Patients with metastatic NRAS melanoma MedDRA version: 20.0 Level: LLT Classification code 10027481 Term: Metastatic melanoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Mekinist
Product Name: Trametinib
Pharmaceutical Form: Tablet
Trade Name: Plaquenil
Product Name: Sulfate d'hydroxychloroquine
Pharmaceutical Form: Tablet
Sponsors
Hospices Civils de Lyon
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histologically confirmed metastatic or locally advanced unresectable malignant melanoma with an activating NRAS mutation. 2. Available archival tissue OR if not the patient is willing to provide a baseline tumor biopsy 3. Patient must have progressed during or after a first line treatment by immunotherapy (ipilimumab, pembrolizumab, nivolumab). - Progression will be confirmed by two consecutive CT assessements separated by 4 weeks. - Inclusion is possible if patients progress during an adjuvant treatment by immunotherapy or if they progress less than six months after adjuvant treatment discontinuation. - If patients progress six months after adjuvant treatment discontinuation, they have to be treated by a second line of immunotherapy before they can be included in the trial. 4. Patient age =18 5. Patient Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. 6. Patient able to provide informed consent and sign approved consent forms to participate in the study and provide tumor samples 7. Patient willing and able to comply with all study procedures and able to take oral medications. 8. Patients must be willing and able to undergo skin or tumor biopsies according to the institute’s own guidelines, the study protocol and requirements for such procedures. 9. Patients must have measurable disease as defined by RECIST v1.1 criteria 10. Adequate bone marrow, renal and liver function determined biologically: - Hematologic: absolute neutrophil count (ANC) =1.5x10e9/L, platelet count =100 x10e9/L, and hemoglobin =9g/dL - Hepatic: total bilirubin level =1.5 x the upper limit of the normal (ULN) range ((except subjects with Gilbert’s Syndrome who must have normal direct bilirubin) and ASAT and ALAT levels =3 ULN. For patients with metastatic disease to the liver allow levels =5 ULN - Renal: estimated creatinine clearance =50ml/min according to the Cockcroft-Gault formula (or local institutional standard method). - Albumin = 27 g/l 11. Adequate cardiac function determined by a pre-treatment EKG and cardiac ultra-sound. - QTc interval = 480 ms - Left ventricular ejection fraction (LVEF) =50% 12. Women of childbearing potential must have a negative serum or urine pregnancy test at screening. 13. Both male and female patients must agree to the use of 2 methods of contraception, with one method being highly effective and the other being either highly effective or less effective as listed in annexe 1 throughout the study and for at least 4 months after last study treatment administration if the risk of conception exists. 14. Women of childbearing potential who are continuously not heterosexually active are exempt from contraceptive requirements. However, women of childbearing who abstain from heterosexual activity on a continuous basis must still undergo pregnancy testing as described in this protocol. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 29 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 29
Exclusion criteria
Exclusion criteria: 1. Prior to the first dose of study treatment patient who received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy within 4 weeks (6 weeks for nitrosurea or mitomycin-C, antibodies like ipilimumab, pembrolizumab and nivolumab) or within 7-half lives of the investigational therapy prior to starting study treatment, whichever is longer. 2. Patient received radiotherapy within 2 weeks prior to the first dose of study treatment except localized radiation therapy for symptomatic bone metastasis 3. Patients with multiple primary malignancies may be enrolled if non-melanoma tumor(s) are determined stable by treating investigator and do not require active treatment. 4. Patients with symptomatic brain metastases or cranial epidural disease. Asymptomatic patients with brain metastases can be included. 5. Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension). 6. Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions: - Cardio-vascular disorders: Congestive heart failure NYHA class 3 or 4, unstable angina, serious cardiac arrythmias. Stroke, myocardial infarction or other ischemic event within 3 months before first dose. - History of G6PD deficiency - Patients who have neuromuscular disorders that are associated with elevated CK - Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgement of the PI may impair absorption of study drugs) - Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures. 7. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection. 8. Patients who have undergone major surgery = 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure. 9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 10. Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study 11. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade=3)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •Phase Ib: To assess the safety and tolerability of escalating doses of hydroxychloroquine (HCQ) in combination with a fixed dose of trametinib in subjects with metastatic or locally advanced, unresectable NRAS mutated melanoma and determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of the combination. •Phase II: To assess the efficacy of trametinib and hydroxychloroquine in the study population, when used at the RP2D.;Secondary Objective: To evaluate toxicity and safety of the combination trametinib and hydroxychloroquine and evaluate long term antitumor activity;Primary end point(s): •Phase Ib: Incidence of dose-limiting toxicities (DLTs) to choose the optimal dose for the phase II (RP2D). •Phase II: Evaluate the Overall Response Rate (ORR) by comparing target lesions on a CTscan performed after two cycles of treatment (56 days) to those present on the base line CT prior to treatment initiation, to determinate the percentage of patients with a partial or complete response according to RECIST v1.1. ;Timepoint(s) of evaluation of this end point: Phase I : DLTs will be determined weekly during the first cycle of treatment (28 days). Phase II : 56 days | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): o Median progression Free survival and Overall Survival will be determined in the cohort treated by the RP2D o AEs and SAEs according to CTCAE v 5.0 will be reported ;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Countries
France
Contacts
Public ContactAnnie IUNG
Hospices Civils de Lyon
Outcome results
None listed