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Annals of Oncology 11:735-741, 2000
© 2000 European Society for Medical Oncology

research-article

Phase I open study of the effects of ascending doses of the cytotoxic immunoconjugate CMB-401 (hCTMO1-calicheamicin) in patients with epithelial ovarian cancer

A. M. Gillespie1, T. J. Broadhead2, S. Y. Chan2, J. Owen1, A. P. Farnsworth3, M. Sopwith3 and R. E. Coleman1,

1Yorkshire Cancer Research Department of Clinical Oncology, Weston Park Hospital Sheffield
2Department of Clinical Oncology, City Hospital Nottingham
3Celltech Therapeutics Slough, UK

Correspondence to: R. E. Coleman, MD, Yorkshire Cancer Research Department of Clinical Oncology, Weston Park Hospital, Whitham Road, Sheffield S10 2SJ, UK

Purpose: We have performed a phase I study of the cytotoxic immunoconjugate CMB-401 in women with epithelial ovarian cancer (EOC). CMB-401 is a directed chemotherapy that comprises a genetically engineered human antibody against polymorphic epithelial mucin, to which is attached covalently two to three molecules, on average, of the cytotoxic antibiotic calicheamicin. The primary objectives of this two-centre study were to identify end-organ toxicities and to establish the maximum tolerated dose (MTD).

Patients and methods: Thirty-four patients aged 37–75 years with progressive EOC not amenable to platinum/standard therapy, and with satisfactory WHO performance status (0–2) were recruited. Patients had received a mean of 3.2 previous chemotherapeutic regimens with a median interval since last chemotherapy of 182 days (range 34–1217). Patients received up to four cycles of a dual infusion of 35 mg/m2 hCTMO1 ‘pre-dose’ followed by doses of CMB-401 which were increased for each cohort - a regimen which minimises drug uptake in normal tissues whilst enhancing delivery to the ovarian tumour. CMB-401 dosing commenced at 2 mg/m2 and progressed via seven cohorts to 16 mg/m2.

Results: CMB-401 was generally well tolerated. However, transient fever and emesis occurred, necessitating routine prophylaxis, and increasingly significant malaise was reported as the dose increased. WHO grade 3–4 toxicities, irrespective of causality, included: anaemia 21%, granulocytopenia 9%, thrombocytopenia 9%, liver transaminases 3%, sepsis 3%, haemorrhage 6%, nausea/vomiting 76%; pulmonary 6%, and conscious state/somnolence 6%. The MTD was reached at 16 mg/m2. During the study four patients had a greater than 50% reduction in CA125, and three patients had radiological evidence of reduction in tumour bulk.

Conclusions: CMB-401 appears to have an acceptable toxicity profile with demonstrable activity against EOC.

antibody, calicheamicin, CMB-401, immunotherapy, ovarian cancer


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