title: Phase I open study of the effects of ascending doses of the cytotoxic immunoconjugate CMB-401 (hCTMO1-calicheamicin) in patients with epithelial ovarian cancer.
abstract: OBJECTIVE
  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).
  
  
  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 'predose' 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.
authors.affiliation: Yorkshire Cancer Research Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Gillespie
authors.forename: T J
authors.initials: TJ
authors.lastname: Broadhead
authors.forename: S Y
authors.initials: SY
authors.lastname: Chan
authors.forename: J
authors.initials: J
authors.lastname: Owen
authors.forename: A P
authors.initials: AP
authors.lastname: Farnsworth
authors.forename: M
authors.initials: M
authors.lastname: Sopwith
authors.forename: R E
authors.initials: RE
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D018394:CA-125 Antigen; D002277:Carcinoma / Q000188:drug therapy* / Q000401:mortality; D053281:Enediynes; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018394:CA-125 Antigen; D053281:Enediynes; C421256:hCTMO1-calicheamicin