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 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.

FIGURE 1

The dose escalation part encompasses three sequential cohorts with three (+3) patients each treated with gemcitabine, nab‐paclitaxel, and cobicistat. The starting dose of nab‐paclitaxel for cohort 1 will be 75 mg/m². Inclusion of additional blocks (shaded in gray) of three patients per cohort depends on the number of DLT occurrences in the first three patients. Escalation of subsequent dosing (i.e., opening of cohorts with escalated doses) also depends on the occurrence of DLTs. The data monitoring committee (DMC meetings, represented by black stars) will review safety data when data post 28 days of treatment of at least three patients per cohort are available (C1‐DLT observation period) and then make a recommendation on opening of the next cohorts with an escalated dose or not. DLT, dose limiting toxicity; DMC, data monitoring committee.

FIGURE 2

During cycle 1 (a) patients will be treated with nab‐paclitaxel and gemcitabine at days 1, 8, and 15. Cobicistat will be added starting with day 11. Blood samples for nab‐paclitaxel pharmacokinetics (PKs) will be collected at day 1 and day 15 over 48 h and before the next nab‐paclitaxel dosing (~168 h postdose). Treatment during subsequent cycles (b) will consist of cobicistat once daily (q.d.) with gemcitabine and nab‐paclitaxel at days 1, 8, and 15 in all patients until progression.