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DOX induces atrogin-1 through a p38-MAPK-dependent pathway in cardiac myocytes. Constitutive activation of Akt negatively regulates DOX-mediated atrogin-1 induction by inhibiting p38-MAPK activity as a novel mechanism.

Background Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1–3, FGFRs 1–4, and PDGFR-α) was evaluated for second-line treatment of BTC. Methods In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles. Results Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2–27.2). Median PFS was 3.19 months (95% CI: 2.79–7.23) per investigator assessment and 1.64 months (95% CI: 1.41–3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50–11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related. Conclusions Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population. Trial registration ClinicalTrials.gov NCT02579616. Date of registration: October 19, 2015.

No abstract

310 Background: LEN inhibits the activity of vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor–α. These targets have been shown to be expressed in patients (pts) with BTC. The objective of this study is to evaluate LEN as a potential treatment option for these pts. Methods: This is an open-label, phase 2 study conducted in Japan. Pts aged ≥ 20 years with confirmed diagnosis of unresectable BTC, measureable disease per Response Evaluation Criteria in Solid Tumors v1.1, and 1 prior gemcitabine-based doublet chemotherapy, will receive LEN 24 mg/d. The primary endpoint is objective response rate. Secondary objectives include disease control rate (DCR), safety, and pharmacokinetics. Enrollment of 25 pts is planned. The study includes an interim evaluation for futility. If there is no objective response and disease control is achieved in < 5 pts of 15‒17 pts, the study will end. Results: An interim evaluation was performed with 17 pts enrolled (data cutoff: 25 July 2016). Ten (59%) pts were aged < 65 years, 10 (59%) were male, 2 (12%) had prior surgery, and 13 (76%) received prior gemcitabine + cisplatin therapy. Efficacy results appear in the table. One pt had a partial response (PR) and 13 had stable disease (SD). The DCR was 82%. All pts experienced treatment-emergent adverse events (TEAEs). Grade ≥ 3 TEAEs occurred in 11 (65%) and serious AEs (SAEs) occurred in 7 (41%) pts. There were no fatal SAEs. TEAEs leading to LEN discontinuation, dose reduction, and dose interruption occurred in 1 (6%), 12 (71%), and 9 (53%) pts, respectively. Analysis of trough plasma concentration in 13 pts from this study showed no difference versus that observed in a previous phase 3 study of LEN in differentiated thyroid cancer. Conclusions: Because results of this interim evaluation did not meet futility criteria, the study was continued, with findings suggesting possible activity of LEN in pts with unresectable BTC who failed gemcitabine-based doublet chemotherapy. Toxicities were generally manageable with dose modifications as only 1 pt required discontinuation from LEN. Clinical trial information: NCT02579616. [Table: see text]