Phase I Study of Vorinostat and Temsirolimus in Newly Diagnosed or Progressive Diffuse Intrinsic Pontine Glioma.

Leena M Ketonen, Arnold Paulino, Soumen Khatua, Wafik Zaky, Joya Chandra, Muhammad Usman Baig, Lea M Stitzlein, Suzanne McGovern

Journal: Pediatric blood & cancer 2025;72(5):e31619

PMID: 40000388

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Abstract

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Key molecular features include histone H3 mutation (K27M) and AKT pathway dysregulation. There is currently no curative treatment.

METHODS

This is a Phase I study of vorinostat and temsirolimus in newly diagnosed (Stratum 1) and progressive (Stratum 2) DIPG (NCT02420613). The primary aims are to determine the safety, maximum tolerated dose (MTD), and toxicities. A modified 3 + 3 design was used to establish the MTD, where the first three patients were assigned the first dose level regardless of stratum. Stratum 1 received radiotherapy with vorinostat, followed by up to 10 cycles of vorinostat and temsirolimus. Stratum 2 received up to 12 cycles of vorinostat and temsirolimus. Vorinostat was administered at a fixed dose of 230 mg/m daily on Days 1-8, and temsirolimus was administered on Days 1 and 8 at 25 mg/m (Dose level 1) or 35 mg/m (Dose level 2).

RESULTS

Six patients were enrolled, three in each stratum. No dose-limiting toxicity was observed, and most adverse effects were limited to Grades 1 or 2, including fatigue, myelosuppression, hyperlipidemia, hyperglycemia, elevated creatinine, nausea, vomiting, and headache. One patient experienced Grade 3 leukopenia. In the study, the MTD with acceptable toxicity was vorinostat 230 mg/m and temsirolimus 35 mg/m.

CONCLUSIONS

Overall, the combination of temsirolimus and vorinostat is well-tolerated and safe, prompting the need for larger studies to investigate its efficacy.

Address: Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA.; Department of Pediatrics, Loma Linda University, Loma Linda, California, USA.; Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas, USA.; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Radiation Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Neuroradiology Department, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.; Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

DOI: 10.1002/pbc.31619

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MeSH Terms: Humans, Vorinostat, Brain Stem Neoplasms, Diffuse Intrinsic Pontine Glioma, Male, Female, Antineoplastic Combined Chemotherapy Protocols, Child, Maximum Tolerated Dose, Sirolimus, Child, Preschool, Adolescent, Follow-Up Studies