Synapse - Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma Journal Article

Authors:	Kaley, T. J.; Panageas, K. S.; Pentsova, E. I.; Mellinghoff, I. K.; Nolan, C.; Gavrilovic, I.; DeAngelis, L. M.; Abrey, L. E.; Holland, E. C.; Omuro, A.; Lacouture, M. E.; Ludwig, E.; Lassman, A. B.
Article Title:	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 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. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Journal Title:	Annals of Clinical and Translational Neurology
Volume:	7
Issue:	4
ISSN:	2328-9503
Publisher:	Wiley Blackwell
Date Published:	2020-04-01
Start Page:	429
End Page:	436
Language:	English
DOI:	10.1002/acn3.51009
PUBMED:	32293798
PROVIDER:	scopus
PMCID:	PMC7187704
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083463421&doi=10.1002%2facn3.51009&partnerID=40&md5=8df53845487b3795e2dc843081a74e5e
Notes:	Article -- Export Date: 1 October 2020 -- Source: Scopus