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Investigational New Drugs

, Volume 33, Issue 6, pp 1232–1241 | Cite as

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

  • Åke Berglund
  • Anders Ullén
  • Alla Lisyanskaya
  • Sergey Orlov
  • Hans Hagberg
  • Bengt Tholander
  • Rolf Lewensohn
  • Peter Nygren
  • Jack Spira
  • Johan Harmenberg
  • Markus Jerling
  • Carina Alvfors
  • Magnus Ringbom
  • Eva Nordström
  • Karin Söderlind
  • Joachim GullboEmail author
PHASE I STUDIES

Summary

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.

Keywords

Melphalan flufenamide Melflufen J1 

Notes

Compliance with ethical standards

Conflict of interest

Rolf Lewensohn, Peter Nygren, and Joachim Gullbo are cofounders and minor shareholders of OncoPeptides AB. Jack Spira was, during the conduct of this study, employed by OncoPeptides AB. Johan Harmenberg and Markus Jerling are consultants to OncoPeptides AB. Eva Nordström and Karin Söderlind are employees of OncoPeptides AB. Carina Alvfors and Magnus Ringbom are employees of Uppsala Clinical Research, conducting the study as a CRO.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Åke Berglund
    • 1
  • Anders Ullén
    • 2
  • Alla Lisyanskaya
    • 3
  • Sergey Orlov
    • 4
  • Hans Hagberg
    • 1
  • Bengt Tholander
    • 1
  • Rolf Lewensohn
    • 2
  • Peter Nygren
    • 1
  • Jack Spira
    • 5
  • Johan Harmenberg
    • 5
  • Markus Jerling
    • 5
  • Carina Alvfors
    • 6
  • Magnus Ringbom
    • 6
  • Eva Nordström
    • 5
  • Karin Söderlind
    • 5
  • Joachim Gullbo
    • 1
    Email author
  1. 1.Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
  2. 2.Department of OncologyKarolinska University HospitalSolnaSweden
  3. 3.St. Petersburg State Healthcare InstitutionCity Clinical Oncology CenterSaint PetersburgRussia
  4. 4.State Educational Institution of Higher Professional EducationSt. Petersburg State Medical UniversitySaint PetersburgRussia
  5. 5.Oncopeptides ABStockholmSweden
  6. 6.Uppsala Clinical Research CenterUppsala University HospitalUppsalaSweden

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