Evaluation of Tebentafusp as Neoadjuvant Therapy in Patients with Metastatic Uveal Melanoma with Resectable Liver Metastasis

Trial ID: 2023-509076-42-00
Protocol: GEM 2302
Sponsor: Grupo Espanol Multidisciplinar De Melanoma

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Diseases & Conditions

Uveal melanoma

Objectives

The primary objective of this study is to evaluate the capacity of **tebentafusp** used as a single agent to generate pathological complete responses (pCR) in patients with metastatic uveal melanoma with resectable liver metastasis and absence of extrahepatic disease. This is clinically relevant as achieving pCR can be indicative of a favorable prognosis and potential long-term survival benefits in this patient population.

Secondary objectives include:

Assessing the efficacy and safety of tebentafusp used as a single agent to maintain disease control and delay relapse/progression.
Exploring mechanisms of resistance to tebentafusp.
Studying the correlation between pathological response and circulating tumor DNA (ctDNA) dynamics or circulating tumor cells (CTCs).
Evaluating dynamics in T-cell receptor (TCR) populations and peripheral lymphocytes memory cells in blood samples before/after tebentafusp and in prospective fresh samples from liver resections.

Participants

The clinical trial involves participants diagnosed with **metastatic uveal melanoma** with resectable liver metastasis and no extra-liver disease. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate organ function and no prior systemic therapy in the metastatic or advanced setting. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria require histologically confirmed metastatic uveal melanoma with Human leukocyte antigen-A*0201 positivity and resectable liver metastases. Lifestyle factors such as diet and physical activity are not specified as considerations for this trial.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **tebentafusp** as a single agent in generating pathological complete responses in patients with metastatic uveal melanoma with resectable liver metastasis and absence of extrahepatic disease. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on August 1, 2025, and conclude by June 30, 2028. The primary endpoint is the pathological complete response rate, assessed by biopsy or surgical resection at approximately seven months after the initiation of treatment. Secondary endpoints include objective response rate, disease control rate, relapse-free survival, event-free survival, overall survival, and safety assessments such as adverse events and treatment-related adverse events.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed metastatic uveal melanoma, Human leukocyte antigen-A*0201 positivity, and adequate organ function. Following the screening, participants will receive the investigational product, **KIMMTRAK**, administered as a solution for infusion. Follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted according to RECIST 1.1 criteria. The end-of-study visit will occur after the final treatment cycle or upon early termination.

The expected duration of participant involvement is up to 72 weeks, depending on individual response and treatment tolerability. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on clinical judgment. The trial will also explore molecular biomarkers and immune response through liver biopsies and blood samples, providing insights into the correlation between circulating tumor DNA levels and clinical outcomes.

Treatment

The clinical trial involves the administration of **KIMMTRAK**, a pharmaceutical product containing the active substance **tebentafusp**. KIMMTRAK is formulated as a **concentrate for solution for infusion** and is provided in a dosage of 100 micrograms per 0.5 mL. The medication is administered via **intravenous infusion**. The maximum daily dose is 68 micrograms, with a total treatment period not exceeding 72 weeks. The product is classified as an orphan drug and is not a pediatric formulation. The active substance, tebentafusp, is a protein of other origin, specifically designed for the treatment of metastatic uveal melanoma.

In this study, tebentafusp is used as a single agent to evaluate its efficacy in generating pathological complete responses in patients with metastatic uveal melanoma, particularly those with resectable liver metastasis and no extrahepatic disease. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy

Efficacy in the clinical trial titled "Neoadjuvant Tebentafusp in Patients with Metastatic Uveal Melanoma" will be assessed using several endpoints. The primary endpoint is the **pathological complete response (pCR)** rate, defined as the absence of residual disease assessed by biopsy or surgical resection at 7 months (± 1 month) after the initiation of treatment with tebentafusp. Patients achieving complete response (CR) according to RECIST after 6 months, who do not proceed to the surgery phase and continue treatment, will also be considered as achieving pCR.

Secondary efficacy endpoints include the objective response rate (ORR), disease control rate (DCR), relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS), all evaluated according to RECIST 1.1 criteria. Exploratory endpoints involve the assessment of molecular biomarkers from liver biopsies at baseline and fresh samples from liver resections, as well as peripheral blood samples. Additionally, the trial will explore the central assessment of TCR populations and peripheral lymphocyte memory cells in blood samples before and after tebentafusp treatment, and the correlation between circulating tumor DNA (ctDNA) levels and the presence of circulating tumor cells (CTCs) in blood samples at various time points with clinical efficacy and safety outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patients must have histologically confirmed metastatic uveal melanoma with Human leukocyte antigen-A*0201 positive determined by local assay.
Patients with histologically proven metastatic uveal melanoma in the liver with resectable or potentially resectable liver metastases evaluated by imaging in a multidisciplinary committee. Metastasis can be considered resectable by any of the following: a. Minor resection (i.e., less than a hemihepatectomy) b. Major resection (i.e., hemihepatectomy or extended hepatectomy) c. Bilobar resection (including atypical resection).
Must meet the following criteria related to prior treatment: No prior sistemic therapy in the metastasic or advanced setting including chemotherapy, inmunotherapy, or targeted therapy; No prior local, liver-directed therapy inlcuding chemotherapy, radiotherapy, radiofrecuency ablation (RFA), or embolization; Prior neoadjuvant therapy is allowed provided it was administered in the curative setting in patients with localized disease
Institucional Review Board (IRB) / Independent Ethics Committee (IEC) approved written and signed informed consent.
Male or female patients age ≥ 18 years of age at the time of informed consent
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 0-1 (Appendix 4)
Adequate organ function as defined below (without transfusion): a. Hemoglobin ≥ 9.0g/dL. b. Absolute neutrophil count (ANC) >1.5 x10⁹/L(>1500 per mm³). c. Platelet count ≥ 100 x10⁹/L (>75000 per mm³). d. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with the Coordinating Investigator. e. Both AST and ALT must be <5 x ULN. f. Creatinine clearance ≥ 50 ml/min calculated be Cockcroft-Gault (Table 4) or another validated method. g. Potassium, magnessium, corrected calcium or phosphate abnormality of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) > grade 1.

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Exclusion Criteria

Presence of extrahepatic disease
History of severe hypersensitibity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies.
Clinically significant cardiac disease or impaired cardiac function, including any of the following: a. Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association ≥ 2), uncontrolled hypertension, or clinically significant arrhythmia currently requiring medical treatment. b. QTcF > 470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome. c. Acute myocardial infarction or unstable angina pectoris < 6 months prior to Screening.
History of adrenal insuffiency
History of intersticial lung disease
History of pneumonitis that required corticosteroid treatment or current pneumonitis
History of colitis or inflammatory bowel disease
Patients whose circumstances will not permit study completion or adequate follow up.
Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)
Women of child-bearing potential who are sexually active with a non-sterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment, and must agree to continue using such precautions for 1 week after the final dose of investigational product. Highly effective methods of contraception are described in Appendix 5.
Male patients must be surgically sterile or use double barrier contraception methods from enrollment through tratment and for 1 week following administration of the last dose of study drug.
Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug.
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated.
Previous treatment with Tebentafusp
Patients receiving systemic steroid therapy or any other immunosuppressive medication at any dose level. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable.
Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary).
Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF, M-CSF) ≤ 2 week prior to the star of study drug. Patients must have completed therapy with hematopoietic colony-stimulating factor at least 2 weeks before the first dose of study drug is given. An erythoid-stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the pacient is not red blood cel transfusion dependent.
Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status is not necessary unless clinically indicated or if required by local regulations.
Patients with concomitant maligancy other than non-melanoma skin cancer, or superficial bladder cancer controlled with local treatment. Patients with prior malignancy must have been disease free for 5 years.
Hypersensitivity to the active substance of tebentafusp or to any of its excipients, including: Citric acid monohydrate (E330) Di-sodium hydrogen phosphate (E339) Mannitol (E421) Trehalose Polysorbate 20 (E432).