Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy
Abstract Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxe...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-12-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13661 |
| _version_ | 1797391747641245696 |
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| author | Nicolas Hohmann Martin Ronald Sprick Moritz Pohl Azaz Ahmed Jürgen Burhenne Marietta Kirchner Lucian Le Cornet Markus Kratzmann Jacek Hajda Albrecht Stenzinger Karen Steindorf Stefan Delorme Heinz‐Peter Schlemmer Sabine Riethdorf Ron vanSchaik Klaus Pantel Jens Siveke Thomas Seufferlein Dirk Jäger Walter E. Haefeli Andreas Trumpp Christoph Springfeld |
| author_facet | Nicolas Hohmann Martin Ronald Sprick Moritz Pohl Azaz Ahmed Jürgen Burhenne Marietta Kirchner Lucian Le Cornet Markus Kratzmann Jacek Hajda Albrecht Stenzinger Karen Steindorf Stefan Delorme Heinz‐Peter Schlemmer Sabine Riethdorf Ron vanSchaik Klaus Pantel Jens Siveke Thomas Seufferlein Dirk Jäger Walter E. Haefeli Andreas Trumpp Christoph Springfeld |
| author_sort | Nicolas Hohmann |
| collection | DOAJ |
| description | Abstract Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study. |
| first_indexed | 2024-03-08T23:37:10Z |
| format | Article |
| id | doaj.art-c68c01273a54478990c71f106d610b42 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-08T23:37:10Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-c68c01273a54478990c71f106d610b422023-12-14T06:03:04ZengWileyClinical and Translational Science1752-80541752-80622023-12-0116122483249310.1111/cts.13661Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacyNicolas Hohmann0Martin Ronald Sprick1Moritz Pohl2Azaz Ahmed3Jürgen Burhenne4Marietta Kirchner5Lucian Le Cornet6Markus Kratzmann7Jacek Hajda8Albrecht Stenzinger9Karen Steindorf10Stefan Delorme11Heinz‐Peter Schlemmer12Sabine Riethdorf13Ron vanSchaik14Klaus Pantel15Jens Siveke16Thomas Seufferlein17Dirk Jäger18Walter E. Haefeli19Andreas Trumpp20Christoph Springfeld21Department of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases Heidelberg GermanyDivision of Stem Cells and Cancer German Cancer Research Center (DKFZ) Heidelberg GermanyInstitute of Medical Biometry University Hospital Heidelberg Heidelberg GermanyDepartment of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases Heidelberg GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology Heidelberg University Hospital Heidelberg GermanyInstitute of Medical Biometry University Hospital Heidelberg Heidelberg GermanyNCT Trial Center, NCT German Cancer Research Center (DKFZ) Heidelberg GermanyNCT Trial Center, NCT German Cancer Research Center (DKFZ) Heidelberg GermanyPharmacovigilance Department, Coordination Centre for Clinical Trials (KKS) Heidelberg University Hospital Heidelberg GermanyInstitute of Pathology University Hospital Heidelberg Heidelberg GermanyDivision of Physical Activity, Prevention and Cancer German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg Heidelberg GermanyDivision of Radiology German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Radiology German Cancer Research Center (DKFZ) Heidelberg GermanyInstitute of Tumor Biology University Medical Center Hamburg‐Eppendorf Hamburg GermanyDepartment of Clinical Chemistry Erasmus University Medical Center Rotterdam The NetherlandsInstitute of Tumor Biology University Medical Center Hamburg‐Eppendorf Hamburg GermanyBridge Institute of Experimental Tumor Therapy, West German Cancer Center University Hospital Essen, University of Duisburg‐Essen Essen GermanyDepartment of Internal Medicine I Ulm University Hospital Ulm GermanyDepartment of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases Heidelberg GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology Heidelberg University Hospital Heidelberg GermanyDivision of Stem Cells and Cancer German Cancer Research Center (DKFZ) Heidelberg GermanyDepartment of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases Heidelberg GermanyAbstract Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m2) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study.https://doi.org/10.1111/cts.13661 |
| spellingShingle | Nicolas Hohmann Martin Ronald Sprick Moritz Pohl Azaz Ahmed Jürgen Burhenne Marietta Kirchner Lucian Le Cornet Markus Kratzmann Jacek Hajda Albrecht Stenzinger Karen Steindorf Stefan Delorme Heinz‐Peter Schlemmer Sabine Riethdorf Ron vanSchaik Klaus Pantel Jens Siveke Thomas Seufferlein Dirk Jäger Walter E. Haefeli Andreas Trumpp Christoph Springfeld Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy Clinical and Translational Science |
| title | Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy |
| title_full | Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy |
| title_fullStr | Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy |
| title_full_unstemmed | Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy |
| title_short | Protocol of the IntenSify‐Trial: An open‐label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab‐paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy |
| title_sort | protocol of the intensify trial an open label phase i trial of the cyp3a inhibitor cobicistat and the cytostatics gemcitabine and nab paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination s pharmacokinetics safety and efficacy |
| url | https://doi.org/10.1111/cts.13661 |
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