Background: SGN-75 is an antibody-drug conjugate composed of a humanized anti-CD70 mAb conjugated to the microtubule-disrupting agent MMAF via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‑mcMMAF which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase 1, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL (ClinicalTrials.gov #NCT01015911). SGN-75 was administered IV in cohort-specific doses using 2 schedules [every 3 weeks (q3wk) or weekly (days 1, 8, 15 q28 days)] at doses of 0.3-4.5 mg/kg. Pts were eligible to receive treatment until PD. Results: A total of 58 pts (39 RCC/19 NHL) with a median age of 60.5 yrs (range 30-82) were treated. The MTD was 3 mg/kg q3wk; 2 pts had DLTs at 4.5 mg/kg q3wk (NHL pt had neutropenia and RCC pt had proteinuria). Weekly dosing (N=11) was terminated at the 0.6 mg/kg dose level after 2 pts with NHL developed idiopathic thrombocytopenic purpura. At the MTD, adverse events (AEs) in ≥30% of RCC pts (N=21) were fatigue (52%), dry eye (48%), nausea (38%), constipation (33%), and corneal epithelium defect (33%). AEs ≥ Grade 3 in >10% of RCC pts treated at the MTD were corneal epithelium defect (19%) and thrombocytopenia (14%). PK analysis suggested that SGN-75 exposure was approximately dose-proportional with a mean terminal half-life of 6-11 days. Among the 32 pts with RCC treated in the q3wk schedule, all had prior nephrectomy and a median of 3 prior therapies (range 1-6). All pts had clear cell RCC, with the exception of 2 pts who had papillary RCC. Most pts had high CD70 expression by central IHC analysis (2 or 3+, 80-100% of cells). The best clinical responses of RCC pts treated q3wk were 2 PR, 12 SD, 12 PD, and 6 were not evaluable. Durations of response for the 2 responding pts were 23 and 41 weeks. The median duration of disease control (PR and SD) was 46.4 weeks [95% CI (12, 46)]. Conclusions: SGN-75 monotherapy was generally well tolerated in pts with metastatic RCC. Evidence of antitumor activity was observed in heavily pretreated RCC pts and further studies of SGN-75 in RCC are warranted. Clinical trial information: NCT01015911.