Background: Somatostatin receptor 2 (SSTR2) is highly expressed in NET and SCLC. PEN-221, a SSA-DM1 conjugate that targets SSTR2, results in complete tumor regressions in SSTR2+ SCLC xenograft models. This study assesses safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-221. Methods: Pts with progressive, advanced, SSTR2+ (by imaging) NET or SCLC were enrolled in escalating cohorts of 2-6 pts. The primary objective was to determine the maximum tolerated dose (MTD) of PEN-221 given every (q) 3 wks. An adaptive Bayesian logistic regression model was used to recommend doses. Intra-patient dose escalation was permitted. Preliminary efficacy was assessed using RECIST 1.1. Results: 23 pts (13 M/ 10 F) with NET (GI, pancreatic, lung, renal or pheochromocytoma; n = 9, 5, 5, 1, 2), or SCLC (n = 1) were treated in 7 cohorts (range 1-25 mg). As of 31 Jan 2018, the median/mean number of cycles is 3/5.8 (range 1-18), with 5 pts ongoing. PEN-221 was well tolerated with no dose limiting toxicities (DLTs) in the first 6 cohorts (1-18 mg; 20 pts). In cohort 7 (25 mg), 2 of 3 pts had DLTs that rapidly and fully resolved: Grade(G)3 ALT/AST rise (2 pts), of whom 1 had concurrent G3 total bilirubin rise and G3 mucositis. The MTD was established at 18 mg. The most frequent (≥20% pts) PEN-221 related adverse events were fatigue (43%), nausea (43%), diarrhea (39%), vomiting (26%), abdominal pain (22%), and decreased appetite (22%). PK was dose proportional, median t_1/2 ~1.7 h, with plasma exposures at MTD above preclinically efficacious levels. Among 15 NET pts who were evaluable for response, 11 had stable disease (SD) at 9 wks, of whom 8 were sustained for 18 – 45 wks, including 2 ongoing pts with SD for 44 and 45 wks. Target lesion shrinkage was observed in 3 pts (dose range 8-18 mg). One pt had a rapid and sustained decrease in chromogranin A and circulating tumor cells. One SCLC pt had SD for 12 wks. Conclusions: PEN-221 appears well tolerated with preliminary evidence of antitumor activity. PEN-221 (18 mg q 3 wks) will be evaluated in Phase 2a expansion cohorts enrolling midgut NET, pancreatic NET, and SCLC pts (EudraCT 2016-001468-12; NCT02936323). Clinical trial information: NCT02936323