Neoadjuvant Tebentafusp for Uveal Melanoma

This is an investigator-initiated, Phase II trial evaluating neoadjuvant treatment for locally advanced, unresectable primary uveal melanoma with Tebentafusp. Given the success of Tebentafusp in the metastatic setting, we are interested in utilizing Tebentafusp in the neoadjuvant setting. Limited clinical research data suggest that Tebentafusp might accumulate in primary uveal melanoma and result in regression of primary uveal melanoma. This clinical trial will explore this possibility for patients with large and unresectable primary uveal melanoma. Changes in primary UM after Tebentafusp treatment and eye toxicity related to treatment will be monitored with ophthalmologic ultrasound, Optical coherence tomography (OCT) and clinical examination. Primary eye tumor biopsy pre-Tebentafusp and post-Tebentafusp treatment will also be performed by fine-needle aspiration. Blood and aqueous humor circulating tumor-derived DNA will also be measured as a potential biomarker for response.

We will consider regression of the primary uveal melanoma by a 20% reduction in tumor volume a meaningful endpoint for this early phase clinical study. Reduction in volume by 20% could result in a proportion of patients who had planned enucleation prior to therapy to become suitable for plaque brachytherapy (exploratory endpoint).

The efficacy of this combination treatment will be assessed using the Simon's two stage design \[Optimal Design\]. The trial is carried out in two stages. In stage I, a total number of 8 patients will be accrued. If there are 0 responses (at least a 20% reduction in tumor volume) among these 8 patients, further enrollment of patients may be stopped. Otherwise, an additional 11 patients will be accrued in stage II, resulting in a total sample size of 19. If there are 2 or more responses among these 19 patients, we reject the null hypothesis and claim that the treatment is promising.

PRIMARY OBJECTIVE:

To assess the efficacy of neoadjuvant Tebentafusp in patients with large surgically unresectable (other than complete enucleation of the eye) primary uveal melanoma.

SECONDARY OBJECTIVES:

1. To assess the local (eye) and systemic toxicity with Tebentafusp treatment. 2. To investigate the usefulness of ctDNA as a biomarker for response.

EXPLORATORY OBJECTIVES:

1. To assess sight preservation. 2. To assess the change in radiation dose to the fovea.