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I1.Adult men and women ≥ 18 years at time of inform consent form signature |
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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 |
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Note: BRAF translocation are eligible |
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I3. Previously treated by at least one prior chemotherapy line of treatment in the advanced/metastatic setting |
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I4. Documented progressive disease and presence of at least one measurable lesion according to RECIST 1.1 based on screening tumor assessment |
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I5.Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale |
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I6. Adequate organ function defined according to the following lab tests performed within 7 days before C1D1 |
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Bone marrow (without transfusion within 7 days) :Absolute neutrophil count (ANC) ≥ 1.5 x |
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L, Hemoglobin ≥ 9 g/ dL, Platelet count ≥ 100 x 109/L |
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Coagulation: INR ≤ 1.5, aPTT ≤ 1.5 ULN. Note: patients receiving therapeutic |
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anticoagulation should be on a stable dose for at least 7 days prior to C1D1 |
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Liver function: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤3 ULN |
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(or ≤ 5.0 ULN in case of liver metastasis or hepatic infiltration), Serum bilirubin ≤ 1.5 |
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ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3 ULN is |
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acceptable). Renal function |
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Calculated creatinine clearance ≥ 50 mL/ min/1.73m2 or serum creatinine ≤1.5ULN. Chronic |
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Kidney Disease Epidemiology Collaboration (CKD-EPI), formulae will be used for creatinine |
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clearance calculation. Proteinuria ≤ +1 on dipstick or ≤ 1 g/24 hours |
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I7.Adequate cardiovascular function QTcF ≤470ms, Resting blood pressure systolic |
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<160mmHg and diastolic<100mmHg, LVEF ≥50% as determined by transthoracic |
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echocardiogram |
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Note: RECIST target lesion are not to be biopsied |
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I8.Presence of at least one biopsable lesion i.e. at least one lesion with a diameter |
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≥10 mm, visible by medical imaging and accessible to repeatable percutaneous or |
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endoscopic sampling that permit core needle biopsy without unacceptable risk and |
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suitable for retrieval of a minimum of three, but ideally four, cores using a biopsy |
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needle of at least 16-gauge |
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I9 Minimal wash out period required for prior treatments (delay from the last dose of the |
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prior treatments to C1D1) : Any investigational drug > 28 days or five half-lives |
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whichever is longer, Major surgery >21 days, Note: If a patient underwent a major surgical |
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procedure, he/she must have adequately recovered from the toxicity (i.e. wound healing) |
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and/or complications from the intervention prior to starting therapy |
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Radiotherapy > 28 days, Immunotherapy > 21 days, Chemotherapy > 14 days, Live vaccines > 28 |
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days. Note: Seasonal influenza vaccines for injection are generally inactivated flu |
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I14 Patients must be covered by a medical insurance |
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vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live |
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attenuated vaccines, and are not allowed |
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Growth factors targeting the myeloid lineage (e.g. GCSF, GM-CSF, M-CSF) > 14 days |
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I10 Patients able to swallow orally administered medication and do not have any |
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clinically significant gastrointestinal abnormalities that may alter absorption of |
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study drugs such as malabsorption syndrome or major resection of the stomach or |
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bowels |
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I11 Fertile men must agree to use effective contraception from C1D1 until 4 months |
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after the last dose of study drugs |
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I12 Women of child-bearing potential must have a negative serum pregnancy test within |
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days of first dose of study drugs and agree to use effective contraception from the |
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date of negative pregnancy test to up to 4 months after the last dose of study drugs |
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I13 Patient should understand, sign, and date the written voluntary informed consent |
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form prior to any protocol-specific procedures performed. Patient should be able and |
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willing to comply with study visits and procedures as per protocol |
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E1 Cancer disease considered curable with surgery or radiotherapy
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E2 Prior exposure to HDM2 inhibitors and/or MEK inhibitors
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E8 Patients requiring the use of the following forbidden concomitant treatments
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E3 Presence of persisting AE related to anticancer treatments and Grade ≥ 2 according
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to CTCAE V5.0 except alopecia, neuropathy and biological values defined in inclusion
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E10 Patients with active hemolysis
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criteria
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E11 Known VIH infection
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E4 Impairment of gastrointestinal (GI) function or GI disease that may significantly
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E12 Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
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alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea
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vomiting, diarrhea, malabsorption syndrome, small bowel resection that requires
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E14 Hypersensitivity to trametinib or HDM201 or any of their excipients
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nutritional support)
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E15 Pregnant or breast-feeding female patients
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E5 Patients with significant active or uncontrolled cardiovascular disease or prior
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medical cardiac function disorders including for example uncontrolled hypertension
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peripheral vascular disease, congestive heart failure (Class III-IV according to New
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York Heart Association [NYHA] scale), cardiac arrhythmia, or acute coronary syndrome
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within 6 months of C1D1 or myocardial infarction, angina pectoris, symptomatic
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pericarditis, within 12 months of C1D1 and patients with drug eluting stents for
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cardiovascular purposes
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E6 .Patients diagnosed with treatment-related interstitial lung disease or
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pneumonitis
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E7 Patients with secondary malignancy unless this malignancy is not expected to
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interfere with the evaluation of study endpoints and is approved by the sponsor
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Examples of the latter include :basal or squamous cell carcinoma of the skin, in-situ
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carcinoma of the cervix, localized prostate cancer, prior malignancy and no evidence
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of disease for ≥ 2 years
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Any anticancer therapy other than the protocol specified therapies including any
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investigational agent, any chemotherapy, radiotherapy (except palliative radiotherapy after
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discussion with the sponsor), immunotherapy, biologic or hormonal therapy for cancer
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treatment. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for
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diabetes and hormone replacement therapy) is acceptable
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Strong and moderate inducers and inhibitors of CYP3A4/5, Live vaccines, CYP3A4/5 substrates
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with a narrow therapeutic index: prohibited 24 hours prior and 1 week after HDM201
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administration, Substrates of OATP1B1: prohibited 24 hours prior and 48 hours after HDM201
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administration
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E9 History or current evidence of Retinal Vein Occlusion (RVO) or central serous
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retinopathy (CSR) or risk factors including uncontrolled glaucoma or ocular
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hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus
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or history of hyperviscosity or hypercoagulability syndromes
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E13 Symptomatic CNS metastases. Note: Patients with CNS metastases are eligible only
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if they are asymptomatic, off corticosteroids, radiographically stable for at least 2
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months prior C1D1 and considered not to be at risk of bleeding
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