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First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Karolinska Univ Hosp, Dept Oncol, Solna, Sweden..
City Clin Oncol Ctr, St Petersburg State Healthcare Inst, St Petersburg, Russia..
St Petersburg State Med Univ, State Educ Inst Higher Profess Educ, St Petersburg, Russia..
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2015 (English)In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 33, no 6, 1232-1241 p.Article in journal (Refereed) PublishedText
Abstract [en]

Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

Place, publisher, year, edition, pages
2015. Vol. 33, no 6, 1232-1241 p.
Keyword [en]
Melphalan flufenamide, Melflufen, J1
National Category
Cancer and Oncology Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-270433DOI: 10.1007/s10637-015-0299-2ISI: 000365192100009PubMedID: 26553306OAI: oai:DiVA.org:uu-270433DiVA: diva2:901600
Available from: 2016-02-08 Created: 2015-12-28 Last updated: 2016-02-08Bibliographically approved

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Berglund, ÅkeHagberg, HansTholander, BengtNygren, PeterAlvfors, CarinaRingbom, MagnusGullbo, Joachim
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Experimental and Clinical OncologyUCR-Uppsala Clinical Research Center
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Investigational new drugs
Cancer and OncologyPharmacology and Toxicology

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