2504 Background: The BET family (BRD2, BRD3, BRD4) regulates transcription, epigenetic memory and cell growth, emerging as a novel therapeutic strategy. BI 894999 is a highly potent and selective orally available BET inhibitor. Methods: BI 894999 was given once a day, continuously (1 cycle = 3 weeks; Arm A). An intermittent schedule was explored: once a day, D1-14 Q21 days (1 cycle = 3 weeks; Arm B). Bayesian Logistic Regression Model was used to guide dose escalation. HEXIM1, HIST2H2BF and CCR2 gene expressions were used as pharmacodynamic (PD) markers. Results: 28 pts were treated: 21 in Arm A, 7 in Arm B. Median number of cycles was 2 (range: 1-12). Pts were treated at 6 dose levels in Arm A (0.2-5 mg) and 2 dose levels in Arm B (1.5 and 2 mg). The maximum tolerated dose (MTD) was exceeded at 2 mg in Arm A. In Arm B, dose escalation was halted due to the observation of ECG changes in 3 pts and raised serum troponin in 8 pts, pending cardiology review. MTD in Arm A was defined as 1.5 mg. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). DLTs included: thrombocytopenia grade (G) 4 (n=3), increased troponin G3 (n=1), hypophosphatemia G3 (n=1), multiple G2 events in 1 pt preventing adequate dose intensity in cycle 1. Of 27 evaluable pts, 3 had partial response (PR; one was confirmed) and 1 had stable disease (SD) lasting >4 cycles. C max and AUC increased with dose in a greater than linear fashion particularly at higher dose levels. Mean terminal T 1/2 was ~1 day with high interpatient variability. PD analyses showed target engagement in all 3 genes at doses ≥1 mg in both schedules. Conclusions: BI 894999 showed target engagement at doses ≥ 1 mg and demonstrated clinical activity (3 PRs and 1 SD lasting >4 cycles). Thrombocytopenia prevented continuous dosing and 1.5 mg was defined the MTD for Arm A, whilst dose escalation was halted in Arm B due to cardiac findings. Mitigating hematological toxicity of BI 894999 via synergistic drug combinations should be explored. Clinical trial information: NCT02516553.
Only a few recent phase III trials with targeted therapies or immune checkpoint inhibitors (ICIs) in metastatic clear-cell renal cell carcinoma (m-ccRCC) demonstrated an overall survival (OS) benefit compared to standard of care. We aimed to study the evolution of OS since the start of systemic therapy from 2000 to 2020.Retrospective study on all consecutively treated m-ccRCC patients in three Belgian hospitals starting with systemic therapy. The study outcome was OS since the start of systemic therapy. We used a univariable Cox model for OS with year of the start of therapy as a predictor, and a multivariable analysis including known prognostic factors. Linear and non-linear trends of time were tested.Five hundred patients were included. In a linear model, the HR for OS depending on the year of the start of therapy was 0.95 (95%CI 0.93-0.97; p < 0.0001), estimated for an increase with 1 year in time. In a non-linear model, OS started to improve from 2006 on, when vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) replaced interferon alfa (IFNa) as a standard of care and continued to increase steadily during the following years. On multivariable analysis, the year of the start of therapy remained an independent prognostic factor for OS. Two-year OS after the start of systemic therapy was 23%, 34%, 50% and 59% for patients who started treatment in 2000-2005, 2006-2011, 2012-2017, and 2018-2020, respectively. The five-year OS of the first three groups was 7%, 14% and 24%. The mean number of administered lines of therapy increased over time, with an incidence rate ratio of 1.07 (95%CI 1.05-1.08; p < 0.0001) per year increase for the period 2000-2016.OS of m-ccRCC patients has been improving significantly over the last 15 years since the introduction of VEGFR-TKIs and ICIs.
<b><i>Background:</i></b> Synovial sarcomas (SS) are malignant mesenchymal neoplasms that account for about 10% of all sarcomas. Complete surgical excision is the mainstay of primary treatment for localized disease, but SS have a high tendency for local relapse and metastases. Metastatic disease is commonly treated with systemic chemotherapy. <b><i>Methods:</i></b> We designed a retrospective analysis to describe the clinical presentation, course of treatment, outcome, and prognosis of patients with SS. Univariate and multivariate analyses were performed for potential prognostic factors. <b><i>Results:</i></b> We identified 134 patients treated between 1987 and 2018, with a cutoff date of December 2018. Demographics, disease characteristics, treatment, and survival rates were collected and analyzed. The median overall survival (mOS) from the date of diagnosis was 96.7 months. The median progression-free survival was 6.37 months. Disease-free survival was 26 months. Age over 65 years was found to be a prognostic factor with statistically significant value in the univariate analysis regarding mOS (<i>p</i> = 0.015) and mOS after local relapse (<i>p</i> = 0.0228). <b><i>Conclusions:</i></b> Even though our study is limited by the retrospective nature of the analysis, it adds an important amount of clinical data regarding the treatment and outcome of SS.
We have performed in vitro incubations of blood from male and female volunteers with gemcitabine and docetaxel alone, and in combination, at different concentration gradients in order to investigate changes in partition between red blood cells (RBCs), total plasma and the free fraction. After extraction and sample pre-treatment, a validated high-performance liquid chromatography method followed by UV detection was used to determine the concentrations of both drugs in the different blood constituents. The partition ratio [the concentration in the erythrocytes divided by the concentration in plasma (E/P)] was calculated. The partition ratio of docetaxel varied from 0.02 to 1.44 (mean 0.35), reflecting its relatively low affinity for RBCs, probably because of its high plasma protein binding (more than 98%). For gemcitabine, the partition ratio varied from 1 to 5, reflecting a high affinity for RBCs (less than 10% plasma protein bound). The partition ratios of both drugs increased significantly with higher whole-blood concentrations, favoring uptake in the erythrocytes when plasma protein binding is saturated. Combination incubations showed a complex and unexplained interaction between gender and the influence of docetaxel on the partition of gemcitabine. We conclude that the incorporation of drugs into the RBC pool may be important for transportation to tumor tissue and efficacy. In combination, one anti-cancer agent can alter the partition ratios of other anti-cancer agents.
The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ). Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk. Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates. Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.
