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

  • STATUS
    Recruiting
  • End date
    Dec 23, 2022
  • participants needed
    24
  • sponsor
    Centre Leon Berard
Updated on 27 February 2022
platelet count
renal function
cancer
measurable disease
carcinoma
sargramostim
growth factor
investigational drug
x-rays
gilbert's syndrome
serum bilirubin
serum bilirubin level
BRAF
KRAS
TP53
major surgery
metastasis
progressive disease
neutrophil count
liver metastasis
metastatic colorectal cancer
g-csf
aptt
mek inhibitor
serum total bilirubin
granulocyte-macrophage colony-stimulating factor
renal function test
ki-ras

Summary

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.

Description

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.

Details
Condition Colorectal Cancer, Advanced Cancer, Metastatic Cancer
Treatment Trametinib, HDM201
Clinical Study IdentifierNCT03714958
SponsorCentre Leon Berard
Last Modified on27 February 2022

Eligibility

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 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
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