The genetic polymorphisms in the ABCB1 gene, which encodes for the membrane pump, P-glycoprotein, have been previously demonstrated to have an association with tacrolimus dosing in organ transplant patients. This study associated the haplotype and genotype for ABCB1 G2677T and C3435T variants with a sequential analysis of tacrolimus blood level (ng/mL) per mg/day dosage ([L/D]) administered to 91 adult lung transplant patients at 1, 3, 6, 9, and 12 months after transplantation. Haplotype 22 carriers had a significantly higher tacrolimus [L/D] value in comparison with nonhaplotype 22 carriers (P = .04) only at 1 month after transplant. Sequential analysis demonstrated that ABCB1 genotypes 00 and 01 had low tacrolimus [L/D] values at 1 and 3 months, but these values increased substantially at 6, 9, and 12 months after transplantation. This was not true of the other genotypes with the exception of genotypes 10 and 21, which had small numbers of patients but had consistently low tacrolimus [L/D]. Haplotype analysis also suggested that the homozygous for ABCB1 2677 variant allele had more of an impact on tacrolimus [L/D] in haplotype analysis than that of ABCB1 3435. In conclusion, sequential analysis of tacrolimus [L/D] with haplotypes can explain previous clinical observations of changes in tacrolimus dosage over time but suggests that this effect is limited to individual patient haplotypes. Sequential analysis of drug dosing and haplotypes relationships can provide important information about the induction or inhibition of drug-drug and disease-drug interactions among specific haplotypes.
TPS8121 Background: Resistance to EGFR tyrosine kinase inhibitors (eg, gefitinib) in EGFRm+ NSCLC patients (pts) is mainly caused by a secondary mutation in the EGFR (ie, T790M) or by activation of the c-Met/HGF signaling pathway (eg, protein overexpression and/or amplification). MSC2156119J, a highly selective small-molecule c-Met inhibitor, displayed promising antitumor activity in pts with advanced solid tumors in a Phase I trial (Falchook et al. J Clin Oncol 2013:31(Suppl):2506). This Phase Ib/II, multicenter, open-label trial investigates the antitumor activity of MSC2156119J + gefitinib in pts with MET+ advanced EGFRm+ NSCLC (NCT01982955). Methods: Primary objectives are determination of the recommended phase II dose (RP2D) for the combination (Phase Ib), and progression-free survival (PFS) per investigator read (Phase II). Secondary objectives include safety, pharmacokinetics, and antitumor activity of MSC2156119J (PFS per independent read, overall survival, objective response, and disease control). Adults with advanced NSCLC with activating EGFR mutation, ECOG status 0–1, and resistance on 1st-line gefitinib (Phase II only) are recruited in mainland China, South Korea, Taiwan, and other Asian countries. Patients must have confirmed MET+ status, defined as either strong or moderate protein overexpression by immunohistochemistry, or MET gene amplification by in situ hybridization. Main exclusion criteria: life expectancy <3 mo, or prior EGFR targeting therapy other than gefitinib (Phase II only). For the Phase Ib part (3+3 design), 15–18 pts are planned to receive 300 or 500 mg MSC2156119J p.o. + 250 mg gefitinib p.o./d (21-d cycle); for the Phase II part, up to 200 pts are planned to be enrolled into 2 predefined subgroups according to their T790M mutation status and subsequently randomized 1:1 to RP2D MSC2156119J p.o. + 250 mg gefitinib p.o./d or 500 mg/m2 pemetrexed i.v. + 75 mg/m2 cisplatin i.v. on day 1 (max. of six 21-d cycles). Enrollment for Phase Ib began on Dec 23, 2013. Clinical trial information: NCT01982955.
2521^ Background: MSC2156119J, a selective c-Met inhibitor, suppresses tumor growth in preclinical models. Methods: Primary endpoint of this dose-escalation study (3+3 design; NCT01014936): to assess an MTD; secondary endpoints: antitumor activity, safety, pharmacokinetics (PK), and pharmacodynamics (Pd). Pts received 1x/d oral MSC2156119J (21-d cycles; 3 regimens [R]): d1–14 followed by 7-d rest (R1); 3x/wk (R2); or d1–21 (R3). An optimized formulation (OF) was introduced in Aug 2011. Results: Up to Nov 25, 2013,126 pts were analyzed (R1=42; R2=45; R3=39). On the initial formulation, doses were escalated from 30–230 mg/d in R1 and 30–115 mg/d in R2; on the OF (R1–3): 30–400 mg/d, 60–315 mg/d, and 300–1400 mg/d. AUC and Cmax increased with dose; bioavailability was higher with OF. An MTD was not reached. Six pts reported dose-limiting toxicities: asymptomatic G4 lipase and G3 amylase increase (R1; 115 mg/d), G3 nausea and vomiting (R2; 130 mg/d; OF), asymptomatic G3 lipase increase (R2; 60 + 100 mg/d; OF), G3 fatigue (R3; 1400 mg/d; OF), and G3 ALT elevation (R3; 1000 mg/d; OF). Other ≥G3 treatment-related adverse events (trAEs) were G3 peripheral edema (1 pt; R3; 300 mg/d; OF) and G3 AST elevation (1 pt; R3; 1000 mg/d; OF). Most frequent G2 trAEs (R1–3): fatigue (n=8), peripheral edema (n=3), vomiting (n=3), nausea (n=2), asymptomatic lipase increase (n=2), and neutropenia (n=2). 79% of pts had no trAE >G1. Pre- and on-therapy tumor biopsies showed phospho-c-Met inhibition in 19/21 evaluable pts. One pt (esophageal adenocarcinoma) had confirmed partial response (PR); 2 pts (nasopharyngeal and colorectal carcinoma) had unconfirmed PRs. Stable disease (SD) ≥4 mo was seen in 18 pts, incl. 1 pt with SD >32 mo. Based on preclinical PK/Pd models and clinical Pd data, 500 mg was considered biologically active and sufficient to reach ≥95% target inhibition. Conclusions: MSC2156119J was well tolerated and showed antitumor activity. Recommended phase II dose (RP2D) is 500 mg 1x/d. Dose escalation was stopped at 2.8xRP2D (1400 mg/d). An MTD was not reached. Additional Pd and biomarker data (c-Met status by immunohistochemistry [IHC] and in situ hybridization) will be presented. Clinical trial information: NCT01014936.
Abstract Background: Acquired resistance to VEGFR/PDGFR inhibitors has been associated with various aspects of epithelial-to-mesenchymal transition. c-MET/HGF, TGF-beta, and CXCR4/CXCL12 are among the main pathways triggered by antiangiogenic therapies, facilitating cellular invasion and occurrence of metastases. The most advanced MET pathway inhibitors are currently under phase 3 clinical evaluation. In addition, initial data suggest that carbonic anhydrase 9 (CA9) is associated with HCC development. The aim of this study was to correlate c-MET and CA9 expression levels by immunochemistry with clinicopathologic characteristics and disease-free survival (DFS) in patients with HCC. Materials and Methods: One-hundred formalin-fixed and paraffin-embedded HCC resection specimens from 100 patients were evaluated by immunohistochemistry using the Ventana platform (anti-c-MET clone Sp44 and a polyclonal CA9). Staining results were qualitatively and quantitatively assessed (using both manual and automated evaluation) and correlated with clinical and serologic parameters. Based on previously published automated quantitative assessment of c-MET staining (Garcia S, 2007), we elaborated our own dedicated macro, using ImageJ software. High c-MET expression was defined as moderate to strong staining (2+ and 3+ on a 0-3+ scale). Univariate analyses were performed using Fisher's exact or chi square test, and multivariate analyses using Cox regression model. Median DFS was calculated by Kaplan-Meier method. Results: Ninety-seven evaluable samples were included in the data analysis. Patients were mainly males (84%). Tumors were classified as BCLC A1 (92%), uninodular (53%), low-AFP-expressing (81%), moderately differentiated (60%), and with portal invasion (70%). c-MET staining was cytoplasmic and membranous. High c-MET expression was observed in 51% of tumors. c-MET expression level was higher in patients with viral hepatitis-associated HCC (p=0.02) and in patients with AFP>400UI/L (p=0.03). High CA9 expression was observed in 41% of tumors and was correlated with viral hepatitis (p=0.002), pathological portal vein invasion (p=0.007), and poor differentiation (p=0.007). c-MET and CA9 expression levels significantly correlated with each other (p=0.008). Median DFS was shorter in the high-c-MET (12.9 months, vs >80 months in low-c-MET; p=0.018) and high-CA9 (10.2 months, vs 34.4 months in low-CA9; p=0.02) populations. Comparison of c-MET and CA9 status discriminated 4 groups with distinct prognosis: in the c-MET-high/CA9-high group the shortest median DFS was 10.7 months, whereas this was not reached in the c-MET-low/CA9-low group (p=0.003). c-MET-high/CA9-low and c-MET-low/CA9-high groups were defined as intermediate risk populations. Multivariate analysis showed that tumor size (p=0.025), morphology (uni- vs multinodular; p=0.004), and CA9 expression level (p=0.007) were independently associated with DFS; c-MET expression level was significantly associated with DFS when CA9 was excluded from the model (p=0.024). Conclusion: c-MET expression is a useful prognostic marker in HCC that could be used for patient stratification. HCC overexpressing c-MET and CA9 represents a subgroup of patients with a particularly poor prognosis who might benefit from therapy with c-MET inhibitors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B31. Citation Format: Annemilai Tijeras-Raballand, Miguel Albuquerque, Cindy Neuzillet, Nathalie Colnot, Friedhelm Badt, Christian Ihling, Manfred Klevesath, Hongxia Zheng, Eric Raymond, Armand de Gramont, Sandrine Faivre, Valérie Paradis. Biomarker selection defines a subgroup of hepatocellular carcinoma (HCC) patients with poor prognosis who are candidates for MET inhibition strategy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B31.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
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