EPCT-05. 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: 2022
Type: conference-abstract
Abstract: BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.
Source: Neuro-Oncology
Authors: Margot A Lazow, Patricia Baxter, Joseph Stanek, Adam Lane, Diana P Rodriguez, Shiva Senthil Kumar, James L Leach, Leonie Mikael, Christine Fuller, Daniel R Boué, Christopher R Pierson, Diana Thomas, John Breneman, Joshua Palmer, Xiao-Nan Li, Ralph Salloum, David Ashley, Peter de Blank, Eugene Hwang, Sarah E S Leary, Ashley Plant, Dorothy Crabtree, Mona Wahba, Marla Weetall, John Baird, Jeffrey Leonard, Clinton F Stewart, Elaine Mardis, Maryam Fouladi, Rachid Drissi
Institutions: Nationwide Children's Hospital, The Ohio State University, Texas Children's Hospital, Cincinnati Children's Hospital Medical Center, University of Cincinnati, SUNY Upstate Medical University, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Lurie Children's Hospital, Duke Children's Hospital & Health Center, Children's National, Seattle 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: W4281790606