title: Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma.
abstract: OBJECTIVE
  The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma.
  
  
  METHODS
  Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity.
  
  
  RESULTS
  One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival.
  
  
  CONCLUSIONS
  Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity.
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ. patrick_ott@dfci.harvard.edu.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Boasberg
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Crowley
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Green
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hawthorne
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Davis
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Mario
authors.initials: M
authors.lastname: Sznol
authors.affiliation: Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY; Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA; Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT; Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX; Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000505:Alopecia / Q000139:chemically induced; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; C551271:glembatumumab vedotin