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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. |
- Whelan, Jeremy, et al.
(författare)
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High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk ewing sarcoma : Results of Euro-E.W.I.N.G.99 and Ewing-2008
- 2018
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 36:31, s. 3110-3119
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Tidskriftsartikel (refereegranskat)abstract
- Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis >200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year eventfree survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel comparedwith VAI: HR, 0.64 (95%CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0%(95% CI, 60.2%to 76.6%) versus 56.7%(95%CI, 47.6%to 65.4%) and 60.7%(95%CI, 51.1%to 69.6%) versus 47.1%(95%CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5%(95%CI, 54.4% to 73.5%) versus 55.6%(95%CI, 45.8%to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.
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