Clinical trial NCT05893654: Melphalan Chemoreduction for Ocular Melanoma
Official title: Melphalan Intra-arterial Chemotherapy for Choroidal Melanoma Chemoreduction - a Phase I Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Uveal Melanoma
Keywords: melanoma
uveal
chemotherapy
chemoreduction
melphalan
ruthenium
brachytherapy
Lead sponsor: Hospital das Clínicas de Ribeirão Preto
Sponsor class: OTHER
Collaborators: name: Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo
First posted: 2023-06-08
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to investigate a new approach for treating large uveal melanomas, a type of eye cancer. The study aims to determine the effectiveness of using intra-arterial melphalan, a chemotherapy drug, to reduce tumor thickness, allowing for subsequent radiation therapy using a Ru-106 plaque.

The main questions this trial seeks to answer are:

* Can intra-arterial melphalan effectively reduce the thickness of large uveal melanomas?
* Is the combination of intra-arterial melphalan and brachytherapy a safe and effective treatment option for these tumors?

Participants enrolled in the trial have clinically diagnosed choroidal melanoma with tumor thickness equal to or greater than 8.00 mm. They will undergo a procedure where the chemotherapy drug is injected directly into the blood vessels that supply the tumor. After a few weeks, they will receive the radiation treatment using a small device placed on the eye. Throughout the trial, participants will have different tests to monitor the tumor and their vision, such as ultrasound scans, pictures of the inside of the eye, and a test called electroretinography (ERG) to check the function of the retina. These tests will be done at the start of the trial and at 1, 3, and 6 months later to track the progress of the treatment.

Detailed description: INTRODUCTION Choroidal melanoma is the most common primary intraocular malignancy in adults, thus being the focus of extensive research. The primary treatment goals of this disease consist in controlling local disease, reducing the risk of distant metastases, and avoiding enucleation whenever possible.

Plaque brachytherapy is currently the standard treatment for small and medium-sized uveal melanomas. In clinical practice, ruthenium (Ru-106) or iodine (I-125) are the most commonly employed radioisotopes. Ruthenium is the most utilized radioisotope in Europe and South America due to its availability and good clinical outcomes. It is currently the only available option in Brazil's public health system (SUS). However, its use for large tumors (greater than 10 mm in thickness and/or 22 mm in diameter) is limited by the inability of delivering an adequate therapeutic dose of radiation without causing further damage to the surrounding retinal tissue.

For this reason, researchers in medical physics have been investigating new treatment options in the last decades, including external beam radiotherapy (EBRT), radiosurgery (gamma knife or linear accelerator), and proton beam therapy. Although gamma knife radiosurgery and proton beam therapy are effective treatments with reliable tumor control rates, they are associated with poor visual outcomes, inadequate globe retention, and their use is reportedly limited in public health systems of low- or middle-income countries. EBRT carries potential side effects related to a broader radiation field, with an increased risk for complications in ocular and periocular structures, such as eyelids, sclera, lens, and retina. Finally, enucleation is an effective management for very large tumors, but it is usually a last resource.

Considering the above-mentioned treatment limitations for large choroidal melanomas, our group explored an alternative approach using intra-arterial melphalan for tumor chemoreduction, aiming to reduce thickness and allow subsequent brachytherapy using a Ru-106 plaque.

Intra-arterial chemotherapy (IAC) with melphalan has been used to treat multiple cancers, including liver metastases from uveal and skin melanomas, but it has never been described as a primary tumor treatment. Previous studies have demonstrated a reasonable safety profile of the therapy when used for the treatment of other tumors.

This is a phase I clinical trial that assesses the safety profile of chemoreduction with intra-arterial melphalan, followed by ruthenium brachytherapy, performed in patients that would otherwise need enucleation due to tumor size.

METHODS Patients enrolled in the trial shall have clinically diagnosed choroidal melanoma with tumor thickness equal to or greater than 8.00 mm. IAC with 7.5 mg of melphalan will be performed through selective catheterization of the ophthalmic artery followed by Ru-106 plaque brachytherapy 4±1 weeks after the IAC. All patients will be followed up with baseline and subsequent B-scan ultrasonography, SD-OCT studies, color fundus pictures, infrared photographs, and electroretinograms (ERG).

Baseline and follow-up visits At baseline, patients will undergo a comprehensive ophthalmologic examination including ETDRS best-corrected visual acuity (BCVA), slit lamp biomicroscopy, indirect ophthalmoscopy, spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG) performed according to the recommendations of the International Society for Clinical Electrophysiology of Vision (ISCEV) standard,14 and ocular B-scan ultrasound.

OCT examinations will be performed using the Spectralis® HRA+OCT image system (Heidelberg Engineering, Germany). The OCT scan center will be determined at baseline based on patient fixation. In subsequent visits, the automatic follow-up from the Heidelberg machine will be used to scan the same region from the initial visit. Scans over the lesions located close to the posterior pole will also be performed.

Ocular ultrasound will be performed using the Accutome 4sight device in mode B, in the initial consultation, and in 1 month, 3 months, and 6 months after the intervention. The examination will take place with the patient in a seated position, in the most ergonomic and comfortable way as possible, respecting the individual characteristics of the participants.

After the initial assessment, confirmation of the signature of the informed consent, explanation about the procedure, and verbal consent, IAC will be performed in a surgical environment. The intraarterial injection of 7.5 mg of melphalan will be performed only once, in the ophthalmic artery corresponding to the eye affected by choroidal melanoma. Chemotherapy infusion will be performed directly into the ostium of the ophthalmic artery through a microcatheter guided by fluoroscopy via the femoral artery. The drug will be infused in a slow pulsatile manner for 30 minutes to avoid backflow of chemotherapy and arterial occlusion.

After 4±1 weeks, Ru-106 brachytherapy will be performed using a 24-mm notched plaque. Due to tumor thickness and previous IAC, the target dose to the tumor apex should be the closest possible to 80 Gy, respecting the safety limits regarding the risk of excessive dosage to the tumor base and scleral melting.

Eligibility criteria: Inclusion Criteria:

* Age equal to or higher than 18 years
* Diagnosis of choroidal melanoma with a thickness equal to or higher than 8 mm on ultrasound evaluation
* Comprehension and signature of the informed consent
* Adequate pupil dilation and sufficient cooperation to carry out the complementary exams

Exclusion Criteria:

* Choroidal melanomas with a greatest basal diameter higher than 18mm
* Any clinical condition that impairs fundus documentation or patient follow-up
* Medical or psychological conditions that prevent comprehension and signature of the informed consent
* Pregnancy, breastfeeding, or plans of getting pregnant in the next year
* Past medical history of allergic reactions or hypersensitivity to melphalan

Primary outcomes:
measure: Determination of treatment safety through electroretinography (ERG)
timeFrame: 6 months
Secondary outcomes:
measure: Reduction of Tumor Size
timeFrame: 6 months
measure: Best Corrected Visual Acuity (BCVA)
timeFrame: 6 months
measure: Signs of intraocular inflammation
timeFrame: 6 months
measure: Treatment-related adverse events
timeFrame: 6 months
measure: Globe salvage
timeFrame: 12 months
Other outcomes:
Locations:
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto - USP
state: SP
Study officials:
affiliation: Professor of Ophthalmology
name: Rodrigo Jorge, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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