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A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial)
PURPOSE: This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory meta...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769092/ https://www.ncbi.nlm.nih.gov/pubmed/31444620 http://dx.doi.org/10.1007/s00280-019-03916-0 |
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author | Clarke, Jeffrey Melson Blobe, Gerard C. Strickler, John H. Uronis, Hope Elizabeth Zafar, S. Yousuf Morse, Michael Dropkin, Evan Howard, Leigh O’Neill, Margot Rushing, Christel N. Niedzwiecki, Donna Watson, Hollie Bolch, Emily Arrowood, Christy Liu, Yingmiao Nixon, Andrew B. Hurwitz, Herbert I. |
author_facet | Clarke, Jeffrey Melson Blobe, Gerard C. Strickler, John H. Uronis, Hope Elizabeth Zafar, S. Yousuf Morse, Michael Dropkin, Evan Howard, Leigh O’Neill, Margot Rushing, Christel N. Niedzwiecki, Donna Watson, Hollie Bolch, Emily Arrowood, Christy Liu, Yingmiao Nixon, Andrew B. Hurwitz, Herbert I. |
author_sort | Clarke, Jeffrey Melson |
collection | PubMed |
description | PURPOSE: This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer. METHODS: The first stage of this study was a standard “3 + 3” open-label dose-escalation scheme. Cohorts of 3–6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis. RESULTS: Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level − 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level − 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events. CONCLUSIONS: The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer. |
format | Online Article Text |
id | pubmed-6769092 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-67690922019-10-16 A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) Clarke, Jeffrey Melson Blobe, Gerard C. Strickler, John H. Uronis, Hope Elizabeth Zafar, S. Yousuf Morse, Michael Dropkin, Evan Howard, Leigh O’Neill, Margot Rushing, Christel N. Niedzwiecki, Donna Watson, Hollie Bolch, Emily Arrowood, Christy Liu, Yingmiao Nixon, Andrew B. Hurwitz, Herbert I. Cancer Chemother Pharmacol Clinical Trial Report PURPOSE: This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer. METHODS: The first stage of this study was a standard “3 + 3” open-label dose-escalation scheme. Cohorts of 3–6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis. RESULTS: Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level − 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level − 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events. CONCLUSIONS: The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer. Springer Berlin Heidelberg 2019-08-23 2019 /pmc/articles/PMC6769092/ /pubmed/31444620 http://dx.doi.org/10.1007/s00280-019-03916-0 Text en © The Author(s) 2019 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 | Clinical Trial Report Clarke, Jeffrey Melson Blobe, Gerard C. Strickler, John H. Uronis, Hope Elizabeth Zafar, S. Yousuf Morse, Michael Dropkin, Evan Howard, Leigh O’Neill, Margot Rushing, Christel N. Niedzwiecki, Donna Watson, Hollie Bolch, Emily Arrowood, Christy Liu, Yingmiao Nixon, Andrew B. Hurwitz, Herbert I. A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) |
title | A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) |
title_full | A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) |
title_fullStr | A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) |
title_full_unstemmed | A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) |
title_short | A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial) |
title_sort | phase ib study of the combination regorafenib with pf-03446962 in patients with refractory metastatic colorectal cancer (regal-1 trial) |
topic | Clinical Trial Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769092/ https://www.ncbi.nlm.nih.gov/pubmed/31444620 http://dx.doi.org/10.1007/s00280-019-03916-0 |
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