A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies.

BACKGROUND: The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. OBJECTIVE: To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Renal toxicity of targeted therapies.

The use of molecular targeted therapies for the treatment of cancer has increased over the last decade. The benefits of these compounds in terms of efficacy are often relatively modest and counter balanced by the occurrence of significant toxicities. Many of these newer agents used in clinical practice lack specificity and selectivity and have a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined and numerous class-specific toxicities have been described. The kidney is an organ where most of these targeted pathways are expressed. Preclinical data and human renal biopsies have generated an understanding of the mechanisms involved in how targeted agents can cause renal toxicity. This review article discusses the observed nephrotoxicity with this burgeoning class of therapeutics and reviews both the biological reasons for its occurrence and possible ways to prevent significant renal damage.

Validation of analytic methods for biomarkers used in drug development.

The role of biomarkers in drug discovery and development has gained precedence over the years. As biomarkers become integrated into drug development and clinical trials, quality assurance and, in particular, assay validation become essential with the need to establish standardized guidelines for analytic methods used in biomarker measurements. New biomarkers can revolutionize both the development and use of therapeutics but are contingent on the establishment of a concrete validation process that addresses technology integration and method validation as well as regulatory pathways for efficient biomarker development. This perspective focuses on the general principles of the biomarker validation process with an emphasis on assay validation and the collaborative efforts undertaken by various sectors to promote the standardization of this procedure for efficient biomarker development.

[Angiogenesis and renal cell carcinoma]. / Angiogenèse et cancer du rein.

Developments in the knowledge of molecular biology of renal cell carcinoma (RCC) over the past 20 years have been identified. Angiogenesis is playing a key role in the physiopathology of RCC. Von Hippel-Lindau (VHL) alterations, HIFalpha accumulation and vascular endothelial growth factor (VEGF) overexpression are important mediators of this process. Several stategies have been developped to target angiogenesis for the treatment of metastatic RCC. These include inhibition of VEGF receptors (inhibition of the tyrosine kinase activity) or binding to the VEGF protein. Several additional kinases inhibitions including PDGF receptors are also targeted. Sunitinib (SU11248) is an orally biovailable small molecule that has demonstrated superiority over interferon-alpha for the treatment of metastatic RCC. In a recent randomized phase III study conducted in 750 patients, the response rate to sunitinib was 31% and to interferon 6%. The median of progression free survival (PFS) was 11 months for sunitinib and 5 months for interferon (p < 0.001). Sorafenib (BAY43-9006) was found to inhibit Raf1, but also VEGFR2 and 3, Flt3, PDGFR-a and b and c-kit, has been tested in a phase III study against placebo after one prior systemic therapy. The median of the time to progression (TTP) for sorafenib was 24 weeks versus 12 weeks for patients in the placebo arm (p = 0,01). Other molecules tested in metastatic RCC will be presented including axitinib, pazopanib and bevacizumab.