Metastatic NRAS Melanoma Clinical Trial
Official title:
MEK and Autophagy Inhibition in Metastatic/Locally Advanced, Unresectable Neuroblastoma RAS (NRAS) Melanoma: A Phase Ib/II Trial of Trametinib Plus Hydroxychloroquine in Patients With NRAS Melanoma
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.
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