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|Ref Type||Journal Article|
|Authors||Kaley TJ, Panageas KS, Mellinghoff IK, Nolan C, Gavrilovic IT, DeAngelis LM, Abrey LE, Holland EC, Lassman AB|
|Title||Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma.|
|Journal||Journal of neuro-oncology|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Perifosine||KRX-0401|NSC-639966||Akt Inhibitor (Pan) 19||Perifosine (KRX-0401) is a synthetic alkylphospholipid that inhibits AKT resulting in apoptotic induction and antitumor activity (PMID: 16418332, PMID: 28864978, PMID: 31325145).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||glioblastoma multiforme||no benefit||Perifosine||Phase II||Actionable||In a Phase II trial, Perifosine (KRX-0401) was well tolerated, but did not demonstrate activity in patients with recurrent glioblastoma multiforme, with a 6-month progression-free rate of 0% (0/16), a median progression-free survival of 1.58 months, and a median overall survival of 3.68 months (PMID: 31325145).||31325145|
|Unknown unknown||astrocytoma||not applicable||Perifosine||Phase II||Actionable||In a Phase II trial, Perifosine (KRX-0401) was well tolerated, but demonstrated limited activity in patients with anaplastic astrocytoma (n=14), with only 1 patient achieved a partial response (PMID: 31325145).||31325145|