Dipg-54. Updated Findings From the Phase Ib Study of Unesbulin (ptc596) in Children With Newly-diagnosed Diffuse Intrinsic Pontine Glioma (dipg) and High-grade Glioma (hgg): a Report From the Collaborative Network for Neuro-oncology Clinical Trials (connect)
Year: 2023
Type: article
Abstract: BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.
Source: Neuro-Oncology
Authors: Margot Lazow, Patricia Baxter, Joseph Stanek, Diana Rodriguez, Shiva Senthil Kumar, Joshua Palmer, James Leach, Leonie Mikael, Diana Thomas, Christine Fuller, Daniel Boué, Christopher Pierson, John Breneman, Xiao-Nan Li, Ralph Salloum, David Ashley, Peter de Blank, Eugene Hwang, Sarah Leary, Ashley Plant, Michael Fisher, Susan Chi, Dorothy Crabtree, Mythili Murali, Marla Weetall, Mark Rance, Pius Maliakal, John Baird, Dhiren D’Silva, Kylie O’Keefe, Jeffrey Leonard, Clinton Stewart, Elaine Mardis, Maryam Fouladi, Rachid Drissi
Institutions: Nationwide Children's Hospital, Texas Children's Hospital, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Cincinnati Children's Hospital Medical Center, SUNY Upstate Medical University, University of Cincinnati, Lurie Children's Hospital, Duke Children's Hospital & Health Center, Children's National, Seattle Children's Hospital, Children's Hospital of Philadelphia, Boston Children's Hospital, PTC Therapeutics (United States), St. Jude Children's Research Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,612
OpenAlex ID: W4380356576