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Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib.

ABSTRACT: Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients by twice-daily dosing in 3-week cycles; 2 weeks of treatment followed by 1 week of rest until discontinuation. Blood samples for plasma proteins were collected on days 1 (baseline), 8, and 15 of cycle 1, and days 1, 8, and 15 of cycle 2. Selected clinical outcomes, including tumor shrinkage and adverse events (AEs), were used for correlative analyses of pharmacokinetic parameters and PD biomarkers.Tumor shrinkage and changes in PD biomarkers (increased vascular endothelial growth factor [VEGF] and stromal cell-derived factor 1 alpha [SDF1?] levels and decreased soluble VEGF receptor 2 [sVEGFR2] levels) significantly correlated with increasing lenvatinib exposure. Observed changes in levels of VEGF, SDF1?, and sVEGFR2 were maintained on day 15 of cycle 1, but returned to baseline during the 1-week rest period, and similar changes were induced by reinstitution of treatment in cycle 2. The worst grades of hypertension, proteinuria, and fatigue were associated with changes in VEGF and HGF at day 8 of cycle 1. Maximum tumor shrinkage was correlated with increased SDF1? levels. Decreased sVEGFR2 level was also correlated with tumor shrinkage and frequency of hypertension, proteinuria, and fatigue. Tumor shrinkage significantly correlated with the worst grade of proteinuria, but not with hypertension or fatigue.PD biomarker changes observed in plasma angiogenic proteins are correlated with lenvatinib-induced tumor shrinkage and AEs. Our findings warrant further assessment of plasma proteins associated with angiogenesis as potential biomarkers of lenvatinib activity.ClinicalTrial.gov: NCT00280397 (January 20, 2006).

SUBMITTER: Koyama N

PROVIDER: S-EPMC4223557 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib.

Koyama Noriyuki N Saito Kenichi K Nishioka Yuki Y Yusa Wataru W Yamamoto Noboru N Yamada Yasuhide Y Nokihara Hiroshi H Koizumi Fumiaki F Nishio Kazuto K Tamura Tomohide T

BMC cancer 20140721

<h4>Background</h4>Lenvatinib (E7080), an oral multi-kinase inhibitor, has inhibitory action on tumor cell proliferation and tumor angiogenesis in preclinical models. We evaluated correlations between pharmacodynamic (PD) biomarkers with patient clinical outcomes in a lenvatinib phase 1 dose-escalation study.<h4>Methods</h4>Plasma angiogenic proteins were evaluated as potential PD biomarkers of response to lenvatinib in a dose-escalation phase 1 study. Lenvatinib was administered to 27 patients ...[more]

PMID: 25047123

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Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

Project description:ImportanceAn oral treatment for neovascular age-related macular degeneration would be less burdensome than repeated intravitreous injections. X-82 is an oral tyrosine kinase inhibitor active against vascular endothelial growth factor (VEGF) and platelet-derived growth factor.ObjectiveTo undertake safety testing of oral X-82 administered for the treatment of neovascular AMD.Design, setting, and participantsPhase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015 (Retina-Vitreous Associates Medical Group, Beverly Hills, California; Blanton Eye Institute, Houston Methodist Hospital, Retina Consultants of Houston, Houston, Texas; New England Retina Associates, Guilford, Connecticut; Elman Retina Group, Baltimore, Maryland; and Retina Research Institute of Texas, Abilene). Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive.InterventionsParticipants received oral X-82 for 24 weeks at 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria. Every 4 weeks, participants underwent best-corrected visual acuity measurement, fundus examination, and spectral-domain optical coherence tomography.Main outcomes and measuresThe main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections.ResultsOf the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite. Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters). Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68). Mean [SD] central subfield thickness reduced by -50 [97] μm, with 8 participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections. The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued. All but 1 were asymptomatic. Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1).Conclusions and relevanceX-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment. Although 17% of participants discontinued X-82 owing to AEs, those who completed the study had lower than expected anti-VEGF injection rates. Further studies appear justified, with a phase 2 randomized clinical study under way.

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Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib.

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Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib.

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