Protocol of the IntenSify-Trial
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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. / Hohmann, Nicolas; Sprick, Martin Ronald; Pohl, Moritz; Ahmed, Azaz; Burhenne, Jürgen; Kirchner, Marietta; Le Cornet, Lucian; Kratzmann, Markus; Hajda, Jacek; Stenzinger, Albrecht; Steindorf, Karen; Delorme, Stefan; Schlemmer, Heinz-Peter; Riethdorf, Sabine; van Schaik, Ron; Pantel, Klaus; Siveke, Jens; Seufferlein, Thomas; Jäger, Dirk; Haefeli, Walter E; Trumpp, Andreas; Springfeld, Christoph.
In: CTS-CLIN TRANSL SCI, Vol. 16, No. 12, 12.2023, p. 2483-2493.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Protocol of the IntenSify-Trial
T2 - 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
AU - Hohmann, Nicolas
AU - Sprick, Martin Ronald
AU - Pohl, Moritz
AU - Ahmed, Azaz
AU - Burhenne, Jürgen
AU - Kirchner, Marietta
AU - Le Cornet, Lucian
AU - Kratzmann, Markus
AU - Hajda, Jacek
AU - Stenzinger, Albrecht
AU - Steindorf, Karen
AU - Delorme, Stefan
AU - Schlemmer, Heinz-Peter
AU - Riethdorf, Sabine
AU - van Schaik, Ron
AU - Pantel, Klaus
AU - Siveke, Jens
AU - Seufferlein, Thomas
AU - Jäger, Dirk
AU - Haefeli, Walter E
AU - Trumpp, Andreas
AU - Springfeld, Christoph
N1 - © 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
U2 - 10.1111/cts.13661
DO - 10.1111/cts.13661
M3 - SCORING: Journal article
C2 - 37920921
VL - 16
SP - 2483
EP - 2493
JO - CTS-CLIN TRANSL SCI
JF - CTS-CLIN TRANSL SCI
SN - 1752-8054
IS - 12
ER -
