title: A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma.
abstract: AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75 mg m-2day-1after a loading dose of 100-200 mg m-2on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal123I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Kushner
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Nai-Kong V
authors.initials: NV
authors.lastname: Cheung
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Shakeel
authors.initials: S
authors.lastname: Modak
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, NC.
authors.forename: Oren J
authors.initials: OJ
authors.lastname: Becher
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Basu
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Roberts
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Kim
authors.initials: K
authors.lastname: Kramer
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Dunkel
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; PI3K pathway; alkylphospholipid; protein kinase B; receptor tyrosine kinases