Hebron University

About: Hebron University is a education organization based out in Hebron, Palestinian Territory. It is known for research contribution in the topics: Population & Cancer. The organization has 2714 authors who have published 4180 publications receiving 163736 citations.

Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/ pharmacodynamic model

Abstract: Aims To identify prospectively a safe therapeutic window for administration of a novel oral transforming growth factor β (TGF-β) inhibitor, LY2157299 monohydrate, based on a pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of population plasma exposures and biomarker responses in tumour were performed for future trials of LY2157299 in glioblastoma and other cancer populations. Methods The model was updated after completion of each cohort during the first-in-human dose (FHD) study. The flexible design allowed continuous assessment of PK variability by recruiting the required number of patients in each cohort. Based on 30% inhibition of TGF-β RI kinase phosphorylates (pSMAD), biologically effective exposures were anticipated to be reached from 160 mg onwards. The therapeutic window was predicted, based on animal data, to be between 160 and 360 mg. Results No medically significant safety issues were observed and no dose limiting toxicities were established in this study. Observed plasma exposures (medians 2.43 to 3.7 mg l−1 h, respectively) with doses of 160 mg to 300 mg were within the predicted therapeutic window. Responses, based on the MacDonald criteria, were observed in these patients. Conclusions A therapeutic window for the clinical investigation of LY2157299 in cancer patients was defined using a targeted PK/PD approach, which integrated translational biomarkers and preclinical toxicity. The study supports using a therapeutic window based on a PK/PD model in early oncology development.

First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors.

Abstract: Purpose: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk). Experimental Design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. Results: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m 2 . Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m 2 , with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose. Conclusion: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study. Clin Cancer Res; 20(8); 2205–14. ©2014 AACR .

Updated efficacy of the MEK inhibitor trametinib (T), BRAF inhibitor dabrafenib (D), and anti-EGFR antibody panitumumab (P) in patients (pts) with BRAF V600E mutated (BRAFm) metastatic colorectal cancer (mCRC).

Abstract: 103 Background: BRAF V600E mutations occur in 5–10% of mCRC and confer a poor prognosis. Unlike BRAFm melanoma, BRAF and MEK inhibitors have minimal activity in BRAFm mCRC. Preclinical data suggest...

Direct transfer to angiosuite to reduce door-to-puncture time in thrombectomy for acute stroke.

Abstract: Objective To evaluate direct transfer to the angiosuite protocol of patients with acute stroke, candidates for endovascular treatment (EVT). Methods We studied workflow metrics of all patients with stroke who had undergone EVT in the past 12 months. Patients followed three protocols: direct transfer to emergency room (DTER), CT room (DTCT) or angiosuite (DTAS, only last 6 months if admission National Institute of Health Stroke Scale (NIHSS) score >9 and time from onset Results 201 patients were included: 87 DTER (43.3%), 74 DTCT (36.8%), 40 DTAS (19.9%). Ten DTAS patients (25%) did not receive EVT: 3 (7.5%) showed intracranial hemorrhage on cone-beam CT and 7 (17.5%) did not show an occlusion on angiography. Mean door-to-puncture (D2P) time was shorter in DTAS (17±8 min) than DTCT (60±29 min; p Conclusion In a subgroup of patients direct transfer and triage in the angiosuite seems feasible, safe, and achieves significant reduction in hospital workflow times.

Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study.

Abstract: 4013Background: Trastuzumab (tras) plus chemotherapy (chemo) is standard-of-care (SOC) 1L therapy for HER2+ metastatic G/GEJ cancer. In two phase 2 studies, tras, chemo, and pembrolizumab (pembro) ...