Abstract CT206: SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results
Authors: Starodub Alexander N. , Ocean Allyson J. , Shah Manish A. , Vahdat Linda T. , Chuang Ellen , Guarino Michael J. , Picozzi Vincent J. , Thomas Sajeve S. , Maliakal Pius P. , Govindan Serengulam V. , Wegener William A. , Sharkey Robert M. , Goldenberg David M. 
Published: May 2015

Abstract
IMMU-132 is an ADC of the active metabolite of CPT-11, SN-38, conjugated by a pH-sensitive linker (average drug-antibody ratio = 7.6) to the humanized anti-Trop-2 antibody, hRS7, exhibiting rapid internalization after binding to Trop-2. Trop-2 is a type I transmembrane protein expressed at high prevalence (∼1 x 10*5) and specificity by many carcinomas. We report the results of a Phase I clinical trial of 25 patients with different metastatic cancers (pancreatic, 7; triple-negative breast [TNBC], 4; colorectal [CRC], 3; gastric, 2; small-cell lung [SCLC], 2; esophageal, prostatic, ovarian, non-small-cell lung, renal, tonsillar, urinary bladder, 1 each) after failing a median of 3 prior treatments (some including topoisomerase-I and -II inhibiting drugs). IMMU-132 was administered in repeated 21-day cycles, with each treatment given on days 1 and 8. Dosing started at 8 mg/kg/dose (i.e., 16 mg/kg/cycle), and escalated to 18 mg/kg before encountering dose-limiting neutropenia, in a 3+3 trial design. Fatigue, alopecia, and occasional mild to moderate diarrhea were some of the more common non-hematological toxicities, with 2 patients also reporting a rash. Over 80% of 24 assessable patients had stable disease or tumor shrinkage (17/24 SD; 3/24 PR) among the various metastatic cancers as best response by CT. Three patients (CRC, TNBC, SCLC) have PRs by RECIST; median TTP for all patients, excluding those with pancreatic cancer, is &gt;18 weeks. Neutropenia has been controlled by dose reduction to 8-10 mg/kg/dose (16-20 mg/kg/cycle), which is the Phase II dose. Immunohistochemistry showed strong expression of Trop-2 in most archived patient tumors, but is not detected in serum. Corresponding reductions in blood tumor marker titers (e.g., CEA, CA19-9) reflected tumor responses. No anti-antibody or anti-SN-38 antibodies have been detected despite repeated dosing. Peak and trough assessments of IMMU-132 concentrations in the serum show that the conjugate clears completely within 7 days, an expected finding based on in vitro studies showing 50% of the SN-38 is released in the serum every day. These results indicate that this novel ADC, given in doses ranging from 16-24 mg/kg per cycle, is active in diverse metastatic solid cancers. A Phase II study is ongoing to determine response rates in CRC, TNBC, and SCLC, while also evaluating its potency in other tumor types.
Citation Format: Alexander N. Starodub, Allyson J. Ocean, Manish A. Shah, Linda T. Vahdat, Ellen Chuang, Michael J. Guarino, Vincent J. Picozzi, Sajeve S. Thomas, Pius P. Maliakal, Serengulam V. Govindan, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT206. doi:10.1158/1538-7445.AM2014-CT206