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Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies
Taxane–gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients incl...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484664/ https://www.ncbi.nlm.nih.gov/pubmed/26020806 http://dx.doi.org/10.1097/CAD.0000000000000250 |
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author | Rixe, Olivier Puzanov, Igor LoRusso, Patricia M. Cohen, Roger B. Morris, John C. Olowokure, Olugbenga O. Yin, Jian Y. Doroumian, Séverine Shen, Liji Olszanski, Anthony J. |
author_facet | Rixe, Olivier Puzanov, Igor LoRusso, Patricia M. Cohen, Roger B. Morris, John C. Olowokure, Olugbenga O. Yin, Jian Y. Doroumian, Séverine Shen, Liji Olszanski, Anthony J. |
author_sort | Rixe, Olivier |
collection | PubMed |
description | Taxane–gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15–20 mg/m(2)) before (part 1a) or after (part 1b) gemcitabine (700–1000 mg/m(2)) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m(2) cabazitaxel plus 1000 mg/m(2) gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3–4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation. |
format | Online Article Text |
id | pubmed-4484664 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-44846642015-07-07 Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies Rixe, Olivier Puzanov, Igor LoRusso, Patricia M. Cohen, Roger B. Morris, John C. Olowokure, Olugbenga O. Yin, Jian Y. Doroumian, Séverine Shen, Liji Olszanski, Anthony J. Anticancer Drugs Clinical Reports Taxane–gemcitabine combinations have demonstrated antitumor activity. This phase I study (NCT01001221) aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus gemcitabine and to assess the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of three to six patients received cabazitaxel (15–20 mg/m(2)) before (part 1a) or after (part 1b) gemcitabine (700–1000 mg/m(2)) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n=12), five patients received 20 mg/m(2) cabazitaxel plus 1000 mg/m(2) gemcitabine (20/1000), five received 15/900, two received 15/700. In part 1b, all six patients received the lowest dose (700/15). At all doses, two or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n=4), grade 4 neutropenia (n=2), grade 4 thrombocytopenia (n=2), and grade 3 aspartate transaminase increase (n=1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade nonhematologic events were fatigue (66.7%), decreased appetite (50.0%), and diarrhea (44.4%). The most frequent grade 3–4 hematologic abnormalities were neutropenia (83.3%), leukopenia (77.8%), and lymphopenia (72.2%). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable partial responses were observed in three patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25% from single-agent doses, preclude further investigation. Lippincott Williams & Wilkins 2015-08 2015-06-06 /pmc/articles/PMC4484664/ /pubmed/26020806 http://dx.doi.org/10.1097/CAD.0000000000000250 Text en Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Clinical Reports Rixe, Olivier Puzanov, Igor LoRusso, Patricia M. Cohen, Roger B. Morris, John C. Olowokure, Olugbenga O. Yin, Jian Y. Doroumian, Séverine Shen, Liji Olszanski, Anthony J. Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
title | Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
title_full | Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
title_fullStr | Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
title_full_unstemmed | Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
title_short | Phase I dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
title_sort | phase i dose-escalation study of cabazitaxel administered in combination with gemcitabine in patients with metastatic or unresectable advanced solid malignancies |
topic | Clinical Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484664/ https://www.ncbi.nlm.nih.gov/pubmed/26020806 http://dx.doi.org/10.1097/CAD.0000000000000250 |
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