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

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.

Conditions

• Metastatic NRAS Melanoma

Interventions

DRUG

Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 1)

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

DRUG

Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 2)

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

DRUG

Trametinib plus hydroxychloroquine in patients with NRAS Melanoma (Dose 3)

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

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Principal Investigators

• Amélie BOESPFLUG, MD · Hospices Civils de Lyon

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-10-15

Primary Completion

2023-01-03

Completion

2023-01-03

Countries

• France

Study Locations