Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

Background: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. Methods: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. Results: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. Conclusions: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

Optimising targeted antibodies for the treatment of metastatic solid tumours

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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Optimising targeted antibodies for the treatment of metastatic solid tumours

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

High Acceptability of Donating Hair and Other Biological Samples for Research Among People Living with HIV in an Outpatient Clinic in Lagos, Nigeria

Willingness to donate hair samples is a rate-limiting step for assaying antiretroviral (ARV) concentrations in hair, an emerging technique for HIV prevention and treatment monitoring. We surveyed ethnically diverse Nigerians to determine their willingness to donate hair for biomedical research. A cross-sectional survey of people living with HIV on ARV therapy (ART) was conducted at the HIV clinic of Nigerian Institute of Medical Research, using systematic sampling. The researcher-administered questionnaire was designed to capture sociodemographic data, length of time on ART, and willingness to donate hair. Univariate analysis was performed on sociodemographic characteristics, and independent-samples t-test and chi-square tests were used for bivariate analysis. Multivariable logistic regression analysis was performed to assess factors associated with willingness to donate hair samples, with a significance level of 0.05. Of the 398 participants enrolled in the study, 258 (64.8%) were female, the average age was 40 years (±9.8), and the average time spent on ART was 7.3 years (±4.2). More than half (64.8%) of the respondents were willing to donate hair samples for biomedical research and they were 1.5 times more likely to donate hair than blood. For one-third of the participants, the anticipated benefit from the eventual research findings was the primary motivation to donate hair samples. Fear of use of hair for rituals was the most common stated reason for unwillingness to donate hair samples (21.2%). In an ethnically diverse, urban-based Nigerian study population, nearly two-thirds of the participants were willing to donate hair samples for biomedical research. These findings support the feasibility of hair sampling for future HIV clinical research conducted within Nigeria

Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers

Purpose: This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti-Lewis Y (Le) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Le antigen. Experimental Design: The primary objectiveswere to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Le positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m. The first cycle was trace labeled with In for biodistribution assessment using υ camera imaging. Subsequent cycleswere administered every 3weeks upto amaximumof six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA. Results: Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall Tβ of 111In-CMD-193 was 102.88±35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on F-fluorodeoxyglucose-positron emission tomography ( F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects. Conclusions: CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development