Journal Article

DKFZ-2023-02249

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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, N. ; Sprick, M. (First author)DKFZ* ; Ahmed, A. ; Burhenne, J. ; Kirchner, M. ; Le Cornet, L.DKFZ* ; Kratzmann, M.DKFZ* ; Hajda, J. ; Stenzinger, A. ; Steindorf, K.DKFZ* ; Delorme, S.DKFZ* ; Schlemmer, H.-P.DKFZ* ; Riethdorf, S. ; van Schaik, R. ; Pantel, K. ; Siveke, J.DKFZ* ; Seufferlein, T. ; Jäger, D.DKFZ* ; Haefeli, W. E. ; Trumpp, A. (Last author)DKFZ* ; Springfeld, C.

2023
Blackwell [[-2008]] Oxford

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Please use a persistent id in citations: doi:10.1111/cts.13661

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.

Note: Clinical Trial / #EA:A010#LA:A010# / 2023 Dec;16(12):2483-2493

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Contributing Institute(s):

1. A010 Stammzellen und Krebs (A010)
2. Klinische Studienzentrale (W010)
3. Bewegung, Präventionsforschung und Krebs (C110)
4. E010 Radiologie (E010)
5. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)
6. D120 Angewandte Tumor-Immunität (D120)
7. DKTK HD zentral (HD01)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2023

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