Population Pharmacokinetic Analysis of Pazopanib in Patients and Determination of Target AUC.

Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L-1. However, routine monitoring of trough plasma concentrations at fixed hours is difficult in daily practice. Herein, we aimed to characterize the pharmacokinetic (PK) profile of pazopanib and to identify a target area under the curve (AUC) more easily extrapolated from blood samples obtained at various timings after drug intake. A population pharmacokinetic (popPK) model was constructed to analyze pazopanib PK and to estimate the pazopanib clearance of a patient regardless of the time of sampling. Data from the therapeutic drug monitoring (TDM) of patients with cancer at Institute Gustave Roussy and a clinical study (phase I/II) that evaluates the tolerance to pazopanib were used. From the individual clearance, it is then possible to obtain the patient's AUC. A target AUC for maximum efficacy and minimum side effects of 750 mg·h·L-1 was determined. The comparison of the estimated AUC with the target AUC would enable us to determine whether plasma exposure is adequate or whether it would be necessary to propose therapeutic adjustments.

Phase II study of concomitant radiotherapy with atezolizumab in oligometastatic soft tissue sarcomas: STEREOSARC trial protocol.

INTRODUCTION: Up to 50% of soft tissue sarcoma (STS) patients develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumour response rates of 25% at first line and ≤10% at later lines. In oligometastatic stage, stereotactic body radiation therapy (SBRT) allows reaching high control rates at treated sites (≥80%) and is potentially equally effective to surgery in term of overall survival. In order to shift the balance towards antitumour immunity by multisite irradiation, radiation could be combined with inhibitors of the immunosuppressive pathways. METHODS AND ANALYSIS: STEREOSARC is a prospective, multicentric, randomised phase II, designed to evaluate the efficacy of SBRT associated with immunotherapy versus SBRT only. Randomisation is performed with a 2:1 ratio within two arms. The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic multisite irradiation in oligometastatic sarcoma patients. The secondary objectives include PFS by immune response criteria, overall survival, quality-of-life evaluation and developing mathematical models of tumour growth and dissemination predictive of oligometastatic versus polymetastatic evolution. Patients will be randomised in two groups: SBRT with atezolizumab and SBRT alone. The total number of included patients should be 103. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (ID: NCT03548428). ETHICS AND DISSEMINATION: This study has been approved by Comité de Protection des Personnes du sud-ouest et outre-mer 4 on 18 October 2019 (Reference CPP2019-09-076-PP) and from National Agency for Medical and Health products Safety (Reference: MEDAECNAT-2019-08-00004_2017-004239-35) on 18 September 2019.The results will be disseminated to patients upon individual request or through media release from scientific meetings. The results will be communicated through scientific meetings and publications.

Radiology workflow for RECIST assessment in clinical trials: Can we reconcile time-efficiency and quality?

PURPOSE: In oncology clinical trials, nonconformity issues are frequently reported. Radiological workload is increasing, thus reducing radiologists' availability and affecting diagnostic quality. We compared performances of a standard radiological workflow (SW) and a novel "hybrid workflow" (HW). METHOD: We prospectively studied imaging data of 40 patients included in RECIST 1.1 clinical trials. Ninety-six time-points were reviewed by 7 radiologists and one trained technologist. Nonconformities using the SW were retrieved from hospital archives. For the HW, radiologists performed all baseline evaluations; the technologist made subsequent measurements. Finally, the radiologists checked the technologist's findings before confirming the evaluations. The HW enabled implementation of an electronic reporting system. An independent body compared SW and HW reading times and nonconformity occurrences. RESULTS: Using SW, 19 types of nonconformity were found: blank report (13%); unsigned report (11%); undocumented change of tumor burden (10%); undocumented new lesions (9%); missing/wrong patients' appointment dates (7%); undocumented tumor location (5%); error in tumor burden change (5%). SW and HW nonconformities affected 55% (179/323) and 5% (2/40) of reports, respectively (p < 0.001). HW nonconformities were: one inaccurate login name was used on the platform, and one erroneous time-point number. On average, SW required 11'30″ [10'06″; 13'20″] per time-point. HW required 1'35″ [40″; 5'08″] for radiologists, and 12'18″ [11'12″; 14'18″] for the technologist. CONCLUSIONS: HW significantly reduced the number of trial nonconformities and saved 87% of radiologists' time while enabling them to apply their expertise to final decisions. HW could offer an effective opportunity for cost reduction associated with improved imaging trial quality.