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

Q1 · MEDICINE

Article

Author: A. M. Gillespie ; M. Sopwith ; S. Y. Chan ; J. Owen ; T. J. Broadhead ; A. P. Farnsworth ; R. E. Coleman

PURPOSEWe 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 METHODSThirty-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.RESULTSCMB-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.CONCLUSIONSCMB-401 appears to have an acceptable toxicity profile with demonstrable activity against EOC.

01 Jan 1999·BJOG: An International Journal of Obstetrics & Gynaecology

An immunoscintigraphic evaluation of the engineered human monoclonal antibody (hCTMO1) for use in the treatment of ovarian carcinoma

Article

Author: A. C. Perkins ; J. C. Roos ; M. Frier ; T. Broadhead ; E. M. Symonds ; R. H. M. Verheijen ; Q Davies ; C. F. M. Molthoff ; M. Sopwith ; P. Kenemans

Objective To assess the safety and targeting ability of the engineered human antibody (hCTMO1) in women with ovarian carcinoma.Design The monoclonal antibody labelled with Indium‐1 11 was administered to women with suspected primary or recurrent ovarian carcinoma six days pre‐operatively. The first group of women was given a dose of 0.1 mg per kg body weight of radiolabelled antibody. A second group of women received 1 mg per kg body weight and finally a third group was given 1 mg per kg body weight of unlabelled antibody followed one hour later by 0.1 mg per kg body weight of radiolabelled antibody. All the women were then imaged using a gamma camera one hour and up to 96 hours after injection.Participants Fourty‐four women in whom there was a high suspicion of primary ovarian carcinoma on the basis of ultrasound or CT imaging and serum CA125 and those in whom there was a suspicion of recurrent ovarian carcinoma after being treated for histologically confirmed carcinoma.Setting The Queen's Medical Centre, Nottingham and University Hospital Vrije Universiteit, Amsterdam, The Netherlands.Results At the low dose of antibody the sensitivity for detection of ovarian carcinoma was 70%. After increasing the dose of antibody and also after pre‐dosing with unlabelled antibody the sensitivity increased to 100%, but there was a large number of false positive results at the higher dose, and therefore the specificity was low. The liver and bone marrow were the organs with the highest activities.Conclusion The genetically engineered antibody hCTMO1 is safe for use in women. This antibody effectively targets ovarian carcinoma and has greater potential as a vector for therapeutic use than as a diagnostic agent.

14 Aug 1997·Cancer Immunology, ImmunotherapyQ2 · MEDICINE

Comparison of the biological properties of two anti-mucin-1 antibodies prepared for imaging and therapy

Q2 · MEDICINE

Article

Author: Terry Baker ; Kenia Krauer ; Ian F. C. McKenzie ; L. Wenjun ; G. A. Pietersz ; Daniel Wreschner

A comparison was made between the murine anti-MUC1 antibody BC2 (which reacts with the peptide epitope APDTR) and the "humanised" antibody hCTMO1 from CellTech, which reacts with the MUC1 epitope RPAP. Preliminary studies demonstrated that hCTMO1 was a "good" antibody whereas BC2 was not. Various parameters were determined and conclusions reached. (a) Affinity: the affinity of hCTMO1 was 2.60 x 10(7) M(-1) and that of BC2 was 1.36 x 10(7) M(-1); we did not consider these numbers to be substantially different, although hCTMO1 was clearly of higher affinity than BC2. (b) On/off rate at 4 degrees C: both antibodies bound effectively to the MUC-1 transfectant MOR5-CF2; the association rate for hCTMO1 was 3.8 times that of BC2 and the dissociation rate for BC2 was twice as fast as that of hCTMO1. (c) On/off rates at 37 degrees C: at 37 degrees C the association rate for hCTMO1 was greater than that of BC2. (d) Internalization: hCTMO1 was also more efficient at internalising bound antibody; 70% of bound hCTMO1 was internalised, whilst 6% of bound BC2 was internalised. From these studies it was clear that, while hCTMO1 was of similar affinity to BC2, the faster uptake and internalisation and lower off rate indicated that it was likely to be a superior antibody; this was proven in vivo. (e) Localisation: hCTMO1 bound much better in vivo than BC2 (68% compared to 28%). (f) Therapeutic experiments: BC2-idarubicin conjugates were essentially ineffective in eradicating tumours in mice whereas hCTMO1-idarubicin had a dramatic effect on breast cancer tumour cells growing in mice. We conclude that the simple measurements on/off rates and internalisation at 37 degrees C are the most important parameters to use to determine antibody effectiveness, prior to embarking on clinical studies.

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Indication	Highest Phase	Country/Location	Organization	Date
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