In the current study we aimed to investigate the kinetics and location of the i

The most common grade 3 or higher AEs were skin rash, HFS and fatigue . The skin rash was typically a generalized maculopapular erythematous eruption arising in the first two weeks of treatment and progressing rapidly. With prompt treatment interruption, the rash typically resolved over INNO-406 887650-05-7 a few days and most patients were able to resume and tolerate treatment at the reduced dose of sorafenib while maintaining the same dose of IL 21. The most common laboratory abnormalities in phase 2 patients included cytopenias, electrolyte abnormalities, and elevated hepatic transaminases. These were mostly grade 1 or 2 and were transiently observed during IL 21 treatment weeks. Transient lymphopenia was observed during the IL 21 administration weeks with rapid recovery afterwards, a pattern similar to the observations from IL 21 monotherapy study .

Grade 3 hypo phosphatemia, although common, was typically asymp tomatic and responded well to oral supplementation. Adverse effects on renal and hepatic function were mostly mild and transient, although reversible grade 3 elevations in creatinine and hepatic transaminases occurred sporadically. The majority of Lapatinib HER2 阻害剤 patients required a reduction in the sorafenib dose mostly due to skin rash and HFS. After reduction in sorafenib dose, most patients tolerated the combination treatment well without a recurrence of these toxicities. The IL 21 dose was reduced in 3 patients due to myalgias, pancreatitis, and rash, respectively. No treatment related deaths were observed in this study.

Pharmacokinetics, pharmacodynamics and immunogenicity Exposure parameters for IL 21 increased with dose and did not appear to change Lonafarnib 臨床試験 significantly with repeat dosing. The mean overall exposure based on AUC0 t after a single and repeated doses of 30 mcg kg IL 21 in combination with sorafenib was 188 and 226 h ng mL respectively. The corresponding mean half life estimates were 1. 82 and 1. 95 hours. These PK parameter estimates are similar to those observed with IL 21 monotherapy . As IL 21 PK did not change with time, the addition of oral doses of sorafe nib does not appear to affect the PK of IL 21. Single dose sorafenib exposure parameters in the pres ence of IL 21 appear comparable to reported values for single agent sorafenib . The effect of IL 21 on sorafenib repeat dose PK could not be deter mined due to the frequency of sorafenib dose reductions.

Soluble CD25 is cleaved from T and NK cells on activation . While this study did not specifically assess cytotoxic function of CD8 T or NK cells, the serum levels of sCD25 were measured at multiple time points to broadly assess T and NK cells immune activation from IL 21, as described previously . The serum concentration of sCD25 increased in all dose cohorts following IL 21 dosing. In addition, sCD25 induction following dosing with 30 mcg kg IL 21 in combination with sorafenib was consistent with previous observations with IL 21 monotherapy, suggest ing that sorafenib does not interfere with the pharma cological effects of IL 21 . Neutralizing anti IL 21 antibodies were detected in 3 patients. Two of these 3 patients developed infusion reac tions characterized as transient flushing, chills, and mild hypotension, both patients continued to receive IL 21 after pre medication with antihistaminics and acetamino phen.