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

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.

• Authors: Patrick A Ott, Omid Hamid, Anna C Pavlick, Harriet Kluger, Kevin B Kim, Peter D Boasberg, Ronit Simantov, Elizabeth Crowley, Jennifer A Green, Thomas Hawthorne, Thomas A Davis, Mario Sznol, Patrick Hwu
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 32 Issue 32 Pg. 3659-66 (Nov 10 2014) ISSN: 1527-7755 [Electronic] United States
• PMID: 25267741 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by American Society of Clinical Oncology.

Chemical References

• Antibodies, Monoclonal
• Immunoconjugates
• glembatumumab vedotin

Topics

• Adult
• Aged
• Aged, 80 and over
• Alopecia (chemically induced)
• Antibodies, Monoclonal (adverse effects, therapeutic use)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Exanthema (chemically induced)
• Fatigue (chemically induced)
• Female
• Humans
• Immunoconjugates (adverse effects, therapeutic use)
• Male
• Melanoma (drug therapy, pathology)
• Middle Aged
• Neutropenia (chemically induced)
• Treatment Outcome