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

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 direct ed chemotherapy that comprises a genetically engineered human antibody agai nst polymorphic epithelial mucin, to which is attached covalently two to th ree molecules, on average, of the cytotoxic antibiotic calicheamicin. The p rimary objectives of this two-centre study were to identify end-organ toxic ities and to establish the maximum tolerated dose (MTD). Patients and methods: Thirty-four patients aged 37-75 years with progressiv e 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 chem otherapy of 182 days (range 34-1217). Patients received up to four cycles o f a dual infusion of 35 mg/m(2) hCTMO1 'pre-dose' followed by doses of CMB- 401 which were increased for each cohort - a regimen which minimises drug u ptake in normal tissues whilst enhancing delivery to the ovarian tumour. CM B-401 dosing commenced at 2 mg/m(2) and progressed via seven cohorts to 16 mg/m(2). Results: CMB-401 was generally well tolerated. However, transient fever and emesis occurred, necessitating routine prophylaxis, and increasingly signi ficant malaise was reported as the dose increased. WHO grade 3-4 toxicities , irrespective of causality, included: anaemia 21%, granulocytopenia 9%, th rombocytopenia 9%, liver transaminases 3%, sepsis 3%, haemorrhage 6%, nause a/vomiting 76%; pulmonary 6%, and conscious state/somnolence 6%. The MTD wa s reached at 16 mg/m(2). During the study four patients had a greater than 50% reduction in CA125, and three patients had radiological evidence of red uction in tumour bulk. Conclusions: CMB-401 appears to have an acceptable toxicity profile with de monstrable activity against EOC.