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Rolfo C.,University of Antwerp | Swaisland H.,Therakin Consulting | Leunen K.,University Hospitals Leuven | Rutten A.,Translational Cancer Research Group Antwerp | And 7 more authors.
Advances in Therapy | Year: 2015

Background: The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of ≤400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer. Methods: This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 × 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5–14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID. Results: 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [tmax] was delayed by ~2 h). Maximum plasma concentration (Cmax) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02–1.20] for standard and 1.00 [0.92–1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10–1.33] for standard and 1.19 [1.08–1.31] for high-fat meal). Conclusions: The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib. Funding: AstraZeneca. © 2015, Springer Healthcare. Source

Dirix L.Y.,Translational Cancer Research Group Antwerp | Rutten A.,Sint Augustinus Hospital | Huget P.,Sint Augustinus Hospital | Dirix M.,Sint Augustinus Hospital
Expert Opinion on Biological Therapy | Year: 2013

Introduction: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) composed of trastuzumab, a stable linker (MCC), and the cytotoxic agent DM1 (derivative of maytansine). Administration of T-DM1 leads to limited systemic exposure of free DM1, with no evidence of DM1 accumulation after repeated dosing. Areas covered: Phase I and Phase II clinical trials with T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown substantial clinical activity and a favorable safety profile. A randomized, open-label, first-line trial comparing trastuzumab and docetaxel with single agent T-DM1 showed a significant improved progression-free survival for T-DM1. Expert opinion: T-DM1 has successfully completed second-line Phase III development for advanced HER2-positive breast cancer. The Phase III EMILIA study demonstrated an overall survival benefit for T-DM1 compared to the combination of lapatinib and capecitabine in taxane-trastuzumab pretreated patients. T-DM1 may offer delivery on a personalized basis of very potent cytotoxic agents in a cellular selective manner. © 2013 Informa UK, Ltd. Source

Dawood S.,Dubai Hospital | Merajver S.D.,University of Michigan | Viens P.,Institute Paoli Calmettes | Vermeulen P.B.,General Hospital Sint Augustinus | And 11 more authors.
Annals of Oncology | Year: 2011

Background: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. Methods: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. Results: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. Conclusions: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Dirix L.Y.,Oncology Center | Van Dam P.A.,Translational Cancer Research Group Antwerp | Prove A.M.,Translational Cancer Research Group Antwerp | Vermeulen P.B.,Translational Cancer Research Group Antwerp
Therapeutic Advances in Medical Oncology | Year: 2010

Vast preclinical and clinical evidence has made angiogenesis one of the hallmarks of cancer. In many human tumours, vascular endothelial growth factor (VEGF) has been identified as the crucial mediator of this process. Initial studies suggested that angiogenesis, and VEGF in particular, could be inhibited without the risk of major side effects. After the pivotal data in first-line studies in patients with colorectal cancer, numerous clinical trials have been undertaken in patients with breast cancer. This review attempts to update these investigations and define the role of anti-VEGF antibody treatment in advanced breast cancer. © 2010 The Author(s). Source

Trinh X.B.,Translational Cancer Research Group Antwerp | Trinh X.B.,University of Antwerp | Van Dam P.A.,Translational Cancer Research Group Antwerp | Vermeulen P.B.,Translational Cancer Research Group Antwerp | And 4 more authors.
Clinical and Translational Oncology | Year: 2011

Background The mechanisms of tumour progression during anti-VEGF-A treatment are poorly understood. Patients and materials Two patients with metastatic breast cancer are described who developed new metastases while receiving anti-VEGF-A treatment. Angiogenic parameters were determined by CD34/Ki67 double staining, Chalkley counts (CC) and endothelial cell proliferation fractions (ECP). RT-PCR Taqman low-density arrays with a gene panel of 94 angiogenesis-related genes were performed on both metastases and compared to 10 unselected primary breast tumours. Results Both lesions showed a high and intermediate CC of, respectively, 7.5±0.62 and 4.8±0.2. Both lesions had elevated ECP values of 14% and 8%. Low-density array screening showed that VEGFR1 mRNA was overexpressed in both samples (z-score=7.85 and 7.81) compared to control samples (out of range [min-max]). Additional analysis confi rmed this fi nding at the protein level by immunohistochemistry. Conclusion These observations suggest that tumour progression under continuous anti-VEGF-A continues to be angiogenesis dependent. Further exploration is needed to identify the mechanisms of anti-VEGF-A resistance in order to design combination-targeted therapies. Source

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