Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer
Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following sched...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Infante, Jeffrey R. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Anmerkung: |
© Springer-Verlag Berlin Heidelberg 2017 |
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| Übergeordnetes Werk: |
Enthalten in: Cancer chemotherapy and pharmacology - Berlin : Springer, 1978, 79(2017), 2 vom: 17. Jan., Seite 315-326 |
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| Übergeordnetes Werk: |
volume:79 ; year:2017 ; number:2 ; day:17 ; month:01 ; pages:315-326 |
| Links: |
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| DOI / URN: |
10.1007/s00280-016-3205-5 |
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| Katalog-ID: |
SPR003615200 |
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| 041 | |a eng | ||
| 100 | 1 | |a Infante, Jeffrey R. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer |
| 264 | 1 | |c 2017 | |
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| 337 | |a Computermedien |b c |2 rdamedia | ||
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| 500 | |a © Springer-Verlag Berlin Heidelberg 2017 | ||
| 520 | |a Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. | ||
| 650 | 4 | |a Eg5 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Kinesin spindle protein (KSP) |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a KSP inhibitor |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Antimitotic |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Phase 1 |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Patnaik, Amita |4 aut | |
| 700 | 1 | |a Verschraegen, Claire F. |4 aut | |
| 700 | 1 | |a Olszanski, Anthony J. |4 aut | |
| 700 | 1 | |a Shaheen, Montaser |4 aut | |
| 700 | 1 | |a Burris, Howard A. |4 aut | |
| 700 | 1 | |a Tolcher, Anthony W. |4 aut | |
| 700 | 1 | |a Papadopoulos, Kyriakos P. |4 aut | |
| 700 | 1 | |a Beeram, Muralidhar |4 aut | |
| 700 | 1 | |a Hynes, Scott M. |4 aut | |
| 700 | 1 | |a Leohr, Jennifer |4 aut | |
| 700 | 1 | |a Lin, Aimee Bence |4 aut | |
| 700 | 1 | |a Li, Lily Q. |4 aut | |
| 700 | 1 | |a McGlothlin, Anna |4 aut | |
| 700 | 1 | |a Farrington, Daphne L. |4 aut | |
| 700 | 1 | |a Westin, Eric H. |4 aut | |
| 700 | 1 | |a Cohen, Roger B. |4 aut | |
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10.1007/s00280-016-3205-5 doi (DE-627)SPR003615200 (SPR)s00280-016-3205-5-e DE-627 ger DE-627 rakwb eng Infante, Jeffrey R. verfasserin aut Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag Berlin Heidelberg 2017 Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. Eg5 (dpeaa)DE-He213 Kinesin spindle protein (KSP) (dpeaa)DE-He213 KSP inhibitor (dpeaa)DE-He213 Antimitotic (dpeaa)DE-He213 Phase 1 (dpeaa)DE-He213 Patnaik, Amita aut Verschraegen, Claire F. aut Olszanski, Anthony J. aut Shaheen, Montaser aut Burris, Howard A. aut Tolcher, Anthony W. aut Papadopoulos, Kyriakos P. aut Beeram, Muralidhar aut Hynes, Scott M. aut Leohr, Jennifer aut Lin, Aimee Bence aut Li, Lily Q. aut McGlothlin, Anna aut Farrington, Daphne L. aut Westin, Eric H. aut Cohen, Roger B. aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 79(2017), 2 vom: 17. Jan., Seite 315-326 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:79 year:2017 number:2 day:17 month:01 pages:315-326 https://dx.doi.org/10.1007/s00280-016-3205-5 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_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_152 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_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 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_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 79 2017 2 17 01 315-326 |
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10.1007/s00280-016-3205-5 doi (DE-627)SPR003615200 (SPR)s00280-016-3205-5-e DE-627 ger DE-627 rakwb eng Infante, Jeffrey R. verfasserin aut Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag Berlin Heidelberg 2017 Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. Eg5 (dpeaa)DE-He213 Kinesin spindle protein (KSP) (dpeaa)DE-He213 KSP inhibitor (dpeaa)DE-He213 Antimitotic (dpeaa)DE-He213 Phase 1 (dpeaa)DE-He213 Patnaik, Amita aut Verschraegen, Claire F. aut Olszanski, Anthony J. aut Shaheen, Montaser aut Burris, Howard A. aut Tolcher, Anthony W. aut Papadopoulos, Kyriakos P. aut Beeram, Muralidhar aut Hynes, Scott M. aut Leohr, Jennifer aut Lin, Aimee Bence aut Li, Lily Q. aut McGlothlin, Anna aut Farrington, Daphne L. aut Westin, Eric H. aut Cohen, Roger B. aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 79(2017), 2 vom: 17. Jan., Seite 315-326 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:79 year:2017 number:2 day:17 month:01 pages:315-326 https://dx.doi.org/10.1007/s00280-016-3205-5 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_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_152 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_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 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_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 79 2017 2 17 01 315-326 |
| allfields_unstemmed |
10.1007/s00280-016-3205-5 doi (DE-627)SPR003615200 (SPR)s00280-016-3205-5-e DE-627 ger DE-627 rakwb eng Infante, Jeffrey R. verfasserin aut Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag Berlin Heidelberg 2017 Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. Eg5 (dpeaa)DE-He213 Kinesin spindle protein (KSP) (dpeaa)DE-He213 KSP inhibitor (dpeaa)DE-He213 Antimitotic (dpeaa)DE-He213 Phase 1 (dpeaa)DE-He213 Patnaik, Amita aut Verschraegen, Claire F. aut Olszanski, Anthony J. aut Shaheen, Montaser aut Burris, Howard A. aut Tolcher, Anthony W. aut Papadopoulos, Kyriakos P. aut Beeram, Muralidhar aut Hynes, Scott M. aut Leohr, Jennifer aut Lin, Aimee Bence aut Li, Lily Q. aut McGlothlin, Anna aut Farrington, Daphne L. aut Westin, Eric H. aut Cohen, Roger B. aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 79(2017), 2 vom: 17. Jan., Seite 315-326 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:79 year:2017 number:2 day:17 month:01 pages:315-326 https://dx.doi.org/10.1007/s00280-016-3205-5 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_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_152 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_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 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_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 79 2017 2 17 01 315-326 |
| allfieldsGer |
10.1007/s00280-016-3205-5 doi (DE-627)SPR003615200 (SPR)s00280-016-3205-5-e DE-627 ger DE-627 rakwb eng Infante, Jeffrey R. verfasserin aut Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag Berlin Heidelberg 2017 Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. Eg5 (dpeaa)DE-He213 Kinesin spindle protein (KSP) (dpeaa)DE-He213 KSP inhibitor (dpeaa)DE-He213 Antimitotic (dpeaa)DE-He213 Phase 1 (dpeaa)DE-He213 Patnaik, Amita aut Verschraegen, Claire F. aut Olszanski, Anthony J. aut Shaheen, Montaser aut Burris, Howard A. aut Tolcher, Anthony W. aut Papadopoulos, Kyriakos P. aut Beeram, Muralidhar aut Hynes, Scott M. aut Leohr, Jennifer aut Lin, Aimee Bence aut Li, Lily Q. aut McGlothlin, Anna aut Farrington, Daphne L. aut Westin, Eric H. aut Cohen, Roger B. aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 79(2017), 2 vom: 17. Jan., Seite 315-326 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:79 year:2017 number:2 day:17 month:01 pages:315-326 https://dx.doi.org/10.1007/s00280-016-3205-5 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_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_152 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_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 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_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 79 2017 2 17 01 315-326 |
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10.1007/s00280-016-3205-5 doi (DE-627)SPR003615200 (SPR)s00280-016-3205-5-e DE-627 ger DE-627 rakwb eng Infante, Jeffrey R. verfasserin aut Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Springer-Verlag Berlin Heidelberg 2017 Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. Eg5 (dpeaa)DE-He213 Kinesin spindle protein (KSP) (dpeaa)DE-He213 KSP inhibitor (dpeaa)DE-He213 Antimitotic (dpeaa)DE-He213 Phase 1 (dpeaa)DE-He213 Patnaik, Amita aut Verschraegen, Claire F. aut Olszanski, Anthony J. aut Shaheen, Montaser aut Burris, Howard A. aut Tolcher, Anthony W. aut Papadopoulos, Kyriakos P. aut Beeram, Muralidhar aut Hynes, Scott M. aut Leohr, Jennifer aut Lin, Aimee Bence aut Li, Lily Q. aut McGlothlin, Anna aut Farrington, Daphne L. aut Westin, Eric H. aut Cohen, Roger B. aut Enthalten in Cancer chemotherapy and pharmacology Berlin : Springer, 1978 79(2017), 2 vom: 17. Jan., Seite 315-326 (DE-627)253390435 (DE-600)1458488-8 1432-0843 nnns volume:79 year:2017 number:2 day:17 month:01 pages:315-326 https://dx.doi.org/10.1007/s00280-016-3205-5 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_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_152 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_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_711 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_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 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_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 79 2017 2 17 01 315-326 |
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Enthalten in Cancer chemotherapy and pharmacology 79(2017), 2 vom: 17. Jan., Seite 315-326 volume:79 year:2017 number:2 day:17 month:01 pages:315-326 |
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Enthalten in Cancer chemotherapy and pharmacology 79(2017), 2 vom: 17. Jan., Seite 315-326 volume:79 year:2017 number:2 day:17 month:01 pages:315-326 |
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Infante, Jeffrey R. @@aut@@ Patnaik, Amita @@aut@@ Verschraegen, Claire F. @@aut@@ Olszanski, Anthony J. @@aut@@ Shaheen, Montaser @@aut@@ Burris, Howard A. @@aut@@ Tolcher, Anthony W. @@aut@@ Papadopoulos, Kyriakos P. @@aut@@ Beeram, Muralidhar @@aut@@ Hynes, Scott M. @@aut@@ Leohr, Jennifer @@aut@@ Lin, Aimee Bence @@aut@@ Li, Lily Q. @@aut@@ McGlothlin, Anna @@aut@@ Farrington, Daphne L. @@aut@@ Westin, Eric H. @@aut@@ Cohen, Roger B. @@aut@@ |
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Infante, Jeffrey R. |
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Infante, Jeffrey R. misc Eg5 misc Kinesin spindle protein (KSP) misc KSP inhibitor misc Antimitotic misc Phase 1 Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer |
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Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer Eg5 (dpeaa)DE-He213 Kinesin spindle protein (KSP) (dpeaa)DE-He213 KSP inhibitor (dpeaa)DE-He213 Antimitotic (dpeaa)DE-He213 Phase 1 (dpeaa)DE-He213 |
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Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer |
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Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer |
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Infante, Jeffrey R. |
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Cancer chemotherapy and pharmacology |
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Infante, Jeffrey R. Patnaik, Amita Verschraegen, Claire F. Olszanski, Anthony J. Shaheen, Montaser Burris, Howard A. Tolcher, Anthony W. Papadopoulos, Kyriakos P. Beeram, Muralidhar Hynes, Scott M. Leohr, Jennifer Lin, Aimee Bence Li, Lily Q. McGlothlin, Anna Farrington, Daphne L. Westin, Eric H. Cohen, Roger B. |
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Elektronische Aufsätze |
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Infante, Jeffrey R. |
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10.1007/s00280-016-3205-5 |
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two phase 1 dose-escalation studies exploring multiple regimens of litronesib (ly2523355), an eg5 inhibitor, in patients with advanced cancer |
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Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer |
| abstract |
Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. © Springer-Verlag Berlin Heidelberg 2017 |
| abstractGer |
Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. © Springer-Verlag Berlin Heidelberg 2017 |
| abstract_unstemmed |
Purpose This first-in-human report examined the recommended Phase 2 dose and schedule of litronesib, a selective allosteric kinesin Eg5 inhibitor. Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle. © Springer-Verlag Berlin Heidelberg 2017 |
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| title_short |
Two Phase 1 dose-escalation studies exploring multiple regimens of litronesib (LY2523355), an Eg5 inhibitor, in patients with advanced cancer |
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https://dx.doi.org/10.1007/s00280-016-3205-5 |
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Patnaik, Amita Verschraegen, Claire F. Olszanski, Anthony J. Shaheen, Montaser Burris, Howard A. Tolcher, Anthony W. Papadopoulos, Kyriakos P. Beeram, Muralidhar Hynes, Scott M. Leohr, Jennifer Lin, Aimee Bence Li, Lily Q. McGlothlin, Anna Farrington, Daphne L. Westin, Eric H. Cohen, Roger B. |
| author2Str |
Patnaik, Amita Verschraegen, Claire F. Olszanski, Anthony J. Shaheen, Montaser Burris, Howard A. Tolcher, Anthony W. Papadopoulos, Kyriakos P. Beeram, Muralidhar Hynes, Scott M. Leohr, Jennifer Lin, Aimee Bence Li, Lily Q. McGlothlin, Anna Farrington, Daphne L. Westin, Eric H. Cohen, Roger B. |
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253390435 |
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| doi_str |
10.1007/s00280-016-3205-5 |
| up_date |
2024-07-03T20:40:06.283Z |
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Methods Two concurrent dose-escalation studies investigated litronesib across the dose range of 0.125–16 mg/$ m^{2} $/day, evaluating the following schedules of administration on a 21-day cycle: Days 1, 2, 3; Days 1, 5, 9; Days 1, 8; Days 1, 5; or Days 1, 4, with or without pegfilgrastim. Best overall response was defined per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.0). Pharmacokinetic (PK) evaluations were performed. Exploratory PK/pharmacodynamic analyses investigated the relationship between litronesib plasma exposure and changes in phosphohistone H3 (pHH3) levels. Results One hundred and seventeen patients with advanced malignancies were enrolled. Neutropenia was the primary dose-limiting toxicity. Prophylactic pegfilgrastim reduced neutropenia frequency and severity, allowing administration of higher litronesib doses, but increases in the incidences of mucositis and stomatitis were observed. Among 86 response-evaluable patients, 2 patients (2%) achieved partial response, both on the Days 1, 2, 3 regimen (5 and 6 mg/$ m^{2} $/day with pegfilgrastim), and 17 patients (20%) maintained stable disease for ≥6 cycles. Dose-dependent increases in litronesib plasma exposure were observed, with minor intra- and inter-cycle accumulation, along with exposure-dependent increases in pHH3 expression in tumor and skin biopsies. Conclusions On the basis of the results of these studies, two regimens were selected for Phase 2 exploration: 6 mg/$ m^{2} $/day on Days 1, 2, 3 plus pegfilgrastim and 8 mg/$ m^{2} $/day on Days 1, 5, 9 plus pegfilgrastim, both on a 21-day cycle.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Eg5</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Kinesin spindle protein (KSP)</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">KSP inhibitor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Antimitotic</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Phase 1</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Patnaik, Amita</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Verschraegen, Claire F.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Olszanski, Anthony J.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Shaheen, Montaser</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Burris, Howard A.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Tolcher, Anthony W.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Papadopoulos, Kyriakos P.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Beeram, Muralidhar</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Hynes, Scott M.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Leohr, Jennifer</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Lin, Aimee Bence</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Li, Lily Q.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">McGlothlin, Anna</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Farrington, Daphne L.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Westin, Eric H.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Cohen, Roger B.</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Cancer chemotherapy and pharmacology</subfield><subfield code="d">Berlin : Springer, 1978</subfield><subfield code="g">79(2017), 2 vom: 17. 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| score |
7.4004793 |