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- Jayson, Gordon, et al.
(författare)
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Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody : Implications for trial design of antiangiogenic antibodies
- 2002
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Ingår i: Journal of the National Cancer Institute. - 0027-8874 .- 1460-2105. ; 94:19, s. 1484-1493
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial. Methods: Twenty patients with progressive solid tumors were treated with various doses of HuMV833 0.3, 1, 3, or 10 mg/kg). Positron emission tomography with 124I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (Kfp) to determine tumor vascular permeability. Results: The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic end-points could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumor. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in kfp 48 hours after the first treatment (median = 44%, range = 4%-91%). Conclusions: Because of the heterogeneity in tumor biology with respect to anti-body uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with anitiangiogenic compounds like HuMV833.
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| 2. |
- LoRusso, Patricia M, et al.
(författare)
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Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors
- 2003
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 9:6, s. 2040-2048
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The feasibility and utility of assessing quality of life (QoL) and disease-related symptoms in patients with advanced cancer have been evaluated in two Phase I clinical trials of p.o. administered ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced cancer. EXPERIMENTAL DESIGN: Functional Assessment of Cancer Therapy (FACT) questionnaires, including disease-specific subscales for lung, head and neck, colorectal, prostate, and ovarian cancer, were completed by patients in two open-label, Phase I, escalating multiple-dose safety and tolerability trials. RESULTS: In 157 patients, 92% of whom had received prior therapy, compliance in returning FACT questionnaires was 87% (European/Australian trial) and 57% (United States trial). This did not appear to be influenced by dose level or tumor type. For patients with colorectal, prostate, or ovarian cancer, median QoL [FACT and Trial Outcome Index (TOI)] scores deteriorated over time. In contrast, for patients with non-small cell lung cancer (NSCLC) or head and neck cancer, median FACT and TOI scores did not deteriorate significantly, and in the United States trial, head and neck cancer scores improved significantly over time. In patients with NSCLC, symptom-related scores measured by the Lung Cancer Subscale of FACT-L appeared sensitive to clinical change. CONCLUSIONS: QoL (FACT-L) questionnaires were used successfully in the Phase I clinical trials of ZD1839. They appeared to be a sensitive tool to monitor clinical changes for the five tumor types in these trials and showed that ZD1839 has the potential to improve patients' QoL.
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