Background: IMMU-132 is an ADC of the internalizing, humanized, anti-Trop-2 antibody, hRS7, conjugated by a pH-sensitive linker, to SN-38, the active metabolite of CPT-11 (mean drug-antibody ratio = 7.6). Trop-2 is a type I transmembrane, calcium-transducing, protein expressed at high density (~1 x 10*5), frequency, and specificity by many human carcinomas, with limited normal tissue expression. Methods: We report the initial Phase I trial of 25 patients (pts) who had failed multiple prior therapies (some including topoisomerase-I/II inhibiting drugs), and the ongoing Phase II extension that focused on pts with colorectal (CRC), small-cell lung (SCLC) and triple-negative breast (TNBC) cancers. Results: Trop-2 is not detected in serum, but was strongly expressed (≥2+) in most archived tumors. In a 3+3 trial design, IMMU-132 was given on days 1 and 8 in repeated 21-day cycles, starting at 8 mg/kg/dose, then 12 and 18 mg/kg before dose-limiting neutropenia. To optimize cumulative treatment with minimal delays, phase II is focusing on 8 and 10 mg/kg (n=22 and 14, respectively). Most common non-hematological toxicities were fatigue (17 ≤G2 ,4 G3), nausea (20 ≤G2), diarrhea (12 ≤G2, 3 G3), alopecia (14), and vomiting (10 ≤G2) ; 2 pts had a rash. Homozygous UGT1A1 *28/*28 was found in 5 pts, 2 of whom had more severe hematological and GI toxicities. Over 80% of 24 assessable pts in Phase I had stable disease or tumor shrinkage (17 SD; 3 PR [CRC, TNBC, SCLC]) as best CT response; median TTP = 18 weeks for all pts, except pancreatic cancer. Of the 36 pts in the Phase II, 14 had their first response assessment by CT: 6 PD, 7 SD; 1 PR (SCLC) by RECIST1.1. Tumor markers (CEA, CA19-9) correlated with responses. No anti-hRS7 or anti-SN-38 antibodies were detected despite dosing over months. The conjugate clears within 7 days, consistent with in vivo animal studies where 50% of the SN-38 is released daily. Conclusions: These results indicate that this novel SN-38-containing ADC is active in metastatic solid cancers, with manageable diarrhea and neutropenia. The Phase II continues, while also accruing in other epithelial tumors. Clinical trial information: NCT01631552.