Evaluation of Hepatic Radiotherapy Combined with Tebentafusp in HLA A*02:01 Positive Metastatic Uveal Melanoma Patients

Trial ID: 2024-519760-40-00
Protocol: TEBE-RT
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Trial statistics

science

test molecule

location_city

research site

public

country

medical_information

disease

person_search

investigator

Diseases & Conditions

Uveal melanoma

Objectives

The primary objective of this study is to **prolong progression-free survival (PFS)** in patients with **metastatic uveal melanoma HLA A*02:01 positive** by adding liver-directed therapy to tebentafusp. This is clinically relevant as it aims to delay disease progression, potentially improving patient outcomes and quality of life.

Secondary objectives include:

To increase the clinical benefit.
To prolong overall survival (OS).
To extend the time patients stay on treatment.
To delay the time to subsequent treatment initiation.
To investigate the markers of immune response and resistance during treatment.
To explore the ctDNA modifications during treatment and the correlation with the clinical efficacy of the combination treatment.
To evaluate the tolerability of combination treatment.

Participants

The clinical trial involves participants diagnosed with **metastatic uveal melanoma** who are HLA A*02:01 positive. The study population includes both male and female subjects aged 18 years and older, with a performance status of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. Participants must have histologically or cytologically confirmed metastatic uveal melanoma with liver metastases, including at least one measurable lesion, and the largest liver metastasis should not exceed 8 cm. The trial requires participants to have adequate bone marrow, renal, and liver functions. The total number of participants is not provided by the sponsor. The selection criteria ensure that participants are capable of complying with the study protocol and have provided written informed consent. Lifestyle considerations such as the use of contraception are relevant for both female and male subjects of childbearing potential. The trial does not include a vulnerable population.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of adding hepatic radiotherapy to the standard of care for patients with **metastatic uveal melanoma** who are HLA A*02:01 positive. The primary objective is to prolong progression-free survival (PFS) with the addition of liver-directed therapy to **tebentafusp**. This trial is a Phase IV, randomized, double-blind, controlled study, with an estimated duration from July 2025 to January 2028. Participants will be randomly assigned to receive either the investigational treatment or a control, with neither the participants nor the investigators aware of the group assignments to ensure unbiased results.

The study will commence with an inclusion visit, where participants will undergo screening to confirm eligibility based on criteria such as age, performance status, and the presence of liver metastases. Key inclusion criteria include a histologically or cytologically confirmed diagnosis of metastatic uveal melanoma HLA-A*02:01 positive, adequate organ function, and the ability to comply with the protocol. Exclusion criteria are not specified in the provided data. Following the inclusion visit, participants will receive the study treatment, with the maximum treatment period set at 30 days.

Participants will be required to attend regular follow-up visits to monitor their response to treatment and assess any adverse effects. These visits will include evaluations of disease control rate, objective response rate, overall survival, and safety. The primary endpoint, progression-free survival, will be calculated from the day of treatment initiation to the progression of the disease, with the PFS rate at 6 months being a key measure. Secondary endpoints include the analysis of circulating tumor DNA (ctDNA) and its correlation with PFS and overall survival.

The expected length of participant involvement is approximately 30 days for the treatment phase, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The study aims to provide valuable insights into the potential benefits of combining hepatic radiotherapy with **tebentafusp** in this patient population.

Treatment

The clinical trial involves the administration of **TEBENTAFUSP**, an experimental medication, for the treatment of HLA A*02:01 positive Metastatic Uveal Melanoma. **TEBENTAFUSP** is provided in the pharmaceutical form of a concentrate for solution for infusion. The active substance, **TEBENTAFUSP**, is classified as a protein of other origin. The medication is administered via **intravenous infusion**. The maximum daily dose is 68 micrograms, with a total maximum dose of 68 micrograms over a treatment period of up to 30 days. The trial does not involve a pediatric formulation of the drug.

In addition to the experimental treatment, participants may receive standard-of-care therapy, which includes antineoplastic agents. These agents are categorized as other antineoplastic agents and are used in conjunction with the experimental medication to potentially enhance therapeutic outcomes. The study aims to evaluate the efficacy of adding liver-directed therapy to **TEBENTAFUSP** in prolonging progression-free survival in the specified patient population. Compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. PFS will be calculated from the day of treatment initiation to the point of disease progression. The PFS rate at 6 months will be a key metric for evaluation. Secondary endpoints include the disease control rate at the first tumor assessment, objective response rate, overall survival, treatment duration, and time to subsequent treatment initiation. Additionally, the trial will assess safety, evaluate patients' circulating immune profiles, and analyze the inflammatory microenvironment of uveal melanoma, correlating these factors with PFS. The analysis of circulating tumor DNA (ctDNA) will also be conducted to explore correlations with PFS and overall survival.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

written informed consent
Age ≥18 years
Female and male
PS (ECOG) 0 or 1
Histologically or cytologically confirmed metastatic uveal melanoma HLA-A*02:01 positive
Presence of liver metastases, at least one measurable lesion (RECIST v 1.1), with largest liver metastasis ≤ 8 cm
Adequate bone marrow, renal and liver functions: absolute neutrophil count > 1.0 x 109/L; absolute lymphocyte count > 0.5 x 109/L; platelet count > 100 x 109/L;hemoglobin > 8 g/dl;serum creatinine < 1.5 x upper limit of normal (ULN) and/or creatinine clearance > 50 ml/min;total bilirubin < 1.5 x ULN (with the exception of patients with Gilbert Syndrome who will be excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN); alanine aminotransferase < 3.0 x ULN; aspartate aminotransferase < 3.0 x ULN
Woman of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drugs
Male subjects with female partners of childbearing potential must be willing to use adequate contraception as outlined in Section 8.3 – of the protocol, starting with the first dose of study therapy through at least 1 weeks after the last dose of treatment
Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 8.3, for the course of the study starting with the first dose of study therapy through at least 1 weeks after the last dose of treatment
Will and ability to comply with the protocol

cancel

Exclusion Criteria

Previous systemic therapy for metastatic uveal melanoma
other serious or uncontrolled medical disorder, active infection, physical exam or laboratory findings, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject’s ability to comply with the study requirements
Previous liver directed therapy
Largest liver metastasis > 8 cm
Symptomatic central nervous system metastases
Participants with clinically significant cardiac disease or impaired cardiac function, including any of the following: - Congestive heart failure (New York Heart Association Class ≥ 3). - Uncontrolled hypertension (consistent findings of systolic blood pressure > 160 mmHg or diastolic > 110 mmHg). - History of ventricular arrhythmia currently requiring medical treatment. - Uncontrolled atrial fibrillation. - Electrocardiogram (ECG) QT interval corrected > 470 msec during screening obtained on triplicate ECGs or known history of congenital prolonged QT syndrome. - Acute myocardial infarction or unstable angina pectoris ≤ 6 months prior to screening
Morning cortisol < lower limit of normal (unless the participant has asymptomatic adrenal insufficiency and is receiving stable replacement doses)
Participants with active autoimmune disease requiring immunosuppressive treatment, including inflammatory bowel disease (ulcerative colitis or Crohn’s disease), within2 years of screening. The following exceptions are permitted: - Vitiligo - Alopecia - Managed hypothyroidism (on stable replacement doses) - Asymptomatic adrenal insufficiency (on stable replacement doses) - Psoriasis - Resolved childhood asthma/atopy - Well-controlled asthma - Type I diabetes mellitus
Participants who received systemic treatment with steroids or any other immunosuppressive drug within 2 weeks of the planned first dose of study intervention. The following exceptions are permitted: - Treatment for well-controlled and asymptomatic adrenal insufficiency, but replacement dosing is limited to prednisone ≤ 12 mg daily or the equivalent. - Local steroid therapies (eg, optic, ophthalmic, intra-articular, or inhaled medications). - Premedication for allergy to contrast reagent. - Steroids for management of CNS metastases > 14 days prior to the planned first dose of study intervention. - To treat asthma or chronic obstructive pulmonary disease exacerbations > 14 days prior to the planned first dose of study intervention (only short-term oral or IV use in doses>12 mg/day prednisone equivalent). - For inhalation in the management of asthma or chronic obstructive pulmonary disease. - Any premedications required per protocol
Previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) or active malignancy requiring intervention
Hypersensitivity to the active substance or to any of the excipients