Association of cabozantinib pharmacokinetics, progression and toxicity in metastatic renal cell carcinoma patients: results from a pharmacokinetics/pharmacodynamics study.

BACKGROUND: Cabozantinib is a tyrosine kinase inhibitor with a substantial efficacy in metastatic renal cell carcinoma, and is associated with a challenging toxicity profile leading to frequent drug discontinuations. Whereas an exposure/safety relationship was demonstrated for this drug, an exposure/efficacy relationship is still unknown. PATIENTS AND METHODS: We carried out a monocentric, observational, pharmacokinetics/pharmacodynamics (PK/PD) study in patients with metastatic renal cell carcinoma (INDS MR 5612140520). We used measured blood concentrations of cabozantinib (Cmeas) to determine the area under the curve (AUC), apparent clearance (Cl/F) and residual blood concentration (Ctrough). Best overall response according to RECIST 1.1 and relevant toxicity (adverse event grade 3-4 or grade 2 requiring dose reduction or discontinuation) were assessed according to Cmeas, Ctrough, AUC and Cl/F. RESULTS: We enrolled 76 patients, including 35 who experienced disease progression and 30 with grade 3-4 toxicity. Patients with progressive disease had a significantly lower median Ctrough (406 versus 634 ng/ml, P = 0.001), Cl/F (2 versus 2.9 l/h, P = 0.002) and AUC (16 versus 20 µg h/ml, P = 0.037) compared with patients who had disease control as best response. Patients with relevant toxicity had a significantly higher Cmeas (732 versus 531 ng/ml, P = 0.006), Ctrough (693 versus 521 ng/ml, P = 0.005) and AUC (21 versus 16 µg h/ml, P = 0.046) compared with patients who did not experience any grade relevant toxicity. Receiver operating characteristic curves obtained from our study defined a threshold for drug efficacy of 536.8 ng/ml and of 617.7 ng/ml for toxicity. CONCLUSION: We first demonstrate the PK/PD relationship for cabozantinib. Severe toxicities are associated with a higher drug exposure, whereas inefficacy is associated with a lower drug exposure. Cabozantinib plasma drug monitoring may be useful to optimize clinical practice.

A randomized phase III trial comparing trabectedin to best supportive care in patients with pre-treated soft tissue sarcoma: T-SAR, a French Sarcoma Group trial.

BACKGROUND: The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: This randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/m2 every 3 weeks or BSC, stratified into L-STS (liposarcoma/leiomyosarcoma) and non-L-STS groups (other histotypes). Patients from the BSC arm were allowed to cross over to trabectedin at progression. The primary efficacy endpoint was progression-free survival (PFS) confirmed by blinded central review and analyzed in the intention-to-treat population. RESULTS: Between 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months [95% confidence interval (CI) 1.8-5.9 months] in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P < 0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin. CONCLUSION: Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS.

[A randomized controlled trial of metastases-directed treatment in patients with metastatic prostate cancer using stereotactic body irradiation: A GETUG-AFU trial]. / Rôle de la radiothérapie ablative des métastases chez les patients atteints de cancer de la prostate oligométastatique hormonosensible : un essai du Groupe d'étude des tumeurs urogénitales et de l'Association française d'urologie.

The goal of treatment of metastatic prostate cancer remains palliation. The oligometastatic state could be the right time to intensify therapy by introducing metastases directed treatments. The aim of this trial was to evaluate the benefit of radiotherapy to all macroscopic metastatic sites and to the primary disease in patients with hormone sensitive oligometastatic prostate cancer.

Thrombolysis rate and impact of a stroke code: a French hospital experience and a systematic review.

BACKGROUND: Intravenous rt-PA is effective in hyperacute ischemic stroke (HAIS) but is administered only in few patients. OBJECTIVES: To report the thrombolysis rate in our stroke unit using a stroke code (SC) protocol with a prenotification system and to analyze the SC impact on the thrombolysis rate in a systematic review. METHODS: We report, from 2005 to 2009, the intravenous rt-PA rate in our prospective registry of hyperacute strokes suspicions. The systematic review was conducted in searching PubMed and EMBASE for prospective studies reporting thrombolysis rates and their use of a SC. We categorized SC between those with a prenotification by the Emergency Medical Services and those with only an in-hospital SC system. RESULTS: Among the 1450 stroke patients hospitalized in our stroke unit, 349 were admitted via the SC protocol as suspicions of hyperacute strokes. Intravenous rt-PA rates were: 12.9% of the ischemic strokes, 36% of the suspicions of hyperacute strokes and 59.6% of the HAIS. We found 23 studies reporting thrombolysis rates ranging from 10.3% to 58% of HAIS. Ten studies gave data concerning the use of a SC in case of HAIS. Thrombolysis rate was higher in hospitals with a prenotification system (54.7%) compared with both those with no specific organization (18.2%) (OR=5.43, 95% CI: 3.84-7.73) and those with an in-hospital restricted SC (37.9%) (OR=1.97, 95% CI: 1.53-2.54). CONCLUSIONS: Thrombolysis rate of HAIS is improved by a SC, especially when a prenotification system of thrombolysis candidates by Emergency Medical Services to the stroke unit is used.

Path integral approach to closed-form option pricing formulas with applications to stochastic volatility and interest rate models.

We present a path integral method to derive closed-form solutions for option prices in a stochastic volatility model. The method is explained in detail for the pricing of a plain vanilla option. The flexibility of our approach is demonstrated by extending the realm of closed-form option price formulas to the case where both the volatility and interest rates are stochastic. This flexibility is promising for the treatment of exotic options. Our analytical formulas are tested with numerical Monte Carlo simulations.

Density of a gas of spin-polarized fermions in a magnetic field.

For a fermion gas with equally spaced energy levels that is subjected to a magnetic field, the particle density is calculated. The derivation is based on the path integral approach for identical particles, in combination with the inversion techniques for the generating function of the static response functions. Explicit results are presented for the ground state density as a function of the magnetic field with a number of particles ranging from 1 to 45.