Background: Trop-2 is a tumor-associated glycoprotein highly expressed in many epithelial cancers. Elevated expression has been linked to more aggressive disease and a poorer prognosis. IMMU-132 is an ADC comprising a humanized mAb binding to Trop-2 and conjugated to SN-38 (drug: Ab ratio = 7.6), the active metabolite of irinotecan. After finding potent activity in human tumor xenografts, a phase I/II trial was undertaken (NCT01631552). Methods: Pts with relapsed/refractory metastatic cancers were enrolled, starting at a dose of 8 mg/kg given on days 1 and 8 of a 3-week cycle. Dose levels of 8 and 10 mg/kg were chosen for phase II (N=47). Results: Sixty pts with advanced GI cancers were enrolled in phase I/II. Neutropenia was the principal dose-limiting toxicity, with fatigue, diarrhea, nausea, and vomiting as other reported toxicities. In the phase II pts with median prior therapies of 3 (range 1-7), the following moderate/severe drug-related toxicities occurred: neutropenia (Gr 3, 18.8%; Gr 4, 10.4%); fatigue (Gr 3, 14.6%; Gr 4, 0%), anemia (Gr 3, 10.4%; Gr 4, 0%); diarrhea (Gr 3, 4.2%; Gr 4, 0%). Of 29 CRC pts (10 mg/kg [N=9], 8 mg/kg [N=20]), 1 had a PR and 14 had SD as the best response by RECIST, with a time to progression (TTP) of 11.5+ months (mo) for the PR (65% shrinkage) and a median of 4.8+ mo for the SD pts (5 ongoing). This is a disease control rate (DCR) of 51.7%. Thirteen CRC pts had KRAS mutations, 7 with SD (median TTP = 4.4+ mo [range, 2.8-7.8 mo; 3 ongoing]). Of 15 pts with pancreatic ca, 8 had SD as best RECIST response (median TTP = 3.4 mo); DCR=53.3%. Among 11 pts with esophageal ca, 7 had CT assessments with 1 PR (TTP, 6.9+ mo), and 4 SD (TTP, 4.0+, 5.0, 6.0, and 6.9 mo) as best response; DCR=62.5%. Of 5 gastric ca pts, only 3 had post-baseline CT assessments, all with SD (1 with 19% target lesion reduction and an ongoing TTP of 6.7+ mo). Conclusions: IMMU-132 is a novel anti-cancer therapeutic, conjugating a topoisomerase I inhibitor to an internalizing, cancer-selective mAb. This ADC can be given safely and repeatedly over many months to heavily pretreated patients. Encouraging activity in pts with several metastatic gastrointestinal tumors has been observed. Clinical trial information: NCT01631552