Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma
Abstract Purpose Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well‐tolerated as single agents but...
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doaj-12a34fde3fdf4d90a2d5bd4a3dc14ad82021-05-02T15:47:33ZengWileyAnnals of Clinical and Translational Neurology2328-95032020-04-017442943610.1002/acn3.51009Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastomaThomas J. Kaley0Katherine S. Panageas1Elena I. Pentsova2Ingo K. Mellinghoff3Craig Nolan4Igor Gavrilovic5Lisa M. DeAngelis6Lauren E. Abrey7Eric C. Holland8Antonio Omuro9Mario E. Lacouture10Emmy Ludwig11Andrew B. Lassman12Department of Neurology Memorial Sloan Kettering Cancer Center New York New YorkBrain Tumor Center Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkBrain Tumor Center Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Dermatology Memorial Sloan Kettering Cancer Center New York New YorkGastroenterology and Nutrition Service Memorial Sloan Kettering Cancer Center New York New YorkDepartment of Neurology Memorial Sloan Kettering Cancer Center New York New YorkAbstract Purpose Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well‐tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti‐tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. Methods Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. Results We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose‐limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). Conclusion Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.https://doi.org/10.1002/acn3.51009 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thomas J. Kaley Katherine S. Panageas Elena I. Pentsova Ingo K. Mellinghoff Craig Nolan Igor Gavrilovic Lisa M. DeAngelis Lauren E. Abrey Eric C. Holland Antonio Omuro Mario E. Lacouture Emmy Ludwig Andrew B. Lassman |
spellingShingle |
Thomas J. Kaley Katherine S. Panageas Elena I. Pentsova Ingo K. Mellinghoff Craig Nolan Igor Gavrilovic Lisa M. DeAngelis Lauren E. Abrey Eric C. Holland Antonio Omuro Mario E. Lacouture Emmy Ludwig Andrew B. Lassman Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma Annals of Clinical and Translational Neurology |
author_facet |
Thomas J. Kaley Katherine S. Panageas Elena I. Pentsova Ingo K. Mellinghoff Craig Nolan Igor Gavrilovic Lisa M. DeAngelis Lauren E. Abrey Eric C. Holland Antonio Omuro Mario E. Lacouture Emmy Ludwig Andrew B. Lassman |
author_sort |
Thomas J. Kaley |
title |
Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma |
title_short |
Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma |
title_full |
Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma |
title_fullStr |
Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma |
title_full_unstemmed |
Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma |
title_sort |
phase i clinical trial of temsirolimus and perifosine for recurrent glioblastoma |
publisher |
Wiley |
series |
Annals of Clinical and Translational Neurology |
issn |
2328-9503 |
publishDate |
2020-04-01 |
description |
Abstract Purpose Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well‐tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti‐tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. Methods Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. Results We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose‐limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). Conclusion Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs. |
url |
https://doi.org/10.1002/acn3.51009 |
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