Tumor-targeted therapy changing game for choroidal melanoma

Early results of a phase Ib/II study investigating light-activated AU-011 (Aura Biosciences) for treatment of small-medium choroidal melanoma show good safety and evidence of efficacy for this novel tumor-targeted therapy.

Now, patient recruitment is ongoing as the study moves ahead with its dose-escalation protocol, said Carol Shields, MD, at the 2017 Retina Subspecialty Day meeting.

“These initial outcomes are truly exciting, and our hope is that further research will establish that AU-011 can be a real game changer as an effective and vision-sparing treatment for small-medium choroidal melanoma,” said Dr. Shields, a study investigator, director, Oncology Service, Wills Eye Hospital, and professor of ophthalmology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia.

How it works

AU-011 is a light-activated viral nanoparticle conjugate (VNC) that is injected into the vitreous. The VNCs bind to heparin sulfate proteoglycans that encompass and encase melanoma cells, and contain a chromophore that allows for light-activation of the drug by radiation with a 689-nm ophthalmic laser.

The activated drug disrupts the melanoma cell membrane, causing immediate cell incompetence and necrosis. It is believed that by causing cell lysis, the treatment will also act to stimulate an immune system response that will prevent or minimize metastatic spread.

The phase Ib/II study has been under way at eight centers throughout the United States, but more sites in this country and in Europe are expected to be added as the study proceeds in investigating ascending doses and repeat administration.

Eligible patients are 18 years and older whose tumor is between 2.0 and 3.4 mm in thickness and <16 mm at the base.

In addition, the tumor must have shown either documented growth or there must be subretinal fluid on OCT plus one of the following findings: orange pigment, vision loss, or flashes/floaters.

Results of a preclinical dose-response study conducted in rabbits identified 50 mcg as the effective dose of AU-011, but because safety is the primary objective of the phase Ib/II clinical trial, dosing was initiated at a lower dose of 20 μg.

So far, six patients have been treated-three with AU-011 20 μg and three with AU-011 40 μg. All six patients completed follow-up to three months and two were seen at 6 months after receiving a single injection.

There were no serious adverse events, and BCVA in all patients was preserved within 5 letters of the pretreatment level. Intraocular inflammation was the most common safety finding, but it is being looked at as a potentially favorable sign of an immune response.

“The inflammatory response in one patient that we treated lead to keratitic precipitates in the anterior chamber, but I was somewhat pleased to see this because it could be a sign of immune system stimulation,” Dr. Shields said.

Inflammation in all cases was managed with local and/or systemic corticosteroids.

Although the 20 μg and 40 μg injections are considered subtherapeutic doses of AU-011, there were some potential signs of biological activity, which included changes in tumor color and edema, loss of melanin, and reduction in macular subretinal fluid. One patient showed tumor progression and required plaque radiotherapy. 

Dr. Shields is a consultant to Aura Biosciences.