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

Abstract

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).

Keywords: Chemotherapy resistance mechanisms; Cytotoxicity assay; Gemcitabine; Nab-paclitaxel; Pancreas cancer.

Fig. 1

Study treatment including screening, treatment phase, and follow-up. Visits are indicated on x-axis. *SCO-101 orally for 6 days before chemotherapy at day (D) 6 and 20; # gemcitabine and nab-paclitaxel with a starting dose of 80% recommended dose; ~ SCO-101 treatment for a maximum of 9 months; ^o follow-up until end of study or death. EoT, end of treatment

Fig. 2

Synergistic effect in Panc-1-Pac cells when combining paclitaxel with SCO-101 or SRPK1-inhibitor. A Cell viability. Effect of treatment with paclitaxel and SCO-101 alone and in combination for 72 h with drug + 72 h with fresh media without drugs. An experiment with individual treatments in triplicate is shown. Values are represented as percentage normalized to untreated cells. Error bars indicate standard deviation. B Visualization of synergy scores for SCO-101/paclitaxel combinations. The mean ZIP synergy score was 16.795, indicating synergy between SCO-101 and paclitaxel. C Cell viability. Effect of treatment with paclitaxel and SPINX31 (S31) alone and in combination for 144 h. An experiment with individual treatments in triplicate is shown. Values are represented as percentage normalized to untreated cells. Error bars indicate standard deviation. D Visualization of synergy scores for SPHINX31/paclitaxel. The mean ZIP synergy score was 57.037, indicating synergy between SPHINX31 and paclitaxel

Fig. 3

Pharmacokinetics and clinical outcome of SCO-101 and 80% dose of Gem and Nab. a Maximum drug plasma concentration, C_max, and b area under the plasma drug concentration–time curve, AUC_{0-8 h}, of six daily doses of SCO-101. Daily dose of SCO-101 is shown on x-axis and plasma SCO-101 measurements on the y-axis. For comparison, C_max exposures previously measured in a phase I study with healthy volunteers (HV) following repeated dosing of 50 mg and 150 mg SCO-101 for 14 days [18] have in a been extrapolated to 40 mg and 140 mg to better illustrate the similar and overlapping exposures. The AUC_{0 to 8 h} was not calculated in the HV phase I study, and therefore it is not shown in b. c Kaplan-Meyer plot of progression-free survival, and d overall survival of patients. Patients censored are indicated by vertical bars