title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Berglund
authors.affiliation: Department of Oncology, Karolinska University Hospital, Solna, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Ullén
authors.affiliation: St. Petersburg State Healthcare Institution, City Clinical Oncology Center, Saint Petersburg, Russia.
authors.forename: Alla
authors.initials: A
authors.lastname: Lisyanskaya
authors.affiliation: State Educational Institution of Higher Professional Education, St. Petersburg State Medical University, n.a. I.P. Pavlov of Roszdrav, Saint Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Hagberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Tholander
authors.affiliation: Department of Oncology, Karolinska University Hospital, Solna, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Lewensohn
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.affiliation: Oncopeptides AB, Västra Trädgårdsgatan 15, Stockholm, Sweden.
authors.forename: Jack
authors.initials: J
authors.lastname: Spira
authors.affiliation: Oncopeptides AB, Västra Trädgårdsgatan 15, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Harmenberg
authors.affiliation: Oncopeptides AB, Västra Trädgårdsgatan 15, Stockholm, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Jerling
authors.affiliation: Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Alvfors
authors.affiliation: Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ringbom
authors.affiliation: Oncopeptides AB, Västra Trädgårdsgatan 15, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Nordström
authors.affiliation: Oncopeptides AB, Västra Trädgårdsgatan 15, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Söderlind
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. joachim.gullbo@medsci.uu.se.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000478:Alkylation / Q000187:drug effects / Q000502:physiology; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D010447:Peptide Hydrolases / Q000378:metabolism; D010649:Phenylalanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D011446:Prospective Studies
chemical_list: D018906:Antineoplastic Agents, Alkylating; C585069:melflufen; D010649:Phenylalanine; D010447:Peptide Hydrolases; D008558:Melphalan
keywords: J1; Melflufen; Melphalan flufenamide