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

Conditions

• Metastatic NRAS Melanoma

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 1) — DRUG
  Standard dosing of trametinib at 2 milligrams (mg) by mouth once a day, with an escalation of hydroxychloroquine. The escalation of hydroxychloroquine will be decided by a 3+3 design with the goal of estimating the Maximum Tolerated Dose (MTD) of trametinib plus hydroxychloroquine. A cycle of treatment will last 28 days. Patients will be evaluated weekly during the first cycle of treatment. • Level -1 = Hydroxychloroquine 400 mg by mouth once a day
• Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 2) — DRUG
  Standard dosing of trametinib at 2 milligrams (mg) by mouth once a day, with an escalation of hydroxychloroquine. The escalation of hydroxychloroquine will be decided by a 3+3 design with the goal of estimating the Maximum Tolerated Dose (MTD) of trametinib plus hydroxychloroquine. A cycle of treatment will last 28 days. Patients will be evaluated weekly during the first cycle of treatment. • Level 1 (starting dose) = Hydroxychloroquine 800 mg by mouth once a day
• Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 3) — DRUG
  Standard dosing of trametinib at 2 milligrams (mg) by mouth once a day, with an escalation of hydroxychloroquine. The escalation of hydroxychloroquine will be decided by a 3+3 design with the goal of estimating the Maximum Tolerated Dose (MTD) of trametinib plus hydroxychloroquine. A cycle of treatment will last 28 days. Patients will be evaluated weekly during the first cycle of treatment. • Level 2 = Hydroxychloroquine 600 mg by mouth two times a day

Study Details

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.

Key Dates

Start date

Oct 15, 2019

Status verified

May 2025

Primary completion

Jan 3, 2023

Completion

Jan 3, 2023

Study Design

Enrollment

29 participants (actual)

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Arms

• Experimental: Patients with NRAS Melanoma (Dose 1)
  Patients with NRAS Melanoma receiving the 1st dose of the treatment (400 milligrams)
• Experimental: Patients with NRAS Melanoma (Dose 2)
  Patients with NRAS Melanoma receiving the 2nd dose of the treatment (800 milligrams)
• Experimental: Patients with NRAS Melanoma (Dose 3)
  Patients with NRAS Melanoma receiving the 3rd dose of the treatment (600 milligrams twice a day)

Primary Outcome Measure

Incidence of Dose-Limiting Toxicities (DLTs) [ Time Frame: 28 days ]