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

  • End date
    Dec 11, 2022
  • participants needed
  • sponsor
    Centre Leon Berard
Updated on 11 August 2022
platelet count
renal function
measurable disease
growth factor
investigational drug
gilbert's syndrome
serum bilirubin
serum bilirubin level
major surgery
progressive disease
neutrophil count
liver metastasis
metastatic colorectal cancer
mek inhibitor
serum total bilirubin
granulocyte-macrophage colony-stimulating factor
renal function test


Recent preclinical studies suggest that combining MEK and MDM2 inhibition synergize to induce apoptosis in RAS/BRAF-mutant and TP53 wild-type CRC models. In vitro, in RKO cell lines (poorly differentiated colon carcinoma cell line resistant to single agent targeting MDM2 and MEK and BRAF inhibition), the MDM2 plus MEK inhibitor combination generated a synergistic increase in apoptotic index. In vivo, in mice harboring human RKO colon tumor xenografts the combination of MDM2 plus MEK inhibition elicited 93% decreases in tumor volume.

This trial is to conduct a single-center, Phase 1 dose escalation study of trametinib combined with HDM201 (a HDM2 inhibitor) in patients with advanced/metastatic RAS/RAF mutant and TP53 wt CRC.


This trial is a Phase I dose escalation study aiming to evaluate the safety of a combined treatment associating HDM201 (escalating doses) with Trametinib (fixed dose). This study will utilize sequential and adaptive Bayesian design using the method of Time-to-event Continual Reassessment Method (CRM) to guide dose escalation and estimate the MTD.

Condition Colorectal Cancer, Advanced Cancer, Metastatic Cancer
Treatment Trametinib, HDM201
Clinical Study IdentifierNCT03714958
SponsorCentre Leon Berard
Last Modified on11 August 2022


Yes No Not Sure

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
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
Note: RECIST target lesion are not to be biopsied
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
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
I14 Patients must be covered by a medical insurance
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
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
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

Exclusion Criteria

E1 Cancer disease considered curable with surgery or radiotherapy
E2 Prior exposure to HDM2 inhibitors and/or MEK inhibitors
E8 Patients requiring the use of the following forbidden concomitant treatments
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
E10 Patients with active hemolysis
E11 Known VIH infection
E4 Impairment of gastrointestinal (GI) function or GI disease that may significantly
E12 Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
alter the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea
vomiting, diarrhea, malabsorption syndrome, small bowel resection that requires
E14 Hypersensitivity to trametinib or HDM201 or any of their excipients
nutritional support)
E15 Pregnant or breast-feeding female patients
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
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
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
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
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
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