Tebentafusp-tebn With LDT in Metastatic UM

NCT06626516 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 2024-3117JT 31444
• Study Type: interventional
• Target: 109
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a multicenter, open label phase I/ II trial to assess the safety and clinical efficacy of tebentafusp-tebn in combination with liver-directed therapies in HLA-A\*0201 positive patients with metastatic uveal melanoma. In Part 1 of the study, the Prinicipal Investigator will investigate the safety and efficacy of tebentafusp-tebn in combination with hepatic IE in patients with a low to moderate hepatic disease burden. In Part 2, the study will investigate the efficacy of tebentafusp-tebn in combination with TACE in patients with bulky hepatic disease.

Conditions

Metastatic Uveal Melanoma

Keywords

Uveal; uveal melanoma; metastatic uveal melanoma; melanoma; Liver-directed therapy; Liver-directed; Liver; liver-directed therapies; MUM; LDT

Outcome Measures

Primary Outcomes (4)

• Part 1A: Safety lead-in

  Adverse events (AEs) according to NCI CTCAE Version 5.0. Safety and tolerability data will be presented by treatment arm using the safety population. Safety data will be summarized descriptively and will not be formally analyzed. AE presentation will include incidence, severity, and relationship to study drug.

  From when the patient receives the first study treatment to 7 days (for non-serious AEs) or 30 days (for SAEs) after completion of study treatment or withdrawal from the study.

• Part 1A: Efficacy

  6-month progression-free survival rate as determined by response criteria (RECIST 1.1). Will be summarized by count and percentage along with the two-sided 90% exact confidence interval (CI).

  From when the patient receives the first study treatment to 6 months after first treatment

• Part 1B: Progression-free Survival

  Defined as the time from the date of randomization until the date of objective disease progression or death by any cause. The primary Progression-free Survival (PSF) analysis will use a one-sided log-rank test, with a type I error of 0.05. In addition, PFS will be analyzed using Cox proportional hazards model and the estimated HR with 90% Confidence Interval (CI) will be reported. Kaplan-Meier curves of PFS will be presented by treatment arm along with estimated medians PFS (CIs).

  From when patient joins study until disease progression or death, up to 2.5 years after last patient's last treatment.

• Part 2: 6-month progression-free survival rate

  As determined by response criteria (RECIST 1.1). Defined as the proportion of patients alive and progression-free at 6 months after treatment initiation. Will be summarized by count and percentage. In addition, a two-sided 90% Confidence Interval (CI) based on the method of Koyama and Chen will be provided. This method is appropriate because it is proposed for Simon's 2-stage design, accounting for the inherent futility analysis.

  From when the patient receives the first study treatment to 6 months after first treatment.

Secondary Outcomes (4)

• All toxicities using the NCI CTCAE Version 5.0

  From when the patient receives the first study treatment to 7 days (for non-serious AEs) or 30 days (for SAEs) after completion of study treatment or withdrawal from the study.

• Overall response rate (ORR)

  From when the patient receives the first study treatment to at least one year (and up to 2.5 years) after discontinuing treatment

• Liver-specific progression-free survival

  From when patient joins study until disease progression or death, up to 2.5 years after last patient's last treatment.

• Overall survival

  From the start of the treatment to death due to any cause (assessed up to 2.5 years after last patient's last treatment)

Study Arms (4)

Part 1A: Safety Lead-in

EXPERIMENTAL

Phase I safety lead-in followed by a phase II trial with 6-month PFS rate as the preliminary efficacy endpoint. All patients will receive a 4-week induction course of tebentafusp-tebn alone (Cycle 1) using the approved step-up dosing regimen. Should the 4th dose be tolerated well as an outpatient, patients will receive their first IE treatment on Cycle 2 week 1 followed by continued weekly tebentafusp-tebn on weeks 2, 3, and 4 of Cycle 2 (See Figure 1). Patients will not receive tebentafusp-tebn concurrently with their first IE treatment during Week 1 of Cycle 2. Should Cycle 2 be well tolerated, patients may receive both tebentafusp-tebn and IE on Week 1 of subsequent

Drug: Tebentafusp-Tebn; Drug: GM-CSF (Sargramostim)

Part 1B: Combination

ACTIVE COMPARATOR

If the safety and preliminary efficacy in Part 1A are met, we will then proceed with a randomized phase II trial. 52 patients will be randomized in a 2:1 ratio to receive tebentafusp-tebn in combination with hepatic IE or tebentafusp-tebn alone, with PFS as the primary endpoint. Patients randomized to tebentafusp-tebn + IE arm will be treated as Part 1A.

Drug: Tebentafusp-Tebn; Drug: GM-CSF (Sargramostim)

Part 1B: Tebentafusp-tebn alone

ACTIVE COMPARATOR

If the safety and preliminary efficacy in Part 1A are met, we will then proceed with a randomized phase II trial. 52 patients will be randomized in a 2:1 ratio to receive tebentafusp-tebn in combination with hepatic IE or tebentafusp-tebn alone, with PFS as the primary endpoint. Patients randomized to tebentafusp-tebn alone will receive weekly treatment using the approved step-up dosing regimen.

Drug: Tebentafusp-Tebn

Part 2: Efficacy of Combo

ACTIVE COMPARATOR

To assess the efficacy of tebentafusp-tebn in sequence with TACE in HLA-A\*0201-positive patients with metastatic uveal melanoma to the liver

Drug: Tebentafusp-Tebn; Drug: BCNU

Interventions

Tebentafusp-Tebn DRUG

Dosing: All patients enrolled in this study will receive treatment with tebentafusp-tebn based on the approved step-up dosing regimen of 20 mcg on C1D1, 30 mcg on C1D8, then 68 mcg weekly beginning on C1D15 and thereafter. This escalated dose administered at C1D15 will be the dose used for the remainder of the treatment period unless dose reduction is implemented for toxicity. Beginning with C1D8, tebentafusp-tebn will be administered on the scheduled day (± 2 days), and consecutive infusions of tebentafusp-tebn must be administered at least 5 days apart.

Also known as: kimmtrak, IMCgp100

Part 1A: Safety Lead-in; Part 1B: Combination; Part 1B: Tebentafusp-tebn alone; Part 2: Efficacy of Combo

GM-CSF (Sargramostim) DRUG

Recombinant human GM-CSF (Sargramostim, Leukine®, Sanofi US) 1,500mg will be mixed with ethiodized oil (Ethiodol®). The GM-CSF/ethiodized oil mixture will be injected selectively into one of the hepatic lobes, followed by infusion of gelatin sponge particles to achieve the stasis of blood flow. This will repeat every 4 weeks.

Also known as: yeast-derived recombinant human GM-CSF, Leukine, Hepatic Immunoembolization, GM-CSF, Sargramostim

Part 1A: Safety Lead-in; Part 1B: Combination

BCNU DRUG

Patients will be treated with hepatic artery infusion of 300mg BCNU (1,3-bis \[2-chloroethyl\]-1-nitrosourea, Carmustine) dissolved in ethiodized oil followed by embolization with gelatin sponge particles \[TACE with BCNU 300mg\]; every 4 weeks +/- 7 days in the case of either bilobar or unilobar metastasis

Also known as: Carmustine, BiCNU, bis-chloroethylnitrosourea, Hepatic Chemoembolization, 1,3-bis [2-chloroethyl]-1-nitrosourea

Part 2: Efficacy of Combo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. 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.
• Prior surgery or ablation for oligometastatic disease is allowable.
• 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.
• \. 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:
• Platelet count ≥ 100,000/mm³
• Hemoglobin \> 8.0g/dL
• ANC ≥ 1500
• AST and/or ALT \< 3x upper limited of normal (ULN)
• Total bilirubin ≤ 2.0 mg/ml
• 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.
• PT/PTT \< 1.5x ULN
• Creatinine clearance \> 60mL/min
• 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.
• \. 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.
• \. Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Parts 1 and 2:
• History of prior tebentafusp-tebn use
• Prior chemoembolization in Part 2 is not permitted
• History of severe immediate or delayed hypersensitivity reaction to biologic drugs, monoclonal antibodies, iodinated contrast agent
• Presence of symptomatic liver failure including ascites and hepatic encephalopathy
• 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
• 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.
• 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
• 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.
• 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.
• 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.
• Known history of human immunodeficiency virus infection (HIV). Testing for HIV is not necessary unless clinically indicated
• 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.
• Patients receiving systemic steroid therapy or any immunosuppressive medication. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable.
• History of bleeding diathesis

Sponsors & Collaborators

• Thomas Jefferson University: lead
• Sidney Kimmel Cancer Center at Thomas Jefferson University: collaborator

Study Sites (1)

Thomas Jefferson University

Philadelphia, Pennsylvania, 19107, United States

RECRUITING

MeSH Terms

Conditions

Uveal Melanoma; Melanoma

Interventions

Granulocyte-Macrophage Colony-Stimulating Factor; sargramostim; Carmustine

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Uveal Neoplasms; Eye Neoplasms; Neoplasms by Site; Eye Diseases; Uveal Diseases; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds

Study Officials

• Rino Seedor, MD

  Thomas Jefferson University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rino Seedor, MD

CONTACT

215-955-8874; rino.seedor@jefferson.edu

Carolyn Palumbo

CONTACT

215-955-8874; carolyn.palumbo@jefferson.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Part 1A: Single-arm combination therapy (tebentafusp-tebn with hepatic IE with GM-CSF), with the first cohort of six patients being enrolled in a safety lead in. Part 1B: If the safety and preliminary efficacy in Part 1A are met, we will then proceed with a randomized phase II trial. 52 patients will be randomized in a 2:1 ratio to receive tebentafusp-tebn in combination with hepatic IE or tebentafusp-tebn alone Part 2: Single-arm, two-stage phase II trial of sequential TACE with BCNU followed by tebentafusp-tebn in 39 patients with higher liver tumor burden

Study Record Dates

• First Submitted: September 19, 2024
• First Posted: October 4, 2024
• Study Start: October 15, 2025
• Primary Completion (Estimated): October 1, 2030
• Study Completion (Estimated): August 1, 2032
• Last Updated: November 28, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)