期刊
BRITISH JOURNAL OF CANCER
卷 113, 期 11, 页码 1548-1555出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2015.380
关键词
immunotoxin; EpCAM; clinical phase I; metastatic disease; anti-immunotoxin antibodies; immunosuppression; cyclosporin
类别
资金
- Norwegian Foundation for Health and Rehabilitation
- Norwegian Cancer Society
- Norwegian Research Council
- South-Eastern Norway Regional Health Authority
- Norwegian Radium Hospital legacy
Background: A phase I trial was performed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics and immunogenicity of the anti-EpCAM immunotoxin (IT) MOC31PE in cancer patients. An important part of the study was to investigate whether the addition of Sandimmune (cyclosporin, CsA) suppressed the development of anti-IT antibodies. Methods: Patients with EpCAM-positive metastatic disease were eligible for treatment with intravenous MOC31PE using a modified Fibonacci dose escalation sequence. Maximum tolerated dose was first established without, then with intravenously administered CsA. Results: Sixty-three patients were treated with MOC31PE in doses ranging from 0.5 to 8 mu gkg(-1). Maximum tolerated dose was 8 mu gkg(-1) for MOC31PE alone, and 6.5 mu gkg(-1) when combined with CsA. The dose-limiting adverse event was reversible liver toxicity. No radiological complete or partial responses were observed, whereas stable disease was seen in 36% of the patients receiving MOC31PE only. The pharmacokinetic profile of MOC31PE was characterised by linear kinetics and with a half-life of similar to 3h. The addition of CsA delayed the generation of anti-IT antibodies. Conclusions: Intravenous infusion of MOC31PE can safely be administered to cancer patients. Immune suppression with CsA delays the development of anti-MOC31PE antibodies. The antitumour effect of MOC31PE warrants further evaluation in EpCAM-positive metastatic disease.
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