PANTAX: a phase Ib clinical trial of the efflux pump inhibitor SCO-101 in combination with gemcitabine and nab-paclitaxel in non-resectable or metastatic pancreatic cancer.

De novo or acquired resistance to chemotherapy is ubiquitous in pancreatic ductal adenocarcinoma (PDAC). SCO-101 is an oral compound that may counteract chemo-resistance by interacting with SRPK1, ABCG2 drug transporter, and liver enzyme UGT1A1. We first conducted preclinical experiments in paclitaxel-resistant PDAC cells to access the tumoricidal effects of SCO-101 or SRPK1-inhibitor alone or in combination with paclitaxel. Second, we enrolled 22 patients with non-resectable PDAC in a phase Ib trial to investigate safety and pharmaco-kinetics, and to establish maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) during the first cycle of 80% dose gemcitabine (Gem) and nab-paclitaxel (Nab) together with increasing doses of SCO-101. In paclitaxel-resistant PDAC cells in vitro, a synergistic effect between SCO-101 and paclitaxel was demonstrated. In patients, daily doses for 6 days of SCO-101 resulted in a two- to threefold drug accumulation, and drug exposure was dose proportional. Treatment was well tolerated. Transiently increased blood bilirubin attributable to SCO-101 was observed in 12 cases (55%) and associated with jaundice in three patients. One and two DLTs, respectively, were observed at 150 and 250mg dosing-levels of SCO-101, and the MTD was determined to be 200 mg of SCO-101 daily for 6 days on a bi-weekly schedule together with 80% dose of Gem and Nab. Median progression-free and overall survival was 3.3 and 9.5 months, respectively. In PDAC, SCO-101 can be added to Gem and Nab with little and manageable toxicity. However, no clear added efficacy signal was observed of the combination. Trial registration number: NCT04652205 (Nov 29, 2020).