Trametinib + HDM201 in CRC Patients With RAS/RAF Mutant and TP53 Wild-type Advanced/Metastatic Colorectal Cancer Mutant and TP53 Wild-type

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.