Tebentafusp-tebn With LDT in Metastatic UM
- Conditions
- Metastatic Uveal Melanoma
- Interventions
- Registration Number
- NCT06626516
- Lead Sponsor
- Thomas Jefferson University
- 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.
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 109
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1A: Safety Lead-in Tebentafusp-Tebn 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 Part 1A: Safety Lead-in GM-CSF (Sargramostim) 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 Part 1B: Combination Tebentafusp-Tebn 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. Part 1B: Combination GM-CSF (Sargramostim) 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. Part 1B: Tebentafusp-tebn alone Tebentafusp-Tebn 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. Part 2: Efficacy of Combo Tebentafusp-Tebn To assess the efficacy of tebentafusp-tebn in sequence with TACE in HLA-A\*0201-positive patients with metastatic uveal melanoma to the liver Part 2: Efficacy of Combo BCNU To assess the efficacy of tebentafusp-tebn in sequence with TACE in HLA-A\*0201-positive patients with metastatic uveal melanoma to the liver
- Primary Outcome Measures
Name Time Method Part 1B: Progression-free Survival From when patient joins study until disease progression or death, up to 2.5 years after last patient's last treatment. 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).
Part 1A: Safety lead-in 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. 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.
Part 1A: Efficacy From when the patient receives the first study treatment to 6 months after first treatment 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).
Part 2: 6-month progression-free survival rate From when the patient receives the first study treatment to 6 months after first treatment. 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.
- Secondary Outcome Measures
Name Time Method 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) Measured from the start of the treatment to death due to any cause. Date and cause of death will be recorded. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. The cause of death will be categorized as either cancer-related or cancer-unrelated.
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. 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.
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. 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.
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 Count and percentage of patients with a tumor response (Complete Response/Partial Response)
Trial Locations
- Locations (1)
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University🇺🇸Philadelphia, Pennsylvania, United StatesRino Seedor, MDPrincipal InvestigatorCarolyn PalumboContact215-955-8874carolyn.palumbo@jefferson.eduMarlana Orloff, MDSub Investigator