title: Phase I dose-escalation study of SGN-75 in patients with CD70-positive relapsed/refractory non-Hodgkin lymphoma or metastatic renal cell carcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: MD, FACP; MD Anderson Cancer Center, Department of Genitourinary Medical Oncology, 1155 Pressler St, Unit 1374, Houston, TX, 77030, USA, ntannir@mdanderson.org.
authors.forename: Nizar M
authors.initials: NM
authors.lastname: Tannir
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Ramchandren
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Paul A
authors.initials: PA
authors.lastname: Hamlin
authors.forename: Stella K
authors.initials: SK
authors.lastname: Kim
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Whiting
authors.forename: Elaina M
authors.initials: EM
authors.lastname: Gartner
authors.forename: Baiteng
authors.initials: B
authors.lastname: Zhao
authors.forename: John A
authors.initials: JA
authors.lastname: Thompson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D053282:CD27 Ligand / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D009842:Oligopeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D066066:Response Evaluation Criteria in Solid Tumors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D053282:CD27 Ligand; C505771:CD70 protein, human; D018796:Immunoconjugates; D009842:Oligopeptides; C000599296:SGN-75 antibody-drug conjugate