A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial.

PURPOSE: The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. PATIENTS AND METHODS: Everolimus (5-10 mg once daily, qd) and sorafenib (200-400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM® software. RESULTS: An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6-14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7-4.2, n = 43). CONCLUSION: Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932177.

EVESOR, a model-based, multiparameter, Phase I trial to optimize the benefit/toxicity ratio of everolimus and sorafenib.

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.

Open-label uncontrolled pilot study to evaluate complementary therapy with Ruta graveolens 9c in patients with advanced cancer.

BACKGROUND: Patients with advanced metastatic disease are often treated aggressively with multiple lines of chemotherapy, even in the last month of life. The benefit of such an approach remains uncertain. The objective of the study was to investigate whether Ruta graveolens 9c homeopathic medicine can improve quality of life (QoL) and tumour progression in patients with advanced cancer. MATERIAL AND METHODS: This was a single-centre, open-label, uncontrolled, pilot study. Patients (>18-years, life-expectancy ≥3 months, performance status ≤2) with locally-advanced solid tumours or metastases, previously treated with all available standard anti-cancer treatments were recruited. Oral treatment consisted of two 1-mL ampoules of Ruta graveolens (9c dilution) given daily for a minimum of 8 weeks, or until tumour and/or clinical progression. Primary outcome was QoL measured using the EORTC QLQ-C30 questionnaire. Secondary outcome measures were anxiety/depression measured using the Hospital Anxiety and Depression Scale (HADS), WHO performance status (PS), tumour progression assessed using RECIST criteria and tumour markers, survival and tolerance. RESULTS: Thirty-one patients were included (mean age: 64.3 years). Mean duration of treatment was 3.3 months (median: 2.1). QoL global health status improved significantly between baseline and week 8 (P < 0.001) and week 16 (P = 0.035), but was at the limit of significance (P = 0.057) at the end of the study. There was no significant change in anxiety/depression or PS during treatment. Ruta graveolens 9c had no obvious effect on tumour progression. Median survival was 6.7 months [95%CI: 4.8-14.9]. Ruta graveolens 9c was well-tolerated. CONCLUSION: Some patients treated with Ruta graveolens 9c had a transitory improvement in QoL, but the effectiveness of this treatment remains to be confirmed in further studies.

Population pharmacokinetics and pharmacodynamics of cisplatinum during hyperthermic intraperitoneal chemotherapy using a closed abdominal procedure.

The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software. Different covariables were analyzed to identify those that explain part of the interindividual variability of the pharmacokinetic parameters. Relationships between the area under the concentration-time curve (AUC) and hematological and renal toxicity and efficiency were explored. The pharmacokinetics of cisplatinum were modeled with a 3-compartment model. Estimations of the plasma and peritoneal pharmacokinetic parameters were obtained. No clinical or biological covariates correlated with these parameters. No direct relationship between the AUC of the peritoneal or plasma and toxicity or efficiency was demonstrated. The pharmacokinetics during HIPEC could be modeled with a 3-compartment model using a population pharmacokinetics approach. This work is the basis of further studies. Notably, studies including new patients will analyze the impact of abdominal cavity volume and the variation of the abdominal pressure during HIPEC on the pharmacokinetics of cisplatinum.