Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients
BACKGROUND: To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC)...
| Main Authors: | , , , , , , , , |
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| Format: | info:eu-repo/semantics/article |
| Language: | eng |
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Cancer Research UK
2014
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| Online Access: | https://hdl.handle.net/10171/36370 |
| _version_ | 1793400392009121792 |
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| author | Abajo, A. (Ana) Rodriguez, J. (Javier) Bitarte, N. (Nerea) Zarate, R. (Ruth) Boni, V. (Valentina) Ponz-Sarvise, M. (Mariano) Chopitea, A. (Ana) Bandres, E. (Eva) Garcia-Foncillas, J. (Jesús) |
| author_facet | Abajo, A. (Ana) Rodriguez, J. (Javier) Bitarte, N. (Nerea) Zarate, R. (Ruth) Boni, V. (Valentina) Ponz-Sarvise, M. (Mariano) Chopitea, A. (Ana) Bandres, E. (Eva) Garcia-Foncillas, J. (Jesús) |
| author_sort | Abajo, A. (Ana) |
| collection | DSpace |
| description | BACKGROUND:
To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome.
PATIENTS AND METHODS:
A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m⁻², bevacizumab 5 mg kg⁻¹ and CPT-11 doses ranging from 100 to 160 mg m⁻² were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene.
RESULTS:
CPT-11 RD was 150 mg m⁻². Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04).
CONCLUSION:
The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-36370 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2014 |
| publisher | Cancer Research UK |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-363702020-03-03T10:47:57Z Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients Abajo, A. (Ana) Rodriguez, J. (Javier) Bitarte, N. (Nerea) Zarate, R. (Ruth) Boni, V. (Valentina) Ponz-Sarvise, M. (Mariano) Chopitea, A. (Ana) Bandres, E. (Eva) Garcia-Foncillas, J. (Jesús) Antibodies, Monoclonal Bevacizumab Irinotecan Gemcitabine Colorectal Neoplasms/pathology BACKGROUND: To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome. PATIENTS AND METHODS: A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m⁻², bevacizumab 5 mg kg⁻¹ and CPT-11 doses ranging from 100 to 160 mg m⁻² were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene. RESULTS: CPT-11 RD was 150 mg m⁻². Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04). CONCLUSION: The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested. 2014-08-23T11:03:54Z 2014-08-23T11:03:54Z 2010 info:eu-repo/semantics/article https://hdl.handle.net/10171/36370 eng info:eu-repo/semantics/openAccess application/pdf Cancer Research UK |
| spellingShingle | Antibodies, Monoclonal Bevacizumab Irinotecan Gemcitabine Colorectal Neoplasms/pathology Abajo, A. (Ana) Rodriguez, J. (Javier) Bitarte, N. (Nerea) Zarate, R. (Ruth) Boni, V. (Valentina) Ponz-Sarvise, M. (Mariano) Chopitea, A. (Ana) Bandres, E. (Eva) Garcia-Foncillas, J. (Jesús) Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| title | Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| title_full | Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| title_fullStr | Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| title_full_unstemmed | Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| title_short | Dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| title_sort | dose-finding study and pharmacogenomic analysis of fixed-rate infusion of gemcitabine, irinotecan and bevacizumab in pretreated metastatic colorectal cancer patients |
| topic | Antibodies, Monoclonal Bevacizumab Irinotecan Gemcitabine Colorectal Neoplasms/pathology |
| url | https://hdl.handle.net/10171/36370 |
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