ArticleChild's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery2015
Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study.
Article in Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Medulloblastoma in children and adolescents: a systematic review of contemporary phase I and II clinical trials and biology update.Cancer medicine · 2017Pooled it
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- Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.Cell death & disease · 2024Review
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- Notch signaling pathway in cancer: from mechanistic insights to targeted therapies.Signal transduction and targeted therapy · 2024Review
- Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways.International journal of molecular sciences · 2024Review
- Cancer Stem Cells: Current Challenges and Future Perspectives.Methods in molecular biology (Clifton, N.J.) · 2024Review
- Review
- The Glioblastoma Landscape: Hallmarks of Disease, Therapeutic Resistance, and Treatment Opportunities.Medical research archives · 2023Article
- Gamma Secretase Inhibitors as Potential Therapeutic Targets for Notch Signaling in Uterine Leiomyosarcoma.International journal of molecular sciences · 2022Article
- Identification of 1β,2α-epoxytagitinin C as a Notch inhibitor, oxidative stress mechanism and its anti-leukemia activity.Journal of natural medicines · 2022Article
- Isolation of nocobactin NAs as Notch signal inhibitors from Nocardia farcinica, a possibility of invasive evolution.The Journal of antibiotics · 2021Article
- Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance.The oncologist · 2021Review
- Cancer stem cells: a major culprit of intra-tumor heterogeneity.American journal of cancer research · 2021Review
- Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors.Journal of natural medicines · 2020Article
- Notch pathway in ependymoma RELA-fused subgroup: upregulation and association with cancer stem cells markers expression.Cancer gene therapy · 2020Article
- Targeting cancer stem cell pathways for cancer therapy.Signal transduction and targeted therapy · 2020Review
- Subgroup-specific prognostic signaling and metabolic pathways in pediatric medulloblastoma.BMC cancer · 2019Article
- Embryonal Tumors of the Central Nervous System in Children: The Era of Targeted Therapeutics.Bioengineering (Basel, Switzerland) · 2018Review
- The Notch inhibitor cowanin accelerates nicastrin degradation.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 1 country.
Funding
Abstract
purposeAmplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752.
methodsMK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot.
resultsTen eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 μg/mL (40.6 to 109 μg/mL) and 60.3 μg/mL (59.2 to 91.9 μg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752.
conclusionMK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.
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