title: A phase 2 study of simtuzumab in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis.
abstract: Simtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase-like-2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open-label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post-polycythaemia vera MF and post-essential thrombocythaemia MF. Fifty-four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose-proportionally between the 200-mg and 700-mg treatment groups. Therapy-related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700-mg group, 1 (6·7%) in the simtuzumab 200-mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700-mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Srdan
authors.initials: S
authors.lastname: Verstovsek
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Savona
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Julia D
authors.initials: JD
authors.lastname: Maltzman
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Shringi
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Silverman
authors.affiliation: Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Oh
authors.affiliation: Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D011087:Polycythemia Vera / Q000473:pathology*; D055728:Primary Myelofibrosis / Q000175:diagnosis* / Q000188:drug therapy* / Q000209:etiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013920:Thrombocythemia, Essential / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; C000613471:simtuzumab; D053614:Janus Kinase 2
keywords: LOXL2; bone marrow fibrosis; myelofibrosis; simtuzumab