NCT06626516

Tebentafusp-tebn With LDT in Metastatic UM

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

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 109 (estimated)
• Sponsor: Thomas Jefferson University · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Detailed description

PART 1: TEBENTAFUSP AND IE Part 1A, Phase I/II: This is a single-arm study of 18 patients treated with combination therapy (tebentafusp-tebn with hepatic IE with GM-CSF), with the first cohort of six patients being enrolled in a safety lead in. The SKCC DSMC will monitor and approve the cohort expansion, please refer to section 3.2 for further details. The preliminary clinical efficacy endpoint is defined as a target 6-month liver-specific PFS rate of 60%. 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 cycles, with tebentafusp administered alone on weeks 2-4 of subsequent cycles. Part 1B, Phase II: If the safety and preliminary efficacy in Part 1A are met, the study 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. Secondary endpoints will include ORR, duration of response, systemic PFS, and OS. Patients randomized to tebentafusp-tebn + IE arm will be treated as above (See Figure 1). Patients randomized to tebentafusp-tebn alone will receive weekly treatment using the approved step-up dosing regimen. Tumor biopsies will be optional for all patients on this portion of the study; however, peripheral blood and ctDNA will be collected as above. PART 2: TEBENTAFUSP AND TACE The trial will conduct a single-arm, two-stage phase II trial of sequential TACE with BCNU followed by tebentafusp-tebn in 39 patients with higher liver tumor burden (greatest tumor size \>5 cm and/or ≥50% liver involvement on imaging). Patients with unilobar disease will first receive at least two treatments of TACE with 300mg BCNU (Cycles 1-2, See Figure 2A); patients with bilobar disease will receive at least 4 treatments (Cycles 1-4, See Figure 2B). Following completion of the TACE course, patients will receive tebentafusp-tebn on a weekly basis at the approved step-up dosing regimen. Patients will undergo imaging studies at baseline, after completion of every two TACE treatments, and every 8 weeks thereafter while on tebentafusp-tebn alone. Tumor biopsies will be performed at baseline, following TACE, and after 4 weeks of treatment with tebentafusp-tebn. Peripheral blood will be collected for serum cytokine and PBMC analysis after completion of each TACE treatment and every 4 weeks thereafter. ctDNA will be collected at the time of each interval scan. Correlative studies will be performed as above in Part 1. Following the initial TACE treatments and subsequent tebentafusp induction, patients may receive additional TACE treatments at the discretion of the investigator. These will only be offered once a patient is through tebentafusp induction and has transitioned outpatient. Patients who proceed with additional TACE will hold tebentafusp the week of treatment and be followed with weekly labs to ensure return to baseline before proceeding with next scheduled tebentafusp at the discretion of the investigator. Participants will continue treatment until confirmed disease progression, or for as long as the patient is deriving clinical benefit in the opinion of the treating investigator with approval of the study PI. The treating investigator may provide rationale and request approval for treatment beyond progression via email to the Study PI.

Conditions

• Metastatic Uveal Melanoma

Interventions

Type	Name	Description
DRUG	Tebentafusp-Tebn	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.
DRUG	GM-CSF (Sargramostim)	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.
DRUG	BCNU	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

Timeline

• Start date: 2025-10-15
• Primary completion: 2030-10-01
• Completion: 2032-08-01
• First posted: 2024-10-04
• Last updated: 2025-11-28

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study