Patrick A Ott1, Omid Hamid2, Anna C Pavlick2, Harriet Kluger2, Kevin B Kim2, Peter D Boasberg2, Ronit Simantov2, Elizabeth Crowley2, Jennifer A Green2, Thomas Hawthorne2, Thomas A Davis2, Mario Sznol2, Patrick Hwu2. 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.
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: Keith T Flaherty; Caroline Robert; Peter Hersey; Paul Nathan; Claus Garbe; Mohammed Milhem; Lev V Demidov; Jessica C Hassel; Piotr Rutkowski; Peter Mohr; Reinhard Dummer; Uwe Trefzer; James M G Larkin; Jochen Utikal; Brigitte Dreno; Marta Nyakas; Mark R Middleton; Jürgen C Becker; Michelle Casey; Laurie J Sherman; Frank S Wu; Daniele Ouellet; Anne-Marie Martin; Kiran Patel; Dirk Schadendorf Journal: N Engl J Med Date: 2012-06-04 Impact factor: 91.245
Authors: Charlotte F McDonagh; Eileen Turcott; Lori Westendorf; Jennifer B Webster; Stephen C Alley; Kristine Kim; Jamie Andreyka; Ivan Stone; Kevin J Hamblett; Joseph A Francisco; Paul Carter Journal: Protein Eng Des Sel Date: 2006-04-27 Impact factor: 1.650
Authors: Jeremy N Rich; Qing Shi; Mark Hjelmeland; Thomas J Cummings; Chien-Tsun Kuan; Darell D Bigner; Christopher M Counter; Xiao-Fan Wang Journal: J Biol Chem Date: 2003-02-17 Impact factor: 5.157
Authors: Jeffrey A Sosman; Kevin B Kim; Lynn Schuchter; Rene Gonzalez; Anna C Pavlick; Jeffrey S Weber; Grant A McArthur; Thomas E Hutson; Stergios J Moschos; Keith T Flaherty; Peter Hersey; Richard Kefford; Donald Lawrence; Igor Puzanov; Karl D Lewis; Ravi K Amaravadi; Bartosz Chmielowski; H Jeffrey Lawrence; Yu Shyr; Fei Ye; Jiang Li; Keith B Nolop; Richard J Lee; Andrew K Joe; Antoni Ribas Journal: N Engl J Med Date: 2012-02-23 Impact factor: 91.245
Authors: Svetlana O Doronina; Brian E Toki; Michael Y Torgov; Brian A Mendelsohn; Charles G Cerveny; Dana F Chace; Ron L DeBlanc; R Patrick Gearing; Tim D Bovee; Clay B Siegall; Joseph A Francisco; Alan F Wahl; Damon L Meyer; Peter D Senter Journal: Nat Biotechnol Date: 2003-06-01 Impact factor: 54.908
Authors: Kam Fai Tse; Michael Jeffers; Vincent A Pollack; Denise A McCabe; Melanie L Shadish; Nikolai V Khramtsov; Craig S Hackett; Suresh G Shenoy; Bing Kuang; Ferenc L Boldog; John R MacDougall; Luca Rastelli; John Herrmann; Michael Gallo; Gadi Gazit-Bornstein; Peter D Senter; Damon L Meyer; Henri S Lichenstein; William J LaRochelle Journal: Clin Cancer Res Date: 2006-02-15 Impact factor: 12.531
Authors: Abdulhafez A Selim; Samir M Abdelmagid; Reem A Kanaan; Steven L Smock; Thomas A Owen; Steven N Popoff; Fayez F Safadi Journal: Crit Rev Eukaryot Gene Expr Date: 2003 Impact factor: 1.807
Authors: Gentry T King; Keith D Eaton; Brandon R Beagle; Christopher J Zopf; Gilbert Y Wong; Heike I Krupka; Steven Y Hua; Wells A Messersmith; Anthony B El-Khoueiry Journal: Invest New Drugs Date: 2018-01-15 Impact factor: 3.850
Authors: Lisa M Kopp; Suman Malempati; Mark Krailo; Yun Gao; Allen Buxton; Brenda J Weigel; Thomas Hawthorne; Elizabeth Crowley; Jeffrey A Moscow; Joel M Reid; Victor Villalobos; R Lor Randall; Richard Gorlick; Katherine A Janeway Journal: Eur J Cancer Date: 2019-10-03 Impact factor: 9.162
Authors: Hui K Gan; Martin van den Bent; Andrew B Lassman; David A Reardon; Andrew M Scott Journal: Nat Rev Clin Oncol Date: 2017-07-04 Impact factor: 66.675