Herbertson, Rebecca A.
(2009)
Optimising targeted antibodies for the treatment of metastatic solid tumours.
DM thesis, University of Nottingham.
Abstract
This thesis describes three different strategies employed with the aim of optimising targeted antibodies for the treatment of metastatic solid tumours. Whilst the search for improved predictors of response to anti-EGFR antibodies continues, paired primary and metastatic archived tissue from 32 patients with metastatic colorectal cancer was explored for the immunohistochemical expression of EGFR, pEGFR and pMAPK and activating mutations in KRAS, BRAF and PI3KCA. The resulting discordance between expression of pEGFR and pMAPK between primary and metastatic tissue CRC suggests they are unlikely to be useful biomarkers for response unless metastatic tissue is also analysed. Confirmation that mutations in KRAS, BRAF and PI3KCA are concordant in primary and metastatic tissue supports the analysis of archived primary tissue alone for mutation screening. PI3KCA mutations were shown to be present in patients with both wild-type and mutant KRAS, which provides both an additional method for resistance in wild type tumours and a mechanism for high resistance in those with mutant primary tumours, suggesting screening patients for all 3 mutations should be encouraged for future trials of anti-EGFR antibodies.
The Phase I biodistribution study of Ley targeting immunoconjugate in advanced epithelial cancers, primarily explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 (a humanised anti-Ley antibody conjugated with calicheamicin) in 9 patients with advanced Ley expressing solid tumours. Cycle one was trace labelled with 111In for biodistribution assessment, and subsequent cycles were administered every 3 weeks, to a maximum of 6 cycles, depending on toxicity and response. Tumour targeting was assessed using gamma camera imaging and single photon emission computerised tomography (SPECT), and PK analysis was based on gamma counting of 111In-CMD-193. There were 2 dose cohorts (1.0mg/m2 and 2.6mg/m2), and patients with Ley positive, measurable, advanced and treatment refractory malignancies, were eligible. Nine patients (6 in dose cohort 1, 3 in cohort 2) were enrolled (and received 1-6 cycles of treatment) before the study was terminated. Biodistribution imaging demonstrated initial blood pooling, followed by markedly increased hepatic uptake by day 2 (persisting to day 8), and fast blood clearance. This pattern was seen for all patients and dose levels. There was no significant uptake in tumour visualised in any patient. The overall T 1/2 β of 111In-CMD-193 was 102.88 ± 35.67 hours, with no statistically significant difference between the 2 dose levels. One patient had a partial metabolic response on 18F-FDG PET after 4 cycles, but no radiologic responses were observed. Myelosuppression and effects on liver function were the most significant toxicities, but no severe or unexpected toxicities were observed. The result of this trial highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development.
The Phase I trial of oral capecitabine combined with 131I-huA33 in patients with metastatic colorectal cancer built on the previous development of the humanised antibody huA33 which targets the A33 antigen, known to be expressed in >95% of human colon cancers. This study used radiolabelled huA33 in combination with capecitabine chemotherapy to target chemoradiation to metastatic colorectal cancer, with safety and tolerability being the primary objective. Pharmacokinetics, biodistribution, immunogenicity, and tumour response were also assessed. Eligibility included measurable metastatic colorectal cancer, adequate hematological and biochemical function, and informed consent. An outpatient scout 131I-huA33 dose was followed by a single therapy infusion one week later, when capecitabine was commenced. Dose escalation occurred over 5 dose levels. Patients were evaluated weekly, with tumor response assessment at the end of the 12-week trial. Tumour targeting was assessed using gamma camera and single photon emission computerised tomography (SPECT) imaging. Nineteen patients were enrolled, and although the dose escalation protocol required an amendment following 2 dose-limiting toxicities in the second cohort, subsequent cohorts demonstrated good tolerability. Biodistribution analysis demonstrated excellent tumour targeting of the known tumour sites, expected transient bowel uptake, but no other normal tissue uptake. 131I-huA33 therefore achieves specific targeting of radiotherapy to sites of metastasis and can be safely combined with chemotherapy, providing a promising opportunity to deliver chemoradiation specifically to metastatic disease in colorectal cancer patients.
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