Reference Detail

Ref Type Journal Article
PMID (28357727)
Authors Wise-Draper TM, Moorthy G, Salkeni MA, Karim NA, Thomas HE, Mercer CA, Beg MS, O'Gara S, Olowokure O, Fathallah H, Kozma SC, Thomas G, Rixe O, Desai P, Morris JC
Title A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies.
Journal Targeted oncology
Vol 12
Issue 3
Date 2017 Jun
URL
Abstract Text The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model.To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed.BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed.Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr.The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug-drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 Advanced Solid Tumor no benefit BEZ235 + Everolimus Phase Ib/II Actionable In a Phase Ib trial, the combination of BEZ235 and Afinitor (everolimus) resulted in limited efficacy in patients with advanced solid tumors and was discontinued due to multiple intolerable side effects (PMID: 28357727). 28357727
Unknown unknown astrocytoma not applicable BEZ235 + Everolimus Phase Ib/II Actionable In a Phase Ib trial, the combination of BEZ235 and Afinitor (everolimus) resulted in stable disease in a patient with astrocytoma (PMID: 28357727). 28357727