Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer
Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Van Laethem, Jean-Luc [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2016 |
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| Schlagwörter: |
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| Anmerkung: |
© Springer International Publishing Switzerland 2016 |
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| Übergeordnetes Werk: |
Enthalten in: Targeted oncology - Paris : Springer Verlag France S.A.R.L., 2006, 12(2016), 1 vom: 14. Dez., Seite 97-109 |
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| Übergeordnetes Werk: |
volume:12 ; year:2016 ; number:1 ; day:14 ; month:12 ; pages:97-109 |
| Links: |
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| DOI / URN: |
10.1007/s11523-016-0469-y |
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| Katalog-ID: |
SPR020533276 |
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| 100 | 1 | |a Van Laethem, Jean-Luc |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer |
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| 520 | |a Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. | ||
| 650 | 4 | |a Gemcitabine |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Objective Response Rate |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a KRAS Mutation |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Disease Control Rate |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Advanced Pancreatic Cancer |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Riess, Hanno |4 aut | |
| 700 | 1 | |a Jassem, Jacek |4 aut | |
| 700 | 1 | |a Haas, Michael |4 aut | |
| 700 | 1 | |a Martens, Uwe M. |4 aut | |
| 700 | 1 | |a Weekes, Colin |4 aut | |
| 700 | 1 | |a Peeters, Marc |4 aut | |
| 700 | 1 | |a Ross, Paul |4 aut | |
| 700 | 1 | |a Bridgewater, John |4 aut | |
| 700 | 1 | |a Melichar, Bohuslav |4 aut | |
| 700 | 1 | |a Cascinu, Stefano |4 aut | |
| 700 | 1 | |a Saramak, Piotr |4 aut | |
| 700 | 1 | |a Michl, Patrick |4 aut | |
| 700 | 1 | |a Van Brummelen, David |4 aut | |
| 700 | 1 | |a Zaniboni, Alberto |4 aut | |
| 700 | 1 | |a Schmiegel, Wollf |4 aut | |
| 700 | 1 | |a Dueland, Svein |4 aut | |
| 700 | 1 | |a Giurescu, Marius |4 aut | |
| 700 | 1 | |a Garosi, Vittorio L. |4 aut | |
| 700 | 1 | |a Roth, Katrin |4 aut | |
| 700 | 1 | |a Schulz, Anke |4 aut | |
| 700 | 1 | |a Seidel, Henrik |4 aut | |
| 700 | 1 | |a Rajagopalan, Prabhu |4 aut | |
| 700 | 1 | |a Teufel, Michael |4 aut | |
| 700 | 1 | |a Childs, Barrett H. |4 aut | |
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10.1007/s11523-016-0469-y doi (DE-627)SPR020533276 (SPR)s11523-016-0469-y-e DE-627 ger DE-627 rakwb eng Van Laethem, Jean-Luc verfasserin aut Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. Gemcitabine (dpeaa)DE-He213 Objective Response Rate (dpeaa)DE-He213 KRAS Mutation (dpeaa)DE-He213 Disease Control Rate (dpeaa)DE-He213 Advanced Pancreatic Cancer (dpeaa)DE-He213 Riess, Hanno aut Jassem, Jacek aut Haas, Michael aut Martens, Uwe M. aut Weekes, Colin aut Peeters, Marc aut Ross, Paul aut Bridgewater, John aut Melichar, Bohuslav aut Cascinu, Stefano aut Saramak, Piotr aut Michl, Patrick aut Van Brummelen, David aut Zaniboni, Alberto aut Schmiegel, Wollf aut Dueland, Svein aut Giurescu, Marius aut Garosi, Vittorio L. aut Roth, Katrin aut Schulz, Anke aut Seidel, Henrik aut Rajagopalan, Prabhu aut Teufel, Michael aut Childs, Barrett H. aut Enthalten in Targeted oncology Paris : Springer Verlag France S.A.R.L., 2006 12(2016), 1 vom: 14. Dez., Seite 97-109 (DE-627)507903838 (DE-600)2222136-0 1776-260X nnns volume:12 year:2016 number:1 day:14 month:12 pages:97-109 https://dx.doi.org/10.1007/s11523-016-0469-y lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 12 2016 1 14 12 97-109 |
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10.1007/s11523-016-0469-y doi (DE-627)SPR020533276 (SPR)s11523-016-0469-y-e DE-627 ger DE-627 rakwb eng Van Laethem, Jean-Luc verfasserin aut Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. Gemcitabine (dpeaa)DE-He213 Objective Response Rate (dpeaa)DE-He213 KRAS Mutation (dpeaa)DE-He213 Disease Control Rate (dpeaa)DE-He213 Advanced Pancreatic Cancer (dpeaa)DE-He213 Riess, Hanno aut Jassem, Jacek aut Haas, Michael aut Martens, Uwe M. aut Weekes, Colin aut Peeters, Marc aut Ross, Paul aut Bridgewater, John aut Melichar, Bohuslav aut Cascinu, Stefano aut Saramak, Piotr aut Michl, Patrick aut Van Brummelen, David aut Zaniboni, Alberto aut Schmiegel, Wollf aut Dueland, Svein aut Giurescu, Marius aut Garosi, Vittorio L. aut Roth, Katrin aut Schulz, Anke aut Seidel, Henrik aut Rajagopalan, Prabhu aut Teufel, Michael aut Childs, Barrett H. aut Enthalten in Targeted oncology Paris : Springer Verlag France S.A.R.L., 2006 12(2016), 1 vom: 14. Dez., Seite 97-109 (DE-627)507903838 (DE-600)2222136-0 1776-260X nnns volume:12 year:2016 number:1 day:14 month:12 pages:97-109 https://dx.doi.org/10.1007/s11523-016-0469-y lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 12 2016 1 14 12 97-109 |
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10.1007/s11523-016-0469-y doi (DE-627)SPR020533276 (SPR)s11523-016-0469-y-e DE-627 ger DE-627 rakwb eng Van Laethem, Jean-Luc verfasserin aut Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. Gemcitabine (dpeaa)DE-He213 Objective Response Rate (dpeaa)DE-He213 KRAS Mutation (dpeaa)DE-He213 Disease Control Rate (dpeaa)DE-He213 Advanced Pancreatic Cancer (dpeaa)DE-He213 Riess, Hanno aut Jassem, Jacek aut Haas, Michael aut Martens, Uwe M. aut Weekes, Colin aut Peeters, Marc aut Ross, Paul aut Bridgewater, John aut Melichar, Bohuslav aut Cascinu, Stefano aut Saramak, Piotr aut Michl, Patrick aut Van Brummelen, David aut Zaniboni, Alberto aut Schmiegel, Wollf aut Dueland, Svein aut Giurescu, Marius aut Garosi, Vittorio L. aut Roth, Katrin aut Schulz, Anke aut Seidel, Henrik aut Rajagopalan, Prabhu aut Teufel, Michael aut Childs, Barrett H. aut Enthalten in Targeted oncology Paris : Springer Verlag France S.A.R.L., 2006 12(2016), 1 vom: 14. Dez., Seite 97-109 (DE-627)507903838 (DE-600)2222136-0 1776-260X nnns volume:12 year:2016 number:1 day:14 month:12 pages:97-109 https://dx.doi.org/10.1007/s11523-016-0469-y lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 12 2016 1 14 12 97-109 |
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10.1007/s11523-016-0469-y doi (DE-627)SPR020533276 (SPR)s11523-016-0469-y-e DE-627 ger DE-627 rakwb eng Van Laethem, Jean-Luc verfasserin aut Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. Gemcitabine (dpeaa)DE-He213 Objective Response Rate (dpeaa)DE-He213 KRAS Mutation (dpeaa)DE-He213 Disease Control Rate (dpeaa)DE-He213 Advanced Pancreatic Cancer (dpeaa)DE-He213 Riess, Hanno aut Jassem, Jacek aut Haas, Michael aut Martens, Uwe M. aut Weekes, Colin aut Peeters, Marc aut Ross, Paul aut Bridgewater, John aut Melichar, Bohuslav aut Cascinu, Stefano aut Saramak, Piotr aut Michl, Patrick aut Van Brummelen, David aut Zaniboni, Alberto aut Schmiegel, Wollf aut Dueland, Svein aut Giurescu, Marius aut Garosi, Vittorio L. aut Roth, Katrin aut Schulz, Anke aut Seidel, Henrik aut Rajagopalan, Prabhu aut Teufel, Michael aut Childs, Barrett H. aut Enthalten in Targeted oncology Paris : Springer Verlag France S.A.R.L., 2006 12(2016), 1 vom: 14. Dez., Seite 97-109 (DE-627)507903838 (DE-600)2222136-0 1776-260X nnns volume:12 year:2016 number:1 day:14 month:12 pages:97-109 https://dx.doi.org/10.1007/s11523-016-0469-y lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 12 2016 1 14 12 97-109 |
| allfieldsSound |
10.1007/s11523-016-0469-y doi (DE-627)SPR020533276 (SPR)s11523-016-0469-y-e DE-627 ger DE-627 rakwb eng Van Laethem, Jean-Luc verfasserin aut Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer International Publishing Switzerland 2016 Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. Gemcitabine (dpeaa)DE-He213 Objective Response Rate (dpeaa)DE-He213 KRAS Mutation (dpeaa)DE-He213 Disease Control Rate (dpeaa)DE-He213 Advanced Pancreatic Cancer (dpeaa)DE-He213 Riess, Hanno aut Jassem, Jacek aut Haas, Michael aut Martens, Uwe M. aut Weekes, Colin aut Peeters, Marc aut Ross, Paul aut Bridgewater, John aut Melichar, Bohuslav aut Cascinu, Stefano aut Saramak, Piotr aut Michl, Patrick aut Van Brummelen, David aut Zaniboni, Alberto aut Schmiegel, Wollf aut Dueland, Svein aut Giurescu, Marius aut Garosi, Vittorio L. aut Roth, Katrin aut Schulz, Anke aut Seidel, Henrik aut Rajagopalan, Prabhu aut Teufel, Michael aut Childs, Barrett H. aut Enthalten in Targeted oncology Paris : Springer Verlag France S.A.R.L., 2006 12(2016), 1 vom: 14. Dez., Seite 97-109 (DE-627)507903838 (DE-600)2222136-0 1776-260X nnns volume:12 year:2016 number:1 day:14 month:12 pages:97-109 https://dx.doi.org/10.1007/s11523-016-0469-y lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 12 2016 1 14 12 97-109 |
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Enthalten in Targeted oncology 12(2016), 1 vom: 14. Dez., Seite 97-109 volume:12 year:2016 number:1 day:14 month:12 pages:97-109 |
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Enthalten in Targeted oncology 12(2016), 1 vom: 14. Dez., Seite 97-109 volume:12 year:2016 number:1 day:14 month:12 pages:97-109 |
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Gemcitabine Objective Response Rate KRAS Mutation Disease Control Rate Advanced Pancreatic Cancer |
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Van Laethem, Jean-Luc @@aut@@ Riess, Hanno @@aut@@ Jassem, Jacek @@aut@@ Haas, Michael @@aut@@ Martens, Uwe M. @@aut@@ Weekes, Colin @@aut@@ Peeters, Marc @@aut@@ Ross, Paul @@aut@@ Bridgewater, John @@aut@@ Melichar, Bohuslav @@aut@@ Cascinu, Stefano @@aut@@ Saramak, Piotr @@aut@@ Michl, Patrick @@aut@@ Van Brummelen, David @@aut@@ Zaniboni, Alberto @@aut@@ Schmiegel, Wollf @@aut@@ Dueland, Svein @@aut@@ Giurescu, Marius @@aut@@ Garosi, Vittorio L. @@aut@@ Roth, Katrin @@aut@@ Schulz, Anke @@aut@@ Seidel, Henrik @@aut@@ Rajagopalan, Prabhu @@aut@@ Teufel, Michael @@aut@@ Childs, Barrett H. @@aut@@ |
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2016-12-14T00:00:00Z |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR020533276</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230520000136.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201006s2016 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s11523-016-0469-y</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR020533276</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s11523-016-0469-y-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Van Laethem, Jean-Luc</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Springer International Publishing Switzerland 2016</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. 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|
| author |
Van Laethem, Jean-Luc |
| spellingShingle |
Van Laethem, Jean-Luc misc Gemcitabine misc Objective Response Rate misc KRAS Mutation misc Disease Control Rate misc Advanced Pancreatic Cancer Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer |
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Van Laethem, Jean-Luc |
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Not Illustrated |
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1776-260X |
| topic_title |
Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer Gemcitabine (dpeaa)DE-He213 Objective Response Rate (dpeaa)DE-He213 KRAS Mutation (dpeaa)DE-He213 Disease Control Rate (dpeaa)DE-He213 Advanced Pancreatic Cancer (dpeaa)DE-He213 |
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misc Gemcitabine misc Objective Response Rate misc KRAS Mutation misc Disease Control Rate misc Advanced Pancreatic Cancer |
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misc Gemcitabine misc Objective Response Rate misc KRAS Mutation misc Disease Control Rate misc Advanced Pancreatic Cancer |
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Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer |
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Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer |
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Van Laethem, Jean-Luc |
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Van Laethem, Jean-Luc Riess, Hanno Jassem, Jacek Haas, Michael Martens, Uwe M. Weekes, Colin Peeters, Marc Ross, Paul Bridgewater, John Melichar, Bohuslav Cascinu, Stefano Saramak, Piotr Michl, Patrick Van Brummelen, David Zaniboni, Alberto Schmiegel, Wollf Dueland, Svein Giurescu, Marius Garosi, Vittorio L. Roth, Katrin Schulz, Anke Seidel, Henrik Rajagopalan, Prabhu Teufel, Michael Childs, Barrett H. |
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10.1007/s11523-016-0469-y |
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phase i/ii study of refametinib (bay 86-9766) in combination with gemcitabine in advanced pancreatic cancer |
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Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer |
| abstract |
Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. © Springer International Publishing Switzerland 2016 |
| abstractGer |
Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. © Springer International Publishing Switzerland 2016 |
| abstract_unstemmed |
Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/$ m^{2} $ weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. © Springer International Publishing Switzerland 2016 |
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Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer |
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Riess, Hanno Jassem, Jacek Haas, Michael Martens, Uwe M. Weekes, Colin Peeters, Marc Ross, Paul Bridgewater, John Melichar, Bohuslav Cascinu, Stefano Saramak, Piotr Michl, Patrick Van Brummelen, David Zaniboni, Alberto Schmiegel, Wollf Dueland, Svein Giurescu, Marius Garosi, Vittorio L. Roth, Katrin Schulz, Anke Seidel, Henrik Rajagopalan, Prabhu Teufel, Michael Childs, Barrett H. |
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| score |
7.3975964 |