{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T16:59:00Z","timestamp":1770569940271,"version":"3.49.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T00:00:00Z","timestamp":1698969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010paclitaxel 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\u2010paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3\u2009+\u20093 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab\u2010paclitaxel, and cobicistat. Although the doses of gemcitabine (1000\u2009mg\/m<jats:sup>2<\/jats:sup>) and cobicistat (150\u2009mg) are fixed, three dose levels of nab\u2010paclitaxel (75, 100, and 125\u2009mg\/m<jats:sup>2<\/jats:sup>) 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\u2010Nr. 2019\u2010001439\u201029, drks.de: DRKS00029409, and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/ct.gov\">ct.gov<\/jats:ext-link>: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab\u2010paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large\u2010scale clinical study.<\/jats:p>","DOI":"10.1111\/cts.13661","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T07:53:30Z","timestamp":1698998010000},"page":"2483-2493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Protocol of the <scp>IntenSify\u2010Trial<\/scp>: An open\u2010label phase I trial of the <scp>CYP3A<\/scp> inhibitor cobicistat and the cytostatics gemcitabine and nab\u2010paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and\u00a0efficacy"],"prefix":"10.1111","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8036-8806","authenticated-orcid":false,"given":"Nicolas","family":"Hohmann","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin Ronald","family":"Sprick","sequence":"additional","affiliation":[{"name":"Division of Stem Cells and Cancer German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI\u2010STEM gGmbH)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moritz","family":"Pohl","sequence":"additional","affiliation":[{"name":"Institute of Medical Biometry University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3000-7951","authenticated-orcid":false,"given":"Azaz","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2190-1698","authenticated-orcid":false,"given":"J\u00fcrgen","family":"Burhenne","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0294-2483","authenticated-orcid":false,"given":"Marietta","family":"Kirchner","sequence":"additional","affiliation":[{"name":"Institute of Medical Biometry University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucian","family":"Le\u00a0Cornet","sequence":"additional","affiliation":[{"name":"NCT Trial Center, NCT German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Kratzmann","sequence":"additional","affiliation":[{"name":"NCT Trial Center, NCT German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacek","family":"Hajda","sequence":"additional","affiliation":[{"name":"Pharmacovigilance Department, Coordination Centre for Clinical Trials (KKS) Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1001-103X","authenticated-orcid":false,"given":"Albrecht","family":"Stenzinger","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Steindorf","sequence":"additional","affiliation":[{"name":"Division of Physical Activity, Prevention and Cancer German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Delorme","sequence":"additional","affiliation":[{"name":"Division of Radiology German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinz\u2010Peter","family":"Schlemmer","sequence":"additional","affiliation":[{"name":"Division of Radiology German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Riethdorf","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron","family":"van Schaik","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Pantel","sequence":"additional","affiliation":[{"name":"Institute of Tumor Biology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8772-4778","authenticated-orcid":false,"given":"Jens","family":"Siveke","sequence":"additional","affiliation":[{"name":"Bridge Institute of Experimental Tumor Therapy, West German Cancer Center University Hospital Essen, University of Duisburg\u2010Essen  Essen Germany"},{"name":"Division of Solid Tumor Translational Oncology German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Seufferlein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I Ulm University Hospital  Ulm Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"J\u00e4ger","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases  Heidelberg Germany"},{"name":"Clinical Cooperation Unit Applied Tumor Immunity German Cancer Research Center (DKFZ)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0672-6876","authenticated-orcid":false,"given":"Walter E.","family":"Haefeli","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Pharmacoepidemiology Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-3466","authenticated-orcid":false,"given":"Andreas","family":"Trumpp","sequence":"additional","affiliation":[{"name":"Division of Stem Cells and Cancer German Cancer Research Center (DKFZ)  Heidelberg Germany"},{"name":"Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI\u2010STEM gGmbH)  Heidelberg Germany"},{"name":"German Cancer Consortium (DKTK)  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3843-101X","authenticated-orcid":false,"given":"Christoph","family":"Springfeld","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Heidelberg University Hospital, National Center for Tumor Diseases  Heidelberg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"e_1_2_12_2_1","unstructured":"NCI SEERS Database.Cancer stat facts: pancreatic cancer. Accessed June 15 2023.https:\/\/seer.cancer.gov\/statfacts\/html\/pancreas.html. Last"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.36.5742"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.07.9525"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1011923"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1304369"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2015.12.026"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00986-1"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.21037\/tcr.2017.09.10"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2016.1163337"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4038"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.36"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.2217\/fon.12.53"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12820"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-013-0160-x"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000421-199712000-00013"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2020.105355"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.2174\/157015906776359568"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-017-0563-z"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.2307\/2531693"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinepi.2015.08.007"},{"key":"e_1_2_12_23_1","volume-title":"EORTC QLQ\u2010C30 Scoring Manual","author":"Fayers P","year":"2001"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(99)00047-7"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djw273"},{"key":"e_1_2_12_26_1","first-page":"678","volume-title":"Handbook of Psychiatric Measures","author":"Buysse DJ","year":"2000"},{"key":"e_1_2_12_27_1","unstructured":"FACT\u2010Cog Scoring Guidelines (Version 3) www.facit.org"},{"key":"e_1_2_12_28_1","unstructured":"Patient Health Questionnaire (PHQ) Screeners.INSTRUCTION MANUAL Instructions for Patient Health Questionnaire (PHQ) and GAD\u20107 Measures."},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-011-5675-y"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12502"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.164"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2180"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-2291"},{"key":"e_1_2_12_34_1","unstructured":"Bristol Myers Squibb.Abraxane 5 mg\/mL powder for dispersion for infusion SmPC.2022[cited 2022 Aug 01].https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/abraxane\u2010epar\u2010product\u2010information_en.pdf"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-016-2798-8"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.21037\/jgo.2016.01.03"},{"key":"e_1_2_12_37_1","doi-asserted-by":"crossref","unstructured":"GradisharW.San Antonio Breast Cancer Symposium 2011:poster P5\u201019\u201013.","DOI":"10.1016\/S1470-2045(11)70390-4"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgo.2020.06.017"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12851"},{"key":"e_1_2_12_40_1","unstructured":"Lilly.Gemzar 200 mg powder for solution for infusion SmPC.2008[cited 2022 Aug 01].https:\/\/www.ema.europa.eu\/en\/documents\/referral\/gemzar\u2010article\u201030\u2010referral\u2010annex\u2010i\u2010ii\u2010iii_en.pdf"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2015.07.022"},{"key":"e_1_2_12_42_1","unstructured":"European Medicines Agency.Guideline on the investigation of drug interactions.2012. [cited 2022 Aug 01].https:\/\/www.ema.europa.eu\/en\/documents\/scientific\u2010guideline\/guideline\u2010investigation\u2010drug\u2010interactions\u2010revision\u20101_en.pdf"},{"key":"e_1_2_12_43_1","unstructured":"U.S. Food and Drug Administration.Clinical Drug Interaction Studies\u2014Cytochrome P450 Enzyme\u2010 and Transporter\u2010Mediated Drug Interactions Guidance for Industry.2020. [cited 2022 Aug 01].https:\/\/www.fda.gov\/media\/134581\/download"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.28"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-0296"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13661","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T12:33:57Z","timestamp":1705840437000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,3]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1111\/cts.13661"],"URL":"https:\/\/doi.org\/10.1111\/cts.13661","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,3]]},"assertion":[{"value":"2023-07-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}