Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors.
PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients wi...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2012
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| _version_ | 1826295957100167168 |
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| author | Patterson, D Zweifel, M Middleton, MR Price, P Folkes, L Stratford, MR Ross, P Halford, S Peters, J Balkissoon, J Chaplin, D Padhani, A Rustin, G |
| author_facet | Patterson, D Zweifel, M Middleton, MR Price, P Folkes, L Stratford, MR Ross, P Halford, S Peters, J Balkissoon, J Chaplin, D Padhani, A Rustin, G |
| author_sort | Patterson, D |
| collection | OXFORD |
| description | PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. RESULTS: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. CONCLUSIONS: The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2). |
| first_indexed | 2024-03-07T04:08:57Z |
| format | Journal article |
| id | oxford-uuid:c72c2934-e197-46c4-a153-4818873f7e60 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:08:57Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:c72c2934-e197-46c4-a153-4818873f7e602022-03-27T06:43:11ZPhase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c72c2934-e197-46c4-a153-4818873f7e60EnglishSymplectic Elements at Oxford2012Patterson, DZweifel, MMiddleton, MRPrice, PFolkes, LStratford, MRRoss, PHalford, SPeters, JBalkissoon, JChaplin, DPadhani, ARustin, G PURPOSE: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. EXPERIMENTAL DESIGN: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. RESULTS: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m(2), then expanded cohorts to 15.4 mg/m(2) in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m(2) or higher. CONCLUSIONS: The maximum tolerated dose was 8.5 mg/m(2) but escalation to 14 mg/m(2) was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m(2) and maximum tumor perfusion reductions were seen at doses of 11 mg/m(2) or higher, the recommended phase II dose is from 11 to 14 mg/m(2). |
| spellingShingle | Patterson, D Zweifel, M Middleton, MR Price, P Folkes, L Stratford, MR Ross, P Halford, S Peters, J Balkissoon, J Chaplin, D Padhani, A Rustin, G Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. |
| title | Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. |
| title_full | Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. |
| title_fullStr | Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. |
| title_full_unstemmed | Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. |
| title_short | Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. |
| title_sort | phase i clinical and pharmacokinetic evaluation of the vascular disrupting agent oxi4503 in patients with advanced solid tumors |
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