Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis
Introduction. PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth fact...
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| Format: | Article |
| Language: | English |
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Elsevier
2010-02-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558610800995 |
| _version_ | 1811234830874050560 |
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| author | Marlies H.G. Langenberg Petronella O. Witteveen Nienke A.G. Lankheet Jeanine M.L. Roodhart Hilde Rosing Ingeborg J.G.M. van den Heuvel Jos H. Beijnen Emile E. Voest |
| author_facet | Marlies H.G. Langenberg Petronella O. Witteveen Nienke A.G. Lankheet Jeanine M.L. Roodhart Hilde Rosing Ingeborg J.G.M. van den Heuvel Jos H. Beijnen Emile E. Voest |
| author_sort | Marlies H.G. Langenberg |
| collection | DOAJ |
| description | Introduction. PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically.
Methods. In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m2 weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed.
Results. Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months.
Conclusions. This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity. |
| first_indexed | 2024-04-12T11:42:01Z |
| format | Article |
| id | doaj.art-6bd3aeff9978448bbf0b19c7a58420cc |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-12T11:42:01Z |
| publishDate | 2010-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-6bd3aeff9978448bbf0b19c7a58420cc2022-12-22T03:34:35ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022010-02-0112220621310.1593/neo.91864Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics AnalysisMarlies H.G. Langenberg0Petronella O. Witteveen1Nienke A.G. Lankheet2Jeanine M.L. Roodhart3Hilde Rosing4Ingeborg J.G.M. van den Heuvel5Jos H. Beijnen6Emile E. Voest7Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The NetherlandsDepartment of Medical Oncology, University Medical Center Utrecht, Utrecht, The NetherlandsThe Netherlands Cancer Institute Amsterdam and Slotervaart Hospital, Amsterdam, The NetherlandsDepartment of Medical Oncology, University Medical Center Utrecht, Utrecht, The NetherlandsThe Netherlands Cancer Institute Amsterdam and Slotervaart Hospital, Amsterdam, The NetherlandsDepartment of Medical Oncology, University Medical Center Utrecht, Utrecht, The NetherlandsThe Netherlands Cancer Institute Amsterdam and Slotervaart Hospital, Amsterdam, The NetherlandsDepartment of Medical Oncology, University Medical Center Utrecht, Utrecht, The NetherlandsIntroduction. PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically. Methods. In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m2 weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed. Results. Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months. Conclusions. This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.http://www.sciencedirect.com/science/article/pii/S1476558610800995 |
| spellingShingle | Marlies H.G. Langenberg Petronella O. Witteveen Nienke A.G. Lankheet Jeanine M.L. Roodhart Hilde Rosing Ingeborg J.G.M. van den Heuvel Jos H. Beijnen Emile E. Voest Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis Neoplasia: An International Journal for Oncology Research |
| title | Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis |
| title_full | Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis |
| title_fullStr | Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis |
| title_full_unstemmed | Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis |
| title_short | Phase 1 Study of Combination Treatment with PTK 787/ZK 222584 and Cetuximab for Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, Pharmacodynamics Analysis |
| title_sort | phase 1 study of combination treatment with ptk 787 zk 222584 and cetuximab for patients with advanced solid tumors safety pharmacokinetics pharmacodynamics analysis |
| url | http://www.sciencedirect.com/science/article/pii/S1476558610800995 |
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