TY - JOUR
T1 - Phase i dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma
AU - Tannir, Nizar M.
AU - Forero-Torres, Andres
AU - Ramchandren, Radhakrishnan
AU - Pal, Sumanta K.
AU - Ansell, Stephen M.
AU - Infante, Jeffrey R.
AU - De Vos, Sven
AU - Hamlin, Paul A.
AU - Kim, Stella K.
AU - Whiting, Nancy C.
AU - Gartner, Elaina M.
AU - Zhao, Baiteng
AU - Thompson, John A.
N1 - Funding Information:
Funding for this study was provided by Seattle Genetics, Inc.
Publisher Copyright:
© 2014 Springer Science+Business Media New York.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Purpose This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.5 mg/kg) or on Days 1, 8, and 15 of 28-day cycles (weekly; doses of 0.3 or 0.6 mg/kg). Dose-limiting toxicities were evaluated during Cycle 1; treatment response was monitored every 2 cycles. Results The maximum tolerated dose of SGN-75 in RCC patients was 3 mg/kg Q3Wk. Due to toxicity concerns (idiopathic thrombocytopenic purpura in 2 NHL patients treated weekly), dose escalation in the weekly schedule was terminated; no regimen was recommended for NHL patients. The most common adverse events reported in patients treated Q3Wk (N = 47) were fatigue (40 %), dry eye (32 %), nausea (30 %), and thrombocytopenia (26 %). The nadir for thrombocytopenia typically occurred during Cycle 1. Ocular adverse events (e.g., corneal epitheliopathy, dry eye) were reported for 57 % of patients treated Q3Wk and were generally reversible. Antitumor activity in patients treated Q3Wk included 1 complete response, 2 partial responses, and 20 stable disease. SGN-75 exposures were approximately dose proportional, with a mean terminal half-life of 10 days. Substantial depletions of CD70-positive peripheral blood lymphocytes were observed after SGN-75 treatment. Conclusions Modest single-agent activity and generally manageable adverse events were observed in heavily pretreated RCC and NHL patients. Administration Q3Wk was better tolerated than weekly dosing. Targeted ablation of CD70-positive lymphocytes was demonstrated.
AB - Purpose This first-in-human study evaluated the CD70-targeted antibody-drug conjugate SGN-75 in patients with relapsed or refractory CD70-positive non-Hodgkin lymphoma (NHL) or metastatic renal cell carcinoma (RCC). Methods SGN-75 was administered intravenously to 58 patients (39 RCC, 19 NHL) every 3 weeks (Q3Wk; doses escalated from 0.3 to 4.5 mg/kg) or on Days 1, 8, and 15 of 28-day cycles (weekly; doses of 0.3 or 0.6 mg/kg). Dose-limiting toxicities were evaluated during Cycle 1; treatment response was monitored every 2 cycles. Results The maximum tolerated dose of SGN-75 in RCC patients was 3 mg/kg Q3Wk. Due to toxicity concerns (idiopathic thrombocytopenic purpura in 2 NHL patients treated weekly), dose escalation in the weekly schedule was terminated; no regimen was recommended for NHL patients. The most common adverse events reported in patients treated Q3Wk (N = 47) were fatigue (40 %), dry eye (32 %), nausea (30 %), and thrombocytopenia (26 %). The nadir for thrombocytopenia typically occurred during Cycle 1. Ocular adverse events (e.g., corneal epitheliopathy, dry eye) were reported for 57 % of patients treated Q3Wk and were generally reversible. Antitumor activity in patients treated Q3Wk included 1 complete response, 2 partial responses, and 20 stable disease. SGN-75 exposures were approximately dose proportional, with a mean terminal half-life of 10 days. Substantial depletions of CD70-positive peripheral blood lymphocytes were observed after SGN-75 treatment. Conclusions Modest single-agent activity and generally manageable adverse events were observed in heavily pretreated RCC and NHL patients. Administration Q3Wk was better tolerated than weekly dosing. Targeted ablation of CD70-positive lymphocytes was demonstrated.
KW - Antibody-drug conjugate
KW - CD70
KW - Non-Hodgkin lymphoma
KW - Phase I clinical trial
KW - Renal cell carcinoma
KW - SGN-75
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U2 - 10.1007/s10637-014-0151-0
DO - 10.1007/s10637-014-0151-0
M3 - Article
C2 - 25142258
AN - SCOPUS:84927557126
SN - 0167-6997
VL - 32
SP - 1246
EP - 1257
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 6
ER -