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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...

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Autores principales: Doi, Toshihiko, Hamaguchi, Tetsuya, Shitara, Kohei, Iwasa, Satoru, Shimada, Yasuhiro, Harada, Mitsunori, Naito, Kenichiro, Hayashi, Naoto, Masada, Atsuhiro, Ohtsu, Atsushi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
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.
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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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