Abstract C67: Safety, efficacy, and pharmacokinetics of a new humanized anti-Trop-2 antibody-SN-38 conjugate (IMMU-132) for the treatment of diverse epithelial cancers: Phase I clinical experience.
Authors: Starodub Alexander N. , Ocean Allyson J. , Guarino Michael J. , Chuang Ellen , Shah Manish A. , Tagawa Scott , Picozzi Vincent J. , Thomas Sajeve S. , Maliakal Pius P. , Wegener William A. , Sharkey Robert M. , Govindan Serengulam V. , Goldenberg David M. 
Published: August 2014

Abstract
Trop-2 (trophoblastic antigen-2; aka EGP-1, GA733-1) is a surface glycoprotein differentially expressed on a variety of malignant epithelial cancers, making it an interesting target for antibody directed therapeutics. Preclinical studies with an anti-Trop-2 IgG, designated RS7 (Stein et al. Cancer Res 1990;50:1330-36), showed targeting of human cancer xenografts and antibody internalization. An antibody-drug conjugate (IMMU-132) was prepared by conjugating humanized RS7 with SN-38 (6 moles SN-38/IgG), the highly potent topoisomerase-I-inhibitor metabolite of irinotecan. The linker allows SN-38 release from the conjugate at low pH, such as in the tumor microenvironment or lysosomes. IMMU-132 was effective against several human cancer xenograft models, with a high therapeutic window. Primate studies found dose-limiting neutropenia and gastrointestinal (GI) toxicity identical to irinotecan, but no selective damage to normal tissues expressing Trop-2 (Cardillo et al. Clin Cancer Res 2011;17:3157-69). A multicenter Phase I clinical trial was initiated in a diverse, metastatic, solid tumor population, who had failed ≥ 1 prior standard therapeutic regimen for their tumor type. In a standard 3+3 trial design, eligible patients (pts) received multiple 21-day cycles of IMMU-132 with weekly dosing in the first 2 weeks followed by 1 week rest. Dose delay and reduction were permitted for treatment-related toxicities occurring on scheduled treatment days. Doses started at 8 mg/kg with 3 pts tolerating multiple cycles with no toxicity. Escalation continued to 12 and 18 mg/kg, when further escalation was stopped due to dose-limiting neutropenia in 2/3 pts at 18 mg/kg. In addition, grade 1-2 GI toxicities were reported in several pts, and grade 1/2 rash in 2 pts. The maximum tolerated dose was 12 mg/kg (0.19 mg/kg SN-38 equivalents), with no pts experiencing a dose-limiting event (i.e., grade 4 neutropenia &gt;5 days) in the first cycle. However, there were frequent interruptions in the planned dosing at this level, which also required dose reductions. To establish a maximum acceptable dose, an intermediate dose level of 10 mg/kg is under evaluation with 5 pts currently in the early stages of treatment without any need for dose reduction or delay. Twenty-four pts have been enrolled to date at all dose levels, with 14 having at least 1 CT assessment and 10 not due yet for the first assessment. Objective partial responses by RECIST 1.0 were observed in 3 pts, one each with colon cancer (CEA also decreased from 781 to 39 ng/mL), triple-negative breast cancer, and small cell lung cancer at the 8 and 12 mg/kg, with lesser degrees of tumor shrinkage (stabilization) in several other pts. Clearance of the intact conjugate and IgG monitored by ELISA showed the intact conjugate clearing more quickly than the IgG, reflecting the expected release of SN-38 from the conjugate. SN-38 concentrations were estimated to be nearly 30-times higher in the serum than that reported with irinotecan therapy. Accrual is completed and therapy continuing in diverse cancers at the 8 and 10 mg/kg dose levels. Thus, IMMU-132 represents a promising, novel antibody-drug conjugate with acceptable toxicity and significant activity in this refractory, advanced, cancer population with difficult-to-treat tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C67.
Citation Format: Alexander N. Starodub, Allyson J. Ocean, Michael J. Guarino, Ellen Chuang, Manish A. Shah, Scott Tagawa, Vincent J. Picozzi, Sajeve S. Thomas, Pius P. Maliakal, William A. Wegener, Robert M. Sharkey, Serengulam V. Govindan, David M. Goldenberg. Safety, efficacy, and pharmacokinetics of a new humanized anti-Trop-2 antibody-SN-38 conjugate (IMMU-132) for the treatment of diverse epithelial cancers: Phase I clinical experience. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C67.