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A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia
Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dos...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055288/ https://www.ncbi.nlm.nih.gov/pubmed/27716819 http://dx.doi.org/10.1371/journal.pone.0164499 |
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author | Schliemann, Christoph Gerss, Joachim Wiebe, Stefanie Mikesch, Jan-Henrik Knoblauch, Nicola Sauer, Tim Angenendt, Linus Kewitz, Tobias Urban, Marc Butterfass-Bahloul, Trude Edemir, Sabine Vehring, Kerstin Müller-Tidow, Carsten Berdel, Wolfgang E. Krug, Utz |
author_facet | Schliemann, Christoph Gerss, Joachim Wiebe, Stefanie Mikesch, Jan-Henrik Knoblauch, Nicola Sauer, Tim Angenendt, Linus Kewitz, Tobias Urban, Marc Butterfass-Bahloul, Trude Edemir, Sabine Vehring, Kerstin Müller-Tidow, Carsten Berdel, Wolfgang E. Krug, Utz |
author_sort | Schliemann, Christoph |
collection | PubMed |
description | Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles. Dose-limiting toxicity (DLT) was defined as non-hematological severe adverse reaction CTC grade ≥ 4 with possible or definite relationship to nintedanib. Between April 2012 and October 2013, 13 patients (median age 73 [range: 62–86] years) were enrolled. One patient did not receive study medication and was replaced. Nine (69%) patients had relapsed or refractory disease and 6 (46%) patients had unfavorable cytogenetics. The most frequently reported treatment-related adverse events (AE) were gastrointestinal events. Twelve SAEs irrespective of relatedness were reported. Two SUSARs were observed, one fatal hypercalcemia and one fatal gastrointestinal infection. Two patients (17%) with relapsed AML achieved a complete remission (one CR, one CRi) and bone marrow blast reductions without fulfilling PR criteria were observed in 3 patients (25%). One-year overall survival was 33%. Nintedanib combined with LDAC shows an adequate safety profile and survival data are promising in a difficult-to-treat patient population. Continuation of this trial with a phase II recommended dose of 2 x 200 mg nintedanib in a randomized, placebo-controlled phase II study is planned. The trial is registered to EudraCT as 2011-001086-41. Trial Registration: ClinicalTrials.gov NCT01488344 |
format | Online Article Text |
id | pubmed-5055288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50552882016-10-27 A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia Schliemann, Christoph Gerss, Joachim Wiebe, Stefanie Mikesch, Jan-Henrik Knoblauch, Nicola Sauer, Tim Angenendt, Linus Kewitz, Tobias Urban, Marc Butterfass-Bahloul, Trude Edemir, Sabine Vehring, Kerstin Müller-Tidow, Carsten Berdel, Wolfgang E. Krug, Utz PLoS One Research Article Nintedanib (BIBF 1120), a potent multikinase inhibitor of VEGFR-1/-2/-3, FGFR-1/-2/-3 and PDGFR-α/-β, exerts growth inhibitory and pro-apoptotic effects in myeloid leukemic cells, especially when used in combination with cytarabine. This phase I study evaluated nintedanib in combination with low-dose cytarabine (LDAC) in elderly patients with untreated or relapsed/refractory acute myeloid leukemia (AML) ineligible for intensive chemotherapy in a 3+3 design. Nintedanib (dose levels 100, 150, and 200 mg orally twice daily) and LDAC (20 mg subcutaneous injection twice daily for 10 days) were administered in 28-day cycles. Dose-limiting toxicity (DLT) was defined as non-hematological severe adverse reaction CTC grade ≥ 4 with possible or definite relationship to nintedanib. Between April 2012 and October 2013, 13 patients (median age 73 [range: 62–86] years) were enrolled. One patient did not receive study medication and was replaced. Nine (69%) patients had relapsed or refractory disease and 6 (46%) patients had unfavorable cytogenetics. The most frequently reported treatment-related adverse events (AE) were gastrointestinal events. Twelve SAEs irrespective of relatedness were reported. Two SUSARs were observed, one fatal hypercalcemia and one fatal gastrointestinal infection. Two patients (17%) with relapsed AML achieved a complete remission (one CR, one CRi) and bone marrow blast reductions without fulfilling PR criteria were observed in 3 patients (25%). One-year overall survival was 33%. Nintedanib combined with LDAC shows an adequate safety profile and survival data are promising in a difficult-to-treat patient population. Continuation of this trial with a phase II recommended dose of 2 x 200 mg nintedanib in a randomized, placebo-controlled phase II study is planned. The trial is registered to EudraCT as 2011-001086-41. Trial Registration: ClinicalTrials.gov NCT01488344 Public Library of Science 2016-10-07 /pmc/articles/PMC5055288/ /pubmed/27716819 http://dx.doi.org/10.1371/journal.pone.0164499 Text en © 2016 Schliemann et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Schliemann, Christoph Gerss, Joachim Wiebe, Stefanie Mikesch, Jan-Henrik Knoblauch, Nicola Sauer, Tim Angenendt, Linus Kewitz, Tobias Urban, Marc Butterfass-Bahloul, Trude Edemir, Sabine Vehring, Kerstin Müller-Tidow, Carsten Berdel, Wolfgang E. Krug, Utz A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia |
title | A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia |
title_full | A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia |
title_fullStr | A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia |
title_full_unstemmed | A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia |
title_short | A Phase I Dose Escalation Study of the Triple Angiokinase Inhibitor Nintedanib Combined with Low-Dose Cytarabine in Elderly Patients with Acute Myeloid Leukemia |
title_sort | phase i dose escalation study of the triple angiokinase inhibitor nintedanib combined with low-dose cytarabine in elderly patients with acute myeloid leukemia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055288/ https://www.ncbi.nlm.nih.gov/pubmed/27716819 http://dx.doi.org/10.1371/journal.pone.0164499 |
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