Abstract LB-159: A Phase I study of IMMU-130 (labetuzumab-SN38) anti-CEACAM5 antibody-drug conjugate (ADC) in patients with metastatic colorectal cancer (mCRC).
Authors: Segal Neil H. , Verghis Jaclyn , Govindan Serengulam , Maliakal Pius , Sharkey Robert M. , Wegener William A. , Goldenberg David M. , Saltz Leonard B. 
Published: August 2014

Abstract
Background: IMMU-130 is an ADC comprising the humanized monoclonal IgG antibody (mAb), hMN-14 (labetuzumab), bound to the active metabolite of irinotecan, SN-38 (6 SN-38/IgG). hMN-14 a slowly-internalizing mAb, recognizes the CEA (CEACAM5; CD66e) antigen, which is expressed in many solid cancers, including &gt;80% of CRC. hMN-14 was safe in prior clinical trials, when administered unconjugated or bound to 131-I for radioimmunotherapy. In vitro studies showed that the antibody-drug linkage was susceptible to cleavage in serum, with 50% of SN-38 released in ~1.0 day. This means that after the antibody binds to its tumor target, SN-38 is released, leading to a locally enhanced concentration within the tumor site. Irinotecan is a standard therapy of mCRC, but has major gastrointestinal and hematologic toxicity. By targeting SN-38 directly to CEA-expressing tumors, delivery of SN-38 may be increased while avoiding systemic toxicity. In animal CRC xenograft models, IMMU-130 exhibited high anti-tumor activity. A safe starting dose for humans was determined from preclinical toxicology studies that showed no gastrointestinal toxicity, and only transient mild myelosuppression. This single-arm, open-label, dose-escalation, phase I study was undertaken to define the maximum-tolerated dose (MTD) of IMMU-130 in patients with mCRC. Methods: Eligible patients were previously treated with at least one prior irinotecan-containing regimen, had serum CEA &gt;5 ng/mL, and measurable disease by CT/MRI. IMMU-130 was administered every-other-week, with a goal of achieving 12 cycles (24 weeks) in the absence of unacceptable toxicity or disease progression. Pts were entered in cohorts treated at increasing dose levels, with DLT defined as Grade 4 neutropenia ≥ 5 days, ≥ Grade 3 thrombocytopenia, Grade 3 anemia, ≥Grade 3 nausea, vomiting or diarrhea persisting &gt;48 hr, and other ≥ Grade 3 non-hematologic toxicity during the first two cycles. Results: So far 9 pts have been treated at the 2, 4, 8, and 16 mg/kg dose levels. Pts had received a median of 2 prior regimens. The median number of cycles given is 3.9, with 6/9 patients receiving 3 or more doses. Of 5 pts having &gt;2 doses of 16 mg/kg, one has currently received 14 doses and has a continuing partial response after 8. One DLT was observed at 16 mg/kg: Grade 3 thrombocytopenia. The same pt experienced Grade 4 neutropenia &lt;5 days. A second pt at the same dose also had Grade 4 neutropenia &lt;5 days. No grade 2 or higher drug-related GI toxicities were observed. A single case of hypersensitivity occurred. No human anti-human antibodies (HAHA) have been detected to date. Analysis of serum samples shows the intact conjugate clears more quickly than the Ig, consistent with SN-38 being gradually released from the ADC. Conclusion: IMMU-130 appears to be safe and reasonably well tolerated within a clinically effective dosage range. Dose escalations are continuing.
Citation Format: Neil H. Segal, Jaclyn Verghis, Serengulam Govindan, Pius Maliakal, Robert M. Sharkey, William A. Wegener, David M. Goldenberg, Leonard B. Saltz. A Phase I study of IMMU-130 (labetuzumab-SN38) anti-CEACAM5 antibody-drug conjugate (ADC) in patients with metastatic colorectal cancer (mCRC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-159. doi:10.1158/1538-7445.AM2013-LB-159