Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroblastoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Neuroepithelial

Neoplasms, Glandular and Epithelial

Neuroendocrine Tumor

Neuroepithelioma

Anti-Infective Agents

Antirheumatic Agents

All Drugs and Chemicals

Antineoplastic Agents

Hydroxychloroquine

Trametinib

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Protein Kinase Inhibitors

Patients with NRAS Melanoma receiving the 1st dose of the treatment (400 milligrams)

Patients with NRAS Melanoma receiving the 2nd dose of the treatment (800 milligrams)

Patients with NRAS Melanoma receiving the 3rd dose of the treatment (600 milligrams twice a day)

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 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 (starting dose) = Hydroxychloroquine 800 mg by mouth once a day

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 2 = Hydroxychloroquine 600 mg by mouth two times a day

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

Amélie BOESPFLUG, MD

Nadjat MEDEGHRI

Sandrine MANSARD, MD

Julie CHARLES, MD

Céleste LEBBE, MD

Nicolas MEYER, MD

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.

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

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

DLTs will be determined weekly during the first cycle of treatment (28 days) in order to choose the optimal dose for the phase II

Percentage of patients with a partial or complete response to treatment according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines version 1.1 which allows the Evaluation of the Overall Response Rate (ORR) based on 3 main criteria: patients' tumor improves ("responds"), stays the same ("stabilizes"), or worsens ("progresses") during treatment. The comparison of target lesions will be based on a Computed Tomography (CT) scan performed after two cycles of treatment (56 days) to those present on the base line CT prior to treatment initiation.

Median progression Free survival will be determined in the cohort treated by the recommended phase 2 dose (RP2D). Subjects who discontinue treatment for reasons other than disease progression will have Computed Tomography (CT) scans at the end of therapy (EOT) visit (unless their previous restaging was performed within 6 weeks).

Overall Survival will be determined in the cohort treated by the recommended phase 2 dose (RP2D); Subjects who discontinue treatment for reasons other than progression will have Computed Tomography (CT) scans at the end of therapy (EOT) visit (unless their previous restaging was performed within 6 weeks).

Adverse events (AEs) and Serious Adverse Events (SAEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be reported

p62 will be quantified by immunohistochemistry (IHC) using a skin punch biopsy of normal tissue in patients without cutaneous metastasis.

LC3 will be quantified by immunohistochemistry (IHC) using a skin punch biopsy of normal tissue in patients without cutaneous metastasis.

p-ERK will be quantified by immunohistochemistry (IHC) using a skin punch biopsy of normal tissue in patients without cutaneous metastasis.

p62 will be quantified by immunohistochemistry (IHC) using a skin punch biopsy of normal tissue in patients with cutaneous metastasis.

LC3 will be quantified by immunohistochemistry (IHC) using a skin punch biopsy of normal tissue in patients with cutaneous metastasis.

p-ERK will be quantified by immunohistochemistry (IHC) using a skin punch biopsy of normal tissue in patients with cutaneous metastasis.

Serum trametinib and hydroxychloroquine concentrations (AUC) will be evaluated and compared to predicted published concentrations

The evaluation of treatment induced immune modifications in the blood serum will be based on patient peripheral blood mononuclear cell (PBMC) collection

Spots Global Cancer Trial Database for trametinib plus hydroxychloroquine in patients with nras melanoma (dose 3)