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Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma

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Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM).


We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort.


Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14).


PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.

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This project was supported by the Brain Tumor Center of Memorial Sloan Kettering Cancer Center, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and The Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center, and Keryx Biopharmaceuticals, Inc. (funding and drug supply, as legacy to Aeterna Zentaris for development of perifosine). In addition, this work was supported by the MSKCC National Cancer Institute Cancer Center Core Grant (P30-CA008748).

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ABL received during the last 3 years (all outside the submitted work): personal fees and non-financial support from Orbus, NW Biotherapeutics, Agios, Celgene, and Novocure; grants, personal fees and non-financial support from Karyopharm, Kadmon, Roche/Genentech, and AbbVie; grants and non-financial support from Oncoceutics, Amgen, Millienium, Celldex, Novartis, Pfizer, Beigene, and VBI Vaccines, non-financial support from Tocagen, BMS; and personal fees from Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial, prIME Oncology, Sapience, WebMD, Physicians' Education Resource/Chemotherapy Foundation Symposium, Astra Zeneca, and Cortice. TJK: outside the submitted work: research funding (Merck, Ludwig, Eli-Lilly). KSP: outside the submitted work: stock ownership in Johnson $ Johnson, Viking Therapeutics, Pfizer and Catalyst Biotech.

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Correspondence to Thomas J. Kaley or Andrew B. Lassman.

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Kaley, T.J., Panageas, K.S., Mellinghoff, I.K. et al. Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. J Neurooncol 144, 403–407 (2019).

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