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Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree. Keywordsbreast cancer resistance protein transporter, cytochrome P450, drug-drug interactions, napabucasin, phase 1 trial Napabucasin (Figure 1) is an orally administered reactive oxygen species (ROS) generator that is bioactivated by the intracellular antioxidant nicotinamide ade-

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RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. We previously discovered aiRNA (asymmetric interfering RNA), a next generation of gene-silencing technology with improved gene silencing efficiency and reduced off-target effects in comparison with siRNA. We have recently developed a nanoscale formulation that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1, named BBI-801. Here we investigate the in vivo delivery and antitumor activity of BBI-801 encapsulating aiRNAs targeting CTNNB1 and PD-L1. CTNNB1 encodes undruggable β-catenin which is a cancer stemness gene that is broadly implicated in multiple cancer types PD-L1 gene encodes a key immune checkpoint factor that mediates cancer immune evasion. In our in vivo studies, we have achieved prolong silencing of β-Catenin/PD-L1 mRNA and protein in a dose-dependent manner in a wide variety of murine tumor models, including subcutaneous human tumor xenografts, orthotopic human liver and lung tumors, as well as syngeneic mouse colorectal, breast and lung tumors. Our biodistribution analysis of fluorescence-labeled aiRNA demonstrated that the delivery of BBI-801 to xenograft tumors happens within 5 minutes of aiRNA administration and lasts at least 8 hours. In all the models we examined, significant tumor growth inhibition by BBI-801 was achieved not only in β-Catenin over-expressed colorectal tumor models, SW480 and APCmin, but also in the rest of β-Catenin normal-expressed tumor models. Finally, BBI-801 is well tolerated and no signs of toxicity were observed after repeated dosing. These exciting data support further investigation of the anti-tumor potential of BBI-801 as an anticancer therapeutic in variety of tumor indications. Citation Format: Youzhi Li, Yuan Gao, Yuxin Wang, Jie Su, Eric Hsu, Ewa Wybieralska, Janet Huang, Keyur Gada, Jun Oishi, Xiaoshu Dai, Erina Koga, Wei Li, Xiangao Sun, Emily Brooks, Chiang J. Li. In vivo delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-069. doi:10.1158/1538-7445.AM2017-LB-069

This phase 1, open‐label study assessed 14 C‐napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18–45 years) received a single oral 240‐mg napabucasin dose containing ~100 μCi 14 C‐napabucasin. Napabucasin was absorbed and metabolized to dihydro‐napabucasin (M1; an active metabolite [12.57‐fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half‐lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per C max and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUC last : 0.376; C max : 0.525) indicated circulating drug‐related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment‐emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240‐mg dose was generally well tolerated.