Tebentafusp plus liver-directed therapy for metastatic uveal melanoma

A Phase I/II Study of Tebentafusp-tebn in Combination With Liver-Directed Therapies for the Treatment of Metastatic Uveal Melanoma

This trial tests whether combining tebentafusp with liver-directed treatments helps HLA-A*02:01-positive adults with metastatic uveal melanoma keep their liver tumors from growing.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 109 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Thomas Jefferson University (other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation
• Locations: 1 site (Philadelphia, Pennsylvania)
• Trial ID: NCT06626516 on ClinicalTrials.gov

What this trial studies

This multicenter, open-label phase I/II trial enrolls HLA-A*02:01-positive adults with metastatic uveal melanoma to test tebentafusp combined with liver-directed therapies. Part 1A is a single-arm safety and preliminary efficacy cohort (about 18 patients) using an induction course of tebentafusp followed by hepatic isolated embolization (IE) with GM-CSF and a safety lead-in for the first six patients. If safety and signals of activity are observed, Part 1B will randomize about 52 patients 2:1 to tebentafusp plus IE versus tebentafusp alone with progression-free survival as the primary endpoint. A separate Part 2 will test tebentafusp plus transarterial chemoembolization (TACE) in patients with bulkier liver disease, with tebentafusp given on a weekly schedule outside of the LDT procedure weeks.

Who should consider this trial

Good fit: Adults who are HLA-A*02:01-positive with metastatic uveal melanoma, at least one measurable liver metastasis, and who meet the trial's liver-burden criteria (low-to-moderate for Part 1 or bulky for Part 2) and have not previously received tebentafusp are the intended participants.

Not a fit: Patients who are HLA-A*02:01-negative, have contraindications to liver-directed procedures, or who do not meet the tumor-size or liver-burden eligibility criteria may not benefit from this protocol.

Why it matters

Potential benefit: If successful, the combination could improve liver-specific progression-free survival and better control liver metastases than tebentafusp alone.

How similar studies have performed: Single-agent tebentafusp has shown an overall survival benefit in HLA-A*02:01 metastatic uveal melanoma, but combining tebentafusp with liver-directed therapies is a newer strategy with limited prior data.

Eligibility criteria

Inclusion Criteria

1\. Age ≥18 years of age 2. Histologically or cytologically confirmed metastatic uveal melanoma in the liver. Patients must have at least one measurable liver metastasis that is ≥ 10 mm in longest diameter by CT scan or MRI. Extra-hepatic disease is allowed. 3. Tumor Size Criteria: i. Part 1: Total volume of tumor must be \< 50% of the liver involvement by CT or MRI; M1a or M1b disease with largest tumor ≤ 5 cm ii. Part 2: M1b disease with largest tumor \> 5 cm, M1c disease, or ≥ 50% liver involvement by CT or MRI 4. No prior systemic treatment with tebentafusp-tebn 5. Prior therapy: i. Part 1: Patients must be treatment naïve in the metastatic setting.

1. Prior surgery or ablation for oligometastatic disease is allowable.
2. Palliative radiation of non-target lesions also allowable. ii. Part 2: Patients may have had prior systemic therapy with chemotherapy, immunotherapy, or targeted therapy. They can also have had prior liver directed therapy including surgery, ablation, immunoembolization, or radioembolization. However cannot have had more than two prior lines of treatment total.

6\. HLA-A\*0201 positive 7. ECOG performance status or 0 or 1 at the time of screening 8. Life expectancy of greater than 3 months as assessed by the investigator 9. Patients must have normal organ and bone marrow function as defined below:

1. Platelet count ≥ 100,000/mm³
2. Hemoglobin \> 8.0g/dL
3. ANC ≥ 1500
4. AST and/or ALT \< 3x upper limited of normal (ULN)
5. Total bilirubin ≤ 2.0 mg/ml
6. Note: Patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator.
7. PT/PTT \< 1.5x ULN
8. Creatinine clearance \> 60mL/min
9. Potassium, magnesium, corrected calcium, and phosphate within normal laboratory parameters 10. Women must not be pregnant or breast-feeding. 11. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for the 6 months after the final dose of the study drug. Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

   12\. Male patients treated or enrolled on this protocol must be surgically sterile or use double barrier contraception methods from enrollment through treatment, and for 6 months after completion of study therapy.

   13\. Ability to understand and the willingness to sign a written informed consent document.

4.1.2 Exclusion Criteria

1. Parts 1 and 2:

   1. Failure to meet any of the criteria set forth in the Inclusion criteria section
   2. History of prior tebentafusp-tebn use
   3. Prior chemoembolization in Part 2 is not permitted
   4. History of severe immediate or delayed hypersensitivity reaction to biologic drugs, monoclonal antibodies, iodinated contrast agent
   5. Presence of symptomatic liver failure including ascites and hepatic encephalopathy
   6. Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require corticosteroids within 21 days prior to initiation of study therapy. Patients with brain metastases may be eligible if lesions have been treated with local therapy and there is no evidence of CNS disease progression for at least 4 weeks as measured by MRI prior to first dose of study drug
   7. History of another malignancy except for: 1) those who have been disease-free for 3 years prior to study treatment; 2) patients with a history of completely resected non-melanoma skin cancer; 3) patients with indolent secondary malignancies not requiring active therapy; 4) patients with completely resected carcinoma in situ. Consult the study Principal Investigator if unsure whether second malignancies meet the requirements specified above.
   8. 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)
   9. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass
   10. No outstanding toxicities from prior therapies greater than Grade 1. Except for prior immune related side effects such as endocrinopathy that are managed with a stable dose of thyroid or steroid supplement.
   11. Use of any investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study therapy and during the study.
   12. Use of hematopoietic colony-stimulating growth factors (eg. G-CSF, GMCSF, M-CSF) within 14 days prior to study treatment initiation. An erythroid-stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is not red blood cell transfusion dependent.
   13. Known history of human immunodeficiency virus infection (HIV). Testing for HIV is not necessary unless clinically indicated
   14. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing for HBV or HCV status is not necessary unless clinically indicated or if the patient has a history of HBV or HCV infection.
   15. Patients receiving systemic steroid therapy or any immunosuppressive medication. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable.
   16. History of bleeding diathesis
   17. Pregnant, likely to become pregnant, or breastfeeding women
   18. Uncontrolled concurrent illness, evaluated at investigator discretion
   19. Biliary obstruction, biliary stent or prior biliary surgery except cholecystectomy, or any anatomic abnormalities that would interfere with immunoembolization or chemoembolization:
   20. Patients with occlusion of the main portal vein
   21. Inadequate collateral flow around an occluded portal vein as determined by angiography
   22. Arteriovenous shunt identified on arteriography of the hepatic artery
   23. Any medical condition that, in the Investigator's judgement, would prevent patient participation in the clinical study due to safety concerns, compliance with study procedures or interpretation of study results
2. Part 1 Only:

   1. History of severe immediate or delayed hypersensitivity reaction to GM-CSF

Where this trial is running

Philadelphia, Pennsylvania

• Thomas Jefferson University — Philadelphia, Pennsylvania, United States (RECRUITING)

Study contacts

• Principal investigator: Rino Seedor, MD — Thomas Jefferson University
• Study coordinator: Rino Seedor, MD

Conditions: Metastatic Uveal Melanoma, Uveal, uveal melanoma, metastatic uveal melanoma, melanoma, Liver-directed therapy, Liver-directed, Liver