Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.
PURPOSE: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemo...
| Những tác giả chính: | , , , , , , , , , , , , , , , , |
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| Định dạng: | Journal article |
| Ngôn ngữ: | English |
| Được phát hành: |
2008
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| _version_ | 1826257620791459840 |
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| author | Plummer, R Jones, C Middleton, M Wilson, R Evans, J Olsen, A Curtin, N Boddy, A McHugh, P Newell, D Harris, A Johnson, P Steinfeldt, H Dewji, R Wang, D Robson, L Calvert, H |
| author_facet | Plummer, R Jones, C Middleton, M Wilson, R Evans, J Olsen, A Curtin, N Boddy, A McHugh, P Newell, D Harris, A Johnson, P Steinfeldt, H Dewji, R Wang, D Robson, L Calvert, H |
| author_sort | Plummer, R |
| collection | OXFORD |
| description | PURPOSE: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. EXPERIMENTAL DESIGN: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide x 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. RESULTS: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. CONCLUSIONS: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents. |
| first_indexed | 2024-03-06T18:21:03Z |
| format | Journal article |
| id | oxford-uuid:064f2be5-62de-48e2-b9c6-765f3f56f4a6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:21:03Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:064f2be5-62de-48e2-b9c6-765f3f56f4a62022-03-26T09:01:49ZPhase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:064f2be5-62de-48e2-b9c6-765f3f56f4a6EnglishSymplectic Elements at Oxford2008Plummer, RJones, CMiddleton, MWilson, REvans, JOlsen, ACurtin, NBoddy, AMcHugh, PNewell, DHarris, AJohnson, PSteinfeldt, HDewji, RWang, DRobson, LCalvert, H PURPOSE: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. EXPERIMENTAL DESIGN: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide x 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. RESULTS: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. CONCLUSIONS: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents. |
| spellingShingle | Plummer, R Jones, C Middleton, M Wilson, R Evans, J Olsen, A Curtin, N Boddy, A McHugh, P Newell, D Harris, A Johnson, P Steinfeldt, H Dewji, R Wang, D Robson, L Calvert, H Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. |
| title | Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. |
| title_full | Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. |
| title_fullStr | Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. |
| title_full_unstemmed | Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. |
| title_short | Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. |
| title_sort | phase i study of the poly adp ribose polymerase inhibitor ag014699 in combination with temozolomide in patients with advanced solid tumors |
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