Phase I study of the antiprogrammed cell death-1 Ab spartalizumab (PDR001) in Japanese patients with advanced malignancies.

Spartalizumab is a humanized IgG4/κ mAb directed against human programmed cell death-1 (PD-1). In this phase I study, we investigated safety, pharmacokinetics, preliminary antitumor activity, and toxicity of spartalizumab in patients with advanced malignancies. Patients (n = 18) with a range of tumor types received spartalizumab i.v. at doses of 1, 3, and 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or discontinuation at the discretion of the investigator or patient. Most patients (61%) had received five or more prior lines of therapy. No dose-limiting toxicities were reported and, hence, the maximum tolerated dose was 10 mg/kg or more. Pharmacokinetics in Japanese patients aligned with those reported in a global dose-escalation study. The safety profile was consistent with other approved anti-PD-1 mAbs; the most common drug-related adverse events were maculopapular rash (22%), followed by malaise and increased blood alkaline phosphatase (11% each). Partial responses were reported in two patients (11%), one with transitional cell carcinoma and the other with hepatocellular carcinoma. In conclusion, this study confirmed the safety of spartalizumab given at a dose of up to 10 mg/kg every 2 weeks in Japanese patients with cancers.

Phase I dose-escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors.

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug-related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.

[Possibility of formation of the S100A8/A9-proinflammatory cytokine complexes in vivo in acute inflammation and their functional roles].

We previously hypothesized that S100A8/A9 binds with several kinds of proinflammatory cytokines, such as TNF-alpha, IL-6 and IL-1beta, to form the S100A8/A9-proinflammatory cytokine complexes in vivo in acute inflammation, leading to subsidence of inflammatory responses. Our goal was to verify the presence of these complexes in liver tissues of rats with lipopolysaccharide (LPS) induced damage. We firstly prepared two kinds of the full-length cDNA encoding amino acid sequences of human S100A8 and S100A9 proteins, and constructed their pCold-I expression vectors. The recombinant S100A8 and S100A9 were successfully expressed in E. coli, and then purified by Ni-agarose columns, respectively. The S100A8/A9 was noncovalently synthesized in 2.0 mol/1 Tris-NaOH solution (pH 12) using the purified S100A8 and S100A9. After purification, this heterodimer (1 mg) was intraperitoneally injected into a rat 1h after injection of LPS. Two kinds of ELISA systems were used to detect the S100A8/A9-inflammatory cytokine complexes in the rat liver tissue. As determined by the ELISA-A and B, the reaction was apparently positive and quantitative. Immunohistochemistry provided such complexes-positive cells in the liver with damage. The S100A8/A9-positive cells almost corresponded to the cytokines-positive ones morphologically, strongly suggested the presence of the S100A8/A9-proinflammatory cytokine complexes. In conclusion, the possibility that these complexes were formed in vivo and accumulated to the immunological cells, such as macrophages and/or activated neutrophils, was indicated. Our effort is currently addressed to isolate the S100A8/A9-proinflammatory cytokine complexes using biochemical techniques, and to comprehensively resolute their clinical significance in the differential diagnosis of inflammatory diseases.