A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

DeWire-Schottmiller, Mariko; Fuller, Christine; Hummel, Trent R.; Chow, Lionel M.L.; Salloum, Ralph; Blank, Peter de; Pater, Luke; Lawson, Sarah; Zhu, Xiaoting; Dexheimer, Phillip; Carle, Adam C.; Kumar, Shiva Senthil; Drissi, Rachid; Stevenson, Charles B.; Lane, Adam; Breneman, John C.; Witte, David P.; Jones, Blaise V.; Leach, James; Fouladi, Maryam

doi:10.1007/s11060-020-03641-2

Cited by 32 publications

(24 citation statements)

References 38 publications

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“…Stable disease was reached in 7/15 NBL and 2/15 MRT patients. The same dose was used in phase I/II trial with 10 newly diagnosed DIPG (HGG K27M mutant) patients following radiotherapy [54]. Nine patients progressed and one patient discontinued treatment after course 14.…”

Section: Resultsmentioning

confidence: 99%

Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Schubert

Chen

Rodríguez

et al. 2022

European Journal of Cancer

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Section: Resultsmentioning

confidence: 99%

Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Schubert

Chen

Rodríguez

et al. 2022

European Journal of Cancer

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“…Ribociclib demonstrates a synergistic effect when combined with ALK or MEK inhibitors in the treatment of neuroblastoma (242). A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma indicated that the regimen was feasible (243).…”

Section: Cdk4/6mentioning

confidence: 99%

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

et al. 2022

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Glioblastoma is the most common primary malignant tumor in the brain and has a dismal prognosis despite patients accepting standard therapies. Alternation of genes and deregulation of proteins, such as receptor tyrosine kinase, PI3K/Akt, PKC, Ras/Raf/MEK, histone deacetylases, poly (ADP-ribose) polymerase (PARP), CDK4/6, branched-chain amino acid transaminase 1 (BCAT1), and Isocitrate dehydrogenase (IDH), play pivotal roles in the pathogenesis and progression of glioma. Simultaneously, the abnormalities change the cellular biological behavior and microenvironment of tumor cells. The differences between tumor cells and normal tissue become the vulnerability of tumor, which can be taken advantage of using targeted therapies. Small molecule inhibitors, as an important part of modern treatment for cancers, have shown significant efficacy in hematologic cancers and some solid tumors. To date, in glioblastoma, there have been more than 200 clinical trials completed or ongoing in which trial designers used small molecules as monotherapy or combination regimens to correct the abnormalities. In this review, we summarize the dysfunctional molecular mechanisms and highlight the outcomes of relevant clinical trials associated with small-molecule targeted therapies. Based on the outcomes, the main findings were that small-molecule inhibitors did not bring more benefit to newly diagnosed glioblastoma, but the clinical studies involving progressive glioblastoma usually claimed “noninferiority” compared with historical results. However, as to the clinical inferiority trial, similar dosing regimens should be avoided in future clinical trials.

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“…CDK 4/6 inhibitors prevent downstream phosphorylation of retinoblastoma, arresting cell division at the G1 check point. From phase I/II trials for pediatric patients with progressive brain tumors, CDK 4/6 inhibitors were well tolerated with neurotoxicities including: ataxia (24%), dizziness (23%), seizure (21%), headache (19-31%), gait disturbance (14%), and muscle weakness (14%) ( 101 , 102 ). Of note, seizures were only seen in the heavily pre-treated patients, defined as those who underwent more than 4 prior interventions, such as RT and/or myeloablative chemotherapy/biologics and/or myeloablative chemotherapy with bone marrow stem cell rescue ( 101 ).…”

Section: Novel Therapiesmentioning

confidence: 99%

Review: Neurological Complications From Therapies for Pediatric Brain Tumors

2022

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Surgery, chemotherapy and radiation have been the mainstay of pediatric brain tumor treatment over the past decades. Recently, new treatment modalities have emerged for the management of pediatric brain tumors. These therapies range from novel radiotherapy techniques and targeted immunotherapies to checkpoint inhibitors and T cell transfer therapies. These treatments are currently investigated with the goal of improving survival and decreasing morbidity. However, compared to traditional therapies, these novel modalities are not as well elucidated and similarly has the potential to cause significant short and long-term sequelae, impacting quality of life. Treatment complications are commonly mediated through direct drug toxicity or vascular, infectious, or autoimmune mechanisms, ranging from immune effector cell associated neurotoxicity syndrome with CART-cells to neuropathy with checkpoint inhibitors. Addressing treatment-induced complications is the focus of new trials, specifically improving neurocognitive outcomes. The aim of this review is to explore the pathophysiology underlying treatment related neurologic side effects, highlight associated complications, and describe the future direction of brain tumor protocols. Increasing awareness of these neurologic complications from novel therapies underscores the need for quality-of-life metrics and considerations in clinical trials to decrease associated treatment-induced morbidity.

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A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)

Cited by 32 publications

References 38 publications

Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours

Small Molecule Inhibitors in Adult High-Grade Glioma: From the Past to the Future

Review: Neurological Complications From Therapies for Pediatric Brain Tumors

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