A Phase I study of safety, pharmacokinetics, and pharmacodynamics of concurrent everolimus and buparlisib treatment in advanced solid tumors
Mené sur 43 patients atteints d'une tumeur solide de stade avancé (âge médian : 63 ans), cet essai de phase I analyse les caractéristiques pharmacocinétiques et pharmacodynamiques d'un traitement combinant évérolimus et buparlisib, et évalue les doses maximales tolérées de ces deux agents
Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor.
Experimental Design: We used the Bayesian EWOC design to test escalating doses of everolimus (5mg or 10mg) and buparlisib (20, 40, 60, 80 and 100 mg) in eligible patients. Pharmacokinetic (PK) assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1.
Results: We enrolled 43 patients, median age of 63 (39-78) years; 25 (58.1%) females, 35 (81.4%) Caucasians and 8 (18.6%) Blacks. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. Dose limiting toxicities observed in 7 patients were: fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1) and urinary tract infection (1). The RP2D for the combination was established as everolimus (5mg) and buparlisib (60mg). The best response in 27 evaluable patients was progressive disease and stable disease in in three (11%) and 24 (89%) respectively. The median PFS and OS were 2.7 (1.8, 4.2) and 9 (6.4, 13.2) months. Steady-state PK analysis showed dose-normalized maximum concentrations and area-under-the-curve values for everolimus and buparlisib in combination to be comparable with single agent PK.
Conclusion: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5mg and 60mg on a continuous daily schedule.
Clinical Cancer Research , résumé, 2019