MEK and Autophagy Inhibition in Metastatic/Locally Advanced Unresectable Neuroblastoma RAS (NRAS) Melanoma

  • STATUS
    Recruiting
  • End date
    Mar 31, 2022
  • participants needed
    29
  • sponsor
    Hospices Civils de Lyon
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Updated on 25 January 2021
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Summary

Patients with metastatic Neuroblastoma RAS (NRAS) melanoma are currently treated with first line immune checkpoint inhibitors (nivolumab, pembrolizumab). Thus far, no targeted therapy has been approved in NRAS mutated melanoma as a second line treatment, because although the use of a MEK inhibitor (binimetinib) alone was superior to the gold standard chemotherapy (dacarbazine) in a phase 3 trial, the progression free survival gain was very modest.

In vitro and in vivo work from the study team's lab (McMAHON, Huntsman Cancer Institute (HCI), Salt Lake City), as well as, Ravi Amaravardi and Jean Mulchey-Levy suggests that the activation of autophagy is a mechanism of resistance to BRAF and MEK inhibitors in RAS and RAF mutated cancers, such as melanoma, pediatric brain tumors and pancreatic adenocarcinoma. The study team has shown in vivo, in four different NRAS mutated melanoma Patient Derived Xenograft (PDX) models that the combination of the MEK inhibitor trametinib and the autophagy inhibitor chloroquine results in a more dramatic tumor regression and inhibition than trametinib or chloroquine used as single agents (Nat Med. 2019 Apr;25(4):620-627. doi: 10.1038/s41591-019-0367-9. Epub 2019 Mar 4). In two of the PDX models, the combination resulted in almost complete tumor regression (quasi disappearance) that was not observed in the single agent treatment arms.

Trametinib (MEKINISTR) is an orally available MEK inhibitor that is currently approved in combination with the BRAF inhibitor dabrafenib (TAFINLARR) to treat BRAF mutated metastatic melanoma at the standard dosing of 2 milligrams (mg) once a day. Hydroxychloroquine (PLAQUENILR) is an orally available autophagy inhibitor that has been used for many years to treat autoimmune diseases like lupus, sarcoidosis and rheumatoid arthritis at the standard dosing of 400-600mg/day. For this study, the investigating team would like to evaluate the safety and tolerability of the combination of hydroxychloroquine and trametinib in a phase I trial in patients with NRAS mutated metastatic melanoma.

Details
Condition Metastatic NRAS Melanoma
Treatment Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 1), Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 2), Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 3)
Clinical Study IdentifierNCT03979651
SponsorHospices Civils de Lyon
Last Modified on25 January 2021

Eligibility

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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Metastatic NRAS Melanoma?
Do you have any of these conditions: Do you have Metastatic NRAS Melanoma??
Histologically confirmed metastatic or locally advanced unresectable malignant melanoma with an activating NRAS mutation
Available archival tissue, or if not, the patient is willing to provide a baseline tumor biopsy
Patient must have progressed during or after a first line treatment by immunotherapy (ipilimumab, pembrolizumab, nivolumab)
Progression will be confirmed by two consecutive Computed Tomography (CT) assessements separated for at least 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
Patient age at least 18 years old
Patient Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1
Patient able to provide informed consent and sign approved consent forms to participate in the study and provide tumor samples
Patient willing and able to comply with all study procedures and able to take oral medications
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
Patients must have measurable disease as defined by RECIST version 1.1 criteria
Adequate bone marrow, renal and liver function determined biologically
Hematologic: Absolute Neutrophil Count (ANC) 1.5x10e9 per Liter, platelet count 100 x10e9 per Liter, and hemoglobin 9grams/deciLiter
Hepatic: total bilirubin level 1.5 times the Upper Limit of the Normal (ULN) range (except subjects with Gilbert's Syndrome who must have normal direct bilirubin) and Aspartate aminotransferase (ASAT) and Alanine Aminotransferase (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
Adequate cardiac function determined by a pre-treatment Electrocardiogram (EKG) and cardiac ultra-sound
Corrected QT (QTc) interval 450 ms for the male population and 470ms for the female population
Left ventricular ejection fraction (LVEF) 50%
Women of childbearing potential must have a negative serum or urine pregnancy test at screening
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 throughout the study and for at least 4 months after last study treatment administration if the risk of conception exists
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

Exclusion Criteria

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
Patient received radiotherapy within 2 weeks prior to the first dose of study treatment except localized radiation therapy for symptomatic bone metastasis
Patients with multiple primary malignancies may be enrolled if nonmelanoma tumor(s) are determined stable by treating investigator and do not require active treatment
Patients with symptomatic brain metastases or cranial epidural disease. Asymptomatic patients with brain metastases can be included
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)
Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions
Cardio-vascular disorders: Congestive heart failure New York Heart Association (NYHA) class 3 or 4, unstable angina, uncontrolled cardiac arrhythmias, uncontrolled hypertension. Stroke, myocardial infarction or other ischemic event within 6 months before first dose
History of Glucose-6-Phosphate dehydrogenase (G6PD) deficiency
Patients who have neuromuscular disorders that are associated with elevated Creatine Kinase (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 Principal Investigator (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
Known positive serology for Human Immunodeficiency Virus (HIV), active Hepatitis B, and/or active Hepatitis C infection
Patients who have undergone major surgery 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
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 Human chorionic gonadotropin (hCG) laboratory test
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
Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 Grade3)
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