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-2  day-1 after a loading dose of 100-200 mg m-2 on 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 abnormal 123 I-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: Brian H Kushner, Nai-Kong V Cheung, Shakeel Modak, Oren J Becher, Ellen M Basu, Stephen S Roberts, Kim Kramer, Ira J Dunkel
• Journal: International journal of cancer (Int J Cancer) Vol. 140 Issue 2 Pg. 480-484 (Jan 15 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 27649927 (Publication Type: Clinical Trial, Phase I, Journal Article)
• Copyright: © 2016 UICC.

Chemical References

• Antineoplastic Agents
• Phosphorylcholine
• perifosine
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Adolescent
• Adult
• Antineoplastic Agents (therapeutic use)
• Child
• Child, Preschool
• Disease-Free Survival
• Female
• Humans
• Male
• Neoplasm Recurrence, Local (drug therapy, metabolism)
• Neuroblastoma (drug therapy, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylcholine (analogs & derivatives, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Young Adult