10 mm, visible by medical imaging and accessible to repeatable percutaneous or
             endoscopic sampling that permit core needle biopsy without unacceptable risk and
             suitable for retrieval of a minimum of three, but ideally four, cores using a biopsy
             needle of at least 16-gauge.

        Note: RECIST target lesion are not to be biopsied.

        -I9 Minimal wash out period required for prior treatments (delay from the last dose of the
        prior treatments to C1D1) : Any investigational drug > 28 days or five half-lives,
        whichever is longer, Major surgery >21 days, Note: If a patient underwent a major surgical
        procedure, he/she must have adequately recovered from the toxicity (i.e. wound healing)
        and/or complications from the intervention prior to starting therapy.

        Radiotherapy > 28 days, Immunotherapy > 21 days, Chemotherapy > 14 days, Live vaccines > 28
        days. Note: Seasonal influenza vaccines for injection are generally inactivated flu
        vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
        attenuated vaccines, and are not allowed.

        Growth factors targeting the myeloid lineage (e.g. GCSF, GM-CSF, M-CSF) > 14 days.

          -  I10 Patients able to swallow orally administered medication and do not have any
             clinically significant gastrointestinal abnormalities that may alter absorption of
             study drugs such as malabsorption syndrome or major resection of the stomach or
             bowels.

          -  I11 Fertile men must agree to use effective contraception from C1D1 until 4 months
             after the last dose of study drugs.

          -  I12 Women of child-bearing potential must have a negative serum pregnancy test within
             7 days of first dose of study drugs and agree to use effective contraception from the
             date of negative pregnancy test to up to 4 months after the last dose of study drugs.

          -  I13 Patient should understand, sign, and date the written voluntary informed consent
             form prior to any protocol-specific procedures performed. Patient should be able and
             willing to comply with study visits and procedures as per protocol.

          -  I14 Patients must be covered by a medical insurance.

        Exclusion Criteria:

          -  E1 Cancer disease considered curable with surgery or radiotherapy.

          -  E2 Prior exposure to HDM2 inhibitors and/or MEK inhibitors.

          -  E3 Presence of persisting AE related to anticancer treatments and Grade ≥ 2 according
             to CTCAE V5.0 except alopecia, neuropathy and biological values defined in inclusion
             criteria.

          -  E4 Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea,
             vomiting, diarrhea, malabsorption syndrome, small bowel resection that requires
             nutritional support).

          -  E5 Patients with significant active or uncontrolled cardiovascular disease or prior
             medical cardiac function disorders including for example uncontrolled hypertension,
             peripheral vascular disease, congestive heart failure (Class III-IV according to New
             York Heart Association [NYHA] scale), cardiac arrhythmia, or acute coronary syndrome
             within 6 months of C1D1 or myocardial infarction, angina pectoris, symptomatic
             pericarditis, within 12 months of C1D1 and patients with drug eluting stents for
             cardiovascular purposes.

          -  E6 .Patients diagnosed with treatment-related interstitial lung disease or
             pneumonitis.

          -  E7 Patients with secondary malignancy unless this malignancy is not expected to
             interfere with the evaluation of study endpoints and is approved by the sponsor.
             Examples of the latter include :basal or squamous cell carcinoma of the skin, in-situ
             carcinoma of the cervix, localized prostate cancer, prior malignancy and no evidence
             of disease for ≥ 2 years.

          -  E8 Patients requiring the use of the following forbidden concomitant treatments :

        Any anticancer therapy other than the protocol specified therapies including any
        investigational agent, any chemotherapy, radiotherapy (except palliative radiotherapy after
        discussion with the sponsor), immunotherapy, biologic or hormonal therapy for cancer
        treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for
        diabetes and hormone replacement therapy) is acceptable.

        Strong and moderate inducers and inhibitors of CYP3A4/5, Live vaccines, CYP3A4/5 substrates
        with a narrow therapeutic index: prohibited 24 hours prior and 1 week after HDM201
        administration, Substrates of OATP1B1: prohibited 24 hours prior and 48 hours after HDM201
        administration.

          -  E9 History or current evidence of Retinal Vein Occlusion (RVO) or central serous
             retinopathy (CSR) or risk factors including uncontrolled glaucoma or ocular
             hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus,
             or history of hyperviscosity or hypercoagulability syndromes.

          -  E10 Patients with active hemolysis.

          -  E11 Known VIH infection

          -  E12 Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

          -  E13 Symptomatic CNS metastases. Note: Patients with CNS metastases are eligible only
             if they are asymptomatic, off corticosteroids, radiographically stable for at least 2
             months prior C1D1 and considered not to be at risk of bleeding.

          -  E14 Hypersensitivity to trametinib or HDM201 or any of their excipients.

          -  E15 Pregnant or breast-feeding female patients.