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NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis
OBJECTIVES: This study was an open-label phase I study to confirm the safety and tolerability of NC-6004 in combination with gemcitabine in Japanese patients with advanced solid tumors and to assess the PK effects of NC-6004 monotherapy. METHODS: This phase I study used a 3 + 3 design to determine t...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344954/ https://www.ncbi.nlm.nih.gov/pubmed/28224231 http://dx.doi.org/10.1007/s00280-017-3254-4 |
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author | Doi, Toshihiko Hamaguchi, Tetsuya Shitara, Kohei Iwasa, Satoru Shimada, Yasuhiro Harada, Mitsunori Naito, Kenichiro Hayashi, Naoto Masada, Atsuhiro Ohtsu, Atsushi |
author_facet | Doi, Toshihiko Hamaguchi, Tetsuya Shitara, Kohei Iwasa, Satoru Shimada, Yasuhiro Harada, Mitsunori Naito, Kenichiro Hayashi, Naoto Masada, Atsuhiro Ohtsu, Atsushi |
author_sort | Doi, Toshihiko |
collection | PubMed |
description | OBJECTIVES: This study was an open-label phase I study to confirm the safety and tolerability of NC-6004 in combination with gemcitabine in Japanese patients with advanced solid tumors and to assess the PK effects of NC-6004 monotherapy. METHODS: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended dose of NC-6004 combined with gemcitabine. Safety and pharmacokinetics were assessed. The administration of NC-6004 alone was started at 60 mg/m(2) every treatment cycle (21 days per cycle). From the second through eighth cycles, patients received NC-6004 in combination with 1000 mg/m(2) of gemcitabine that was administered on day 1 and day 8 of each cycle, except for the first treatment cycle. RESULTS: Twelve patients with advanced solid tumors received 60 or 90 mg/m(2) NC-6004. Both MTD and RD were determined to be 90 mg/m(2). The most common drug-related adverse events were neutrophil decrease (66.7%) and white blood cell count decrease (41.7%). Population pharmacokinetic (PK) analysis revealed that NC-6004 PK profile in Japanese study was not significantly different from that in a previous Caucasian study. CONCLUSIONS: Both MTD and RD of NC-6004 were determined to be 90 mg/m(2). The pharmacodynamic (PD) model well explained the time course of estimated glomerular filtration rate (eGFR) and amplitude of decrease in eGFR. The decrease in eGFR appeared to reach saturation at >100 mg/m(2) with NC-6004. Estimated probability of acute kidney injury on this PK/PD simulation was 30% with NC-6004 and 70% with cisplatin, which may better explain the renal toxicity profile. |
format | Online Article Text |
id | pubmed-5344954 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-53449542017-03-21 NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis Doi, Toshihiko Hamaguchi, Tetsuya Shitara, Kohei Iwasa, Satoru Shimada, Yasuhiro Harada, Mitsunori Naito, Kenichiro Hayashi, Naoto Masada, Atsuhiro Ohtsu, Atsushi Cancer Chemother Pharmacol Original Article OBJECTIVES: This study was an open-label phase I study to confirm the safety and tolerability of NC-6004 in combination with gemcitabine in Japanese patients with advanced solid tumors and to assess the PK effects of NC-6004 monotherapy. METHODS: This phase I study used a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended dose of NC-6004 combined with gemcitabine. Safety and pharmacokinetics were assessed. The administration of NC-6004 alone was started at 60 mg/m(2) every treatment cycle (21 days per cycle). From the second through eighth cycles, patients received NC-6004 in combination with 1000 mg/m(2) of gemcitabine that was administered on day 1 and day 8 of each cycle, except for the first treatment cycle. RESULTS: Twelve patients with advanced solid tumors received 60 or 90 mg/m(2) NC-6004. Both MTD and RD were determined to be 90 mg/m(2). The most common drug-related adverse events were neutrophil decrease (66.7%) and white blood cell count decrease (41.7%). Population pharmacokinetic (PK) analysis revealed that NC-6004 PK profile in Japanese study was not significantly different from that in a previous Caucasian study. CONCLUSIONS: Both MTD and RD of NC-6004 were determined to be 90 mg/m(2). The pharmacodynamic (PD) model well explained the time course of estimated glomerular filtration rate (eGFR) and amplitude of decrease in eGFR. The decrease in eGFR appeared to reach saturation at >100 mg/m(2) with NC-6004. Estimated probability of acute kidney injury on this PK/PD simulation was 30% with NC-6004 and 70% with cisplatin, which may better explain the renal toxicity profile. Springer Berlin Heidelberg 2017-02-21 2017 /pmc/articles/PMC5344954/ /pubmed/28224231 http://dx.doi.org/10.1007/s00280-017-3254-4 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Article Doi, Toshihiko Hamaguchi, Tetsuya Shitara, Kohei Iwasa, Satoru Shimada, Yasuhiro Harada, Mitsunori Naito, Kenichiro Hayashi, Naoto Masada, Atsuhiro Ohtsu, Atsushi NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis |
title | NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis |
title_full | NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis |
title_fullStr | NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis |
title_full_unstemmed | NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis |
title_short | NC-6004 Phase I study in combination with gemcitabine for advanced solid tumors and population PK/PD analysis |
title_sort | nc-6004 phase i study in combination with gemcitabine for advanced solid tumors and population pk/pd analysis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344954/ https://www.ncbi.nlm.nih.gov/pubmed/28224231 http://dx.doi.org/10.1007/s00280-017-3254-4 |
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