Charite Campus Virchow Hospital

Berlin, Germany

Charite Campus Virchow Hospital

Berlin, Germany

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Faivre S.J.,Beaujon University Hospital | Olszanski A.J.,Fox Chase Cancer Center | Weigang-Kohler K.,Paracelsus Medical University | Riess H.,Charite Campus Virchow Hospital | And 10 more authors.
Investigational New Drugs | Year: 2015

Background This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated. Methods Patients received escalating doses of LY2334737 either every other day for 21 days (d) followed by 7 days-drug-free period (QoD-arm) or once daily for 7 days every other week (QD-arm). The 28 days-cycles were repeated until disease progression or unacceptable toxicity. Standard 3 + 3 dose-escalation was succeeded by a dose-confirmation phase (12 additional patients to be enrolled on the maximum tolerated dose [MTD]). Results Forty-one patients received QoD- (40-100 mg) and 32 QD-dosing (40-90 mg). On QoD, 3/9 patients experienced dose-limiting toxicities (DLTs) on the 100 mg dose (2 × G3 diarrhea, 1 × G3 transaminase increase); 1 additional DLT (G3 diarrhea) occurred during dose confirmation at 90 mg (12 patients). On QD, 1 patient each experienced DLTs on 60 mg (G3 transaminase increase) and 80 mg (G3 prolonged QTcF-interval); 2/7 patients had 3 DLTs on the 90 mg dose (diarrhea, edema, liver-failure; all G3). The MTD was established at 90 mg for the QoD-arm. Seven patients on QoD and 4 on QD achieved SD (no CR + PR). Pharmacokinetics showed a dose-proportional increase in exposure of LY2334737 and dFdC without accumulation after repeated dosing. Significant increases in CK18 levels were observed. Genetic polymorphism of the cytidine deaminase gene (rs818202) could be associated with ≥ G3 hepatotoxicity. Conclusions Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day. © 2015 Springer Science+Business Media New York.


Schuepbach W.M.M.,University Pierre and Marie Curie | Rau J.,University of Marburg | Knudsen K.,University of Kiel | Volkmann J.,University of Kiel | And 46 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.) Copyright © 2013 Massachusetts Medical Society.


PubMed | Eli Lilly and Company, University of Pennsylvania, Fox Chase Cancer Center, Medical Oncology and 3 more.
Type: Clinical Trial, Phase I | Journal: Investigational new drugs | Year: 2015

This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated.Patients received escalating doses of LY2334737 either every other day for 21 days (d) followed by 7 days-drug-free period (QoD-arm) or once daily for 7 days every other week (QD-arm). The 28 days-cycles were repeated until disease progression or unacceptable toxicity. Standard 3 + 3 dose-escalation was succeeded by a dose-confirmation phase (12 additional patients to be enrolled on the maximum tolerated dose [MTD]).Forty-one patients received QoD- (40-100 mg) and 32 QD-dosing (40-90 mg). On QoD, 3/9 patients experienced dose-limiting toxicities (DLTs) on the 100 mg dose (2 G3 diarrhea, 1 G3 transaminase increase); 1 additional DLT (G3 diarrhea) occurred during dose confirmation at 90 mg (12 patients). On QD, 1 patient each experienced DLTs on 60 mg (G3 transaminase increase) and 80 mg (G3 prolonged QTcF-interval); 2/7 patients had 3 DLTs on the 90 mg dose (diarrhea, edema, liver-failure; all G3). The MTD was established at 90 mg for the QoD-arm. Seven patients on QoD and 4 on QD achieved SD (no CR + PR). Pharmacokinetics showed a dose-proportional increase in exposure of LY2334737 and dFdC without accumulation after repeated dosing. Significant increases in CK18 levels were observed. Genetic polymorphism of the cytidine deaminase gene (rs818202) could be associated with G3 hepatotoxicity.Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day.

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