title: A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors.
abstract: OBJECTIVE
  This phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of demcizumab (OMP-21M18), a humanized IgG2 mAb targeting the Notch ligand DLL4 in adult patients with advanced malignancies.
  
  
  METHODS
  Standard 3+3 design, with demcizumab 0.5, 1, 2.5, or 5 mg/kg weekly or 2.5, 5, or 10 mg/kg every other week, with an expansion cohort at 10 mg/kg every other week. Dose-limiting toxicities (DLT) were assessed during the first 28 days.
  
  
  RESULTS
  Fifty-five patients received demcizumab (15 weekly, 18 every other week, 21 expansion cohort, 1 loading dose). No more than one DLT was seen at any dose level. The MTD was not reached for either schedule. Treatment-related adverse events occurring in >10% of patients were hypertension or blood pressure increased (47%), fatigue (31%), anemia (22%), headache (20%), nausea (13%), hypoalbuminemia (11%), dizziness (11%), and dyspnea (11%). One patient dosed at 2.5 mg/kg developed reversible right-sided heart failure after 63 days on treatment and 4 dosed at 10 mg/kg developed congestive heart failure after ≥98 days on treatment. Five patients were hospitalized with bleeding episodes (2 episodes of tumor-associated bleeding). Sixteen of 25 (64%) evaluable patients at 10 mg/kg had evidence of stabilization of disease or response.
  
  
  CONCLUSIONS
  Demcizumab was generally well tolerated at doses ≤5 mg weekly with disease stabilization and decreases in tumor size demonstrating antitumor activity. Hypertension was the most common adverse event that was clearly related to treatment. Prolonged administration was associated with an increased risk of congestive heart failure.
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. dcsmith@umich.edu.
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: Marin Specialty Care, Greenbrae, California.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Eisenberg
authors.affiliation: St. Petersburg City Clinical Oncology Center, St. Petersburg, Russia.
authors.forename: Georgy
authors.initials: G
authors.lastname: Manikhas
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Chugh
authors.affiliation: Stanford University, Stanford, California.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Gubens
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, California.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Stagg
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, California.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, California.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: OncoMed Pharmaceuticals, Inc., Redwood City, California.
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.affiliation: Stanford University, Stanford, California.
authors.forename: Branimir
authors.initials: B
authors.lastname: Sikic
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D019233:Retreatment; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein; C000609115:demcizumab