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• W2035852338 abstract "Introduction: Melphalan-flufenamide (previously designated J1) is an enzyme-activated (aminopeptidase N, APN) prodrug of melphalan. The mechanism of enzyme activation results in the selective intracellular trapping of melphalan in tumor cells. Treatment with melphalan-flufenamide results in a 10–20 fold higher intracellular concentration of melphalan in tumor cells than treatment with equal doses of melphalan, and has demonstrated enhanced cytotoxic activity in numerous in-vitro and in-vivo assays. Consistent with these observations, exposure to melphalan-flufenamide results in greater reductions in the rate of DNA synthesis and greater pro-apoptotic effects than direct treatment with the same doses of melphalan. Experimental: In the dose-escalating phase I part of this study patients with end-stage solid tumor malignancies were admitted. After definition of Recommended Phase Two Dose (RPTD) the trial shifted to a phase IIA trial and only patients with selected diagnoses could be included. Results: The dose limiting toxicity was bone marrow suppression, mainly reversible thrombocytopenia. This was particularly evident in heavily pretreated patients, and RPTD was set to an intravenous infusion of 50 mg (fixed dose) every third week. No cumulative toxicity was observed. In the phase IIA part of the study forty patients were included, twenty of which had ovarian cancer, and thirteen NSCLC. The ovarian cancer patients had received 3–8 previous lines of chemotherapy (mean 3.9, and 90 % had received both taxane and platinum drugs), the NSCLC patients 2–4 lines (mean 2.5, 100 % had received platinum drugs). Twenty-four patients could be radiologically evaluated after 3 cycles of melphalan-flufenamide. Out of twelve evaluable ovarian carcinoma patients two had PD, nine had SD and one had PR according to RECIST criteria. Two patients with SD had a CA125 response of −50 and −70 % respectively. Two patients with SD had clinical progression (ascites effusion) shortly after first evaluation. Eleven patients with NSCLC were evaluated; three had PD and eight SD, according to RECIST. Thus, in NSCLC disease stabilization was best response, one patient received nine cycles of melphalan-flufenamide, and progressed after seven months of therapy. Summary: The APN-activated prodrug melphalan-flufenamide can safely be given to cancer patients. Dose is limited by hematological toxicity. The study suggests clinical activity (biochemical and radiological) in ovarian cancer, even after failure to several lines of chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B52." @default.
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• W2035852338 date "2011-11-12" @default.
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• W2035852338 title "Abstract B52: A phase I-IIA, dose-escalating study of intravenous melphalan-flufenamide (J1) in adult patients with advanced solid tumors (I), advanced ovarian cancer, or non-small cell lung cancer (IIA)." @default.
• W2035852338 doi "https://doi.org/10.1158/1535-7163.targ-11-b52" @default.
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