Journal Article

Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma

de Vos, Sven, Whiting, Nancy C., Tannir, Nizar M., Ramchandren, Radhakrishnan, Zhao, Baiteng, Infante, Jeffrey R., Kim, Stella K., Hamlin, Paul A., Thompson, John A., Gartner, Elaina M., Pal, Sumanta K., Forero-Torres, Andres, Ansell, Stephen M.

2014

Overview

Summary 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.

• Publisher: Springer US,Springer,Springer Nature B.V
• Subject: Adult / Aged / Aged, 80 and over / Antibodies / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - pharmacokinetics / Antibodies, Monoclonal, Humanized - pharmacology / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic agents / Antineoplastic Agents - adverse effects / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Biological and medical sciences / Cancer therapies / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - metabolism / CD27 Ligand - metabolism / Cell cycle / Cell division / Clinical trials / Creatinine / Dose-Response Relationship, Drug / Drug dosages / Female / Hematologic and hematopoietic diseases / Humans / Immunoconjugates - adverse effects / Immunoconjugates - pharmacokinetics / Immunoconjugates - pharmacology / Immunoconjugates - therapeutic use / Kidney cancer / Kidney Neoplasms - drug therapy / Kidney Neoplasms - metabolism / Kidneys / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Lymphocytes / Lymphoma / Lymphoma, Non-Hodgkin - drug therapy / Lymphoma, Non-Hodgkin - metabolism / Male / Maximum Tolerated Dose / Medical sciences / Medicine / Medicine & Public Health / Metastasis / Middle Aged / Multiple tumors. Solid tumors. Tumors in childhood (general aspects) / Neoplasm Recurrence, Local - drug therapy / Neoplasm Recurrence, Local - metabolism / Nephrology. Urinary tract diseases / Oligopeptides - adverse effects / Oligopeptides - pharmacokinetics / Oligopeptides - pharmacology / Oligopeptides - therapeutic use / Oncology / Pharmaceutical sciences / Pharmacology. Drug treatments / Pharmacology/Toxicology / Phase I Studies / Remission (Medicine) / Response Evaluation Criteria in Solid Tumors / Studies / Thrombocytopenia / Tumors / Tumors of the urinary system