Abstract P-1254:
Safety and pharmacology of the EpCAM/CD3-bispecific BiTE antibody MT110 in patients with metastatic colorectal, gastric or lung cancer
Citation: European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 136
W. Fiedler1, D. Hönemann2, B. Ritter3, C. Bokemeyer1, P. Fettes4, M. Klinger4, C. Reinhardt4, G. Zugmaier4, S. Kaubitzsch4, M. Wolf3
1Universitätsklinikum Hamburg-Eppendorf, Department of Medicine II, Hamburg, Germany
2Universitätsklinikum Würzburg, Department of Medicine II, Würzburg, Germany
3Klinikum Kassel, Department of Medicine IV, Kassel, Germany
4Micromet AG, Department of Clinical Development, München, Germany
Background: MT110 is a bispecific antibody construct (BiTE) binding to epithelial cell adhesion molecule (EpCAM), expressed on most solid cancers of epithelial origin, and to CD3 on T cells. MT110 has shown high anti-tumor activity in various preclinical models including a human colorectal cancer (CRC) xenograft. Clinical proof of concept for BiTE antibodies has been demonstrated with blinatumomab (CD19xCD3) in patients (pts) with B cell lymphoma [1].
Methods: This phase 1 study evaluates safety, tolerability, pharmacokinetics/-dynamics and anti-tumor effects of MT110 in pts with advanced solid tumors expressing EpCAM. A dose escalation with 3–6 pts per cohort is used to determine the maximum tolerated dose (MTD). Starting dose was 1 µg/d given as continuous i.v. infusion for 1 or more 28-day cycles.
Results: To date, a total of 14 pts (3 gastric, 9 CRC, 1 NSCLC, 1 SCLC; up to 7 previous chemotherapies) have been treated in 4 cohorts up to 10 µg/d. Overall, MT110 was very well tolerated with few clinical adverse events. All but 1 of the treated pts completed at least 4 wks of therapy. Besides initial lymphopenia, an increase in liver enzymes, up to grade 3/4, was the most frequent laboratory abnormality. These events were transient in nature and not found to impact on liver synthesis nor were any abnormal results seen in imaging (ultrasound, CT scan, and/or MRI of the liver). The increase in liver enzymes did not occur on re-exposure to MT110. Concomitant corticosteroids were found to mitigate increases in liver enzymes and further optimization of the treatment schedule is currently ongoing. As observed with blinatumomab, MT110 caused a rapid redistribution of lymphocytes shortly after start of infusion. Signs of T cell expansion/-activation were seen in pts with clinical benefit after 4 wks. Disease stabilization according to RECIST was confirmed in 6 of 13 pts, lasting 12 wks in median. In one patient, a lung metastasis was resected 11 wks after initiation of MT110 treatment. Immunohistochemistry revealed tumor cell necrosis and a massive T cell infiltration as possible evidence of MT110 activity. None of the pts developed antibodies against MT110.
Conclusion: First signs of biological activity of MT110 in pts with advanced EpCAM-expressing tumors have been observed at clinically well tolerated doses. Optimization of the treatment schedule and evaluation of BiTE antibody MT110 at higher doses is currently ongoing.
References:
1. Bargou R et al. (2008) Science 321:974. |
