Carvajal, Richard D, Nathan, Paul, Sacco, Joseph J, Orloff, Marlana, Hernandez-Aya, Leonel F, Yang, Jessica, Luke, Jason J, Butler, Marcus O, Stanhope, Sarah, Collins, Laura et al (show 4 more authors)
(2022)
Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma.
Journal of Clinical Oncology, 40 (17).
1939-+.
ISSN 0732-183X, 1527-7755
Abstract
<jats:sec><jats:title>PURPOSE</jats:title><jats:p> This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM). </jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p> In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators. </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM. </jats:p></jats:sec>
Item Type: | Article |
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Uncontrolled Keywords: | Humans, Melanoma, Uveal Neoplasms, Neoplasms, Second Primary, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Immunoconjugates, HLA-A Antigens |
Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
Depositing User: | Symplectic Admin |
Date Deposited: | 07 Apr 2022 07:54 |
Last Modified: | 07 Dec 2024 22:15 |
DOI: | 10.1200/jco.21.01805 |
Open Access URL: | https://ascopubs.org/doi/10.1200/JCO.21.01805?url_... |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3152348 |