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J Clin Oncol. 2014 Nov 10;32(32):3659-66. doi: 10.1200/JCO.2013.54.8115. Epub 2014 Sep 29.

Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma.

Author information

1
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.
2
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.

Abstract

PURPOSE:

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.

PATIENTS AND 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.

CONCLUSION:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00412828.

PMID:
25267741
PMCID:
PMC4879709
DOI:
10.1200/JCO.2013.54.8115
[Indexed for MEDLINE]
Free PMC Article
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