Vitamin K epoxide reductase complex subunit 1 (VKORC1): A pharmacogenomic predictor of response and survival in patients (pts) on triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-Cet) for initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU trial OPTILIV).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
Francis Levi ◽  
Raphael Saffroy ◽  
Abdoulaye Karaboue ◽  
Christophe Desterke ◽  
Valerie Boige ◽  
...  
Keyword(s):  
Vitamin K ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Early Response ◽  
Hepatic Artery Infusion ◽  
Nucleotide Polymorphisms ◽  
R1 Resection ◽  
Nat2 Polymorphism ◽  
Warfarin Dosing ◽  
C 30

2569 Background: The HAI of Irinotecan-Oxaliplatin-5-Fluorouracil (IFO) with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts (Lévi, Ann Oncol 2016). Methods: To identify pharmacogenomic predictors of outcomes, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA). Relations between SNPs and tumor response, R0+R1, survival, and toxicities were tested using adjusted Mann Whitney, Fisher Exact, Log Rank tests and Hardy-Weinberg Equilibrium. Results: Pts (16F;36M; 33-76 yo; WHO performance status 0-1) received protocol treatment as 2nd (21 pts) or 3-4thline (31 pts). VKORC1 SNPs in promoter (rs9923231) and intron (rs9934438) were consistently associated with early and objective responses, and overall survival. For rs9923231, T/T (N = 8) as compared to C/T (N = 21) had greatest chance of achieving early response (50% vs 5%, p = 0.029) or 4-y survival (46% vs 0%, p = 0.006). VKORC1 SNPs also related to HA thrombosis (rs992331, T/T, 77% vs C/C, 30%, p = 0.04). In contrast, NAT2 SNPs (rs1041983 and rs1801280) were associated with up to 5-fold differences in R0-R1 resection rate. Statistically significant associations (p < 0.05) of SNPs with clinical outcomes were found for oxydo-reduction (CYP2E1 and HA thrombosis; CYP2C9 and diarrhea; CYP2C19 and diarrhea, fatigue, and early response), conjugation (UGT1A1 and diarrhea; NAT2 and fatigue); and transport (ABCB1 or SLC0B3 and neutropenia; SLC22A1 and diarrhea; SLC 15A2 and early response). Conclusions: VKORC1 was highlighted for the first time, as a pharmacogenomic predictor of HAI efficacy for LM-CRC. Conversion-to-resection was associated with NAT2 polymorphism. VKORC1 γ-carboxylates vitamin K-dependent proteins. Its polymorphism guides personalized warfarin dosing. VKORC1 SNPs determination could help identify the uLM-CRC pts who best benefit from intensive HAI therapy. Clinical trial information: NCT00852228.

Pharmacogenomic determinants of cetuximab and oxaliplatin pharmacokinetics during combined intravenous cetuximab (IV-Cet) and triplet hepatic artery chronomodulated infusion in patients (pts) with initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU OPTILIV trial).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14082-e14082
Author(s):  
Abdoulaye Karaboue ◽  
Raphael Saffroy ◽  
Christophe Desterke ◽  
Mohamed Bouchahda ◽  
Pasquale Innominato ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Performance Status ◽  
Systemic Exposure ◽  
Fisher Exact Test ◽  
Hematologic Toxicity ◽  
Nucleotide Polymorphisms ◽  
Exact Test ◽  
Polymorphic Genes ◽  
Direct Exposure ◽  
Polymorphic Gene

e14082 Background: Triplet HAI with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts. While the high antitumour efficacy of this new regimen involved direct exposure of LM to the HAI drugs and their potentiation by cetuximab, haematological and intestinal toxicities mostly related to systemic exposure (Lévi, Ann Oncol 2016; Clin Pharmacokin 2016). Methods: To identify potential pharmacogenomics (PG) determinants of toxicity-related systemic exposure to the HAI drugs, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA) from 11 pts undergoing a first course of chronomodulated triplet HAI and iv-CET (Levi et al. Clin Pharmacokinet 2016). Relations between SNPs and main pharmacokinetics parameters and toxicities were determined using ANOVA or Fisher Exact test. Results: Nine toxicity-related polymorphic genes were identified in the 52 pts of the PG study (ASCO, submitted). Here we investigated whether any of these polymorphic genes modified PK in 4F and 7M (33-72 yo) with WHO performance status 0-1. ABCB1 (rs1045642) was the only polymorphic gene that was significantly associated with both pharmacokinetics and toxicity in this study population. Conclusions: ABCB1 polymorphisms might contribute to the systemic hematologic toxicity of the combined IV-HAI regimen through altering cetuximab and oxaliplatin disposition, yet without affecting efficacy. Consideration of ABCB1 polymorphism could help optimize OPTILIV delivery in individual patients. Clinical trial information: NCT00852228. [Table: see text]

scholarly journals Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir

2015 ◽  
Vol 18 (2) ◽  
pp. 171 ◽  
Author(s):  
Jessica Cusato ◽  
Sarah Allegra ◽  
Amedeo De Nicolò ◽  
Lucio Boglione ◽  
Giovanna Fatiguso ◽  
...  
Keyword(s):  
Triple Therapy ◽  
Mononuclear Cells ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Kinetic Studies ◽  
Pharmacokinetic Data ◽  
Nucleotide Polymorphisms ◽  
Allelic Discrimination ◽  
Peripheral Blood Mononuclear ◽  
Drug Kinetic

PURPOSE: Triple therapy for HCV-1 infection consists in boceprevir or telaprevir, ribavirin and PEG-interferon. Telaprevir is a P-glycoprotein substrate and it is metabolized by CYP3A4/5. No data have been published on intracellular penetration of telaprevir. We determined peripheral blood mononuclear cells (PBMCs) and trough plasma S and R telaprevir isomers concentrations; moreover, we evaluated the influence of some single nucleotide polymorphisms (SNPs) on these pharmacokinetic data after 1 month of triple therapy in humans. METHODS: Plasma and intracellular telaprevir concentrations were determined at the end of dosing interval (Ctrough) using ULPC-MS/MS validated methods; allelic discrimination was performed through real-time PCR. RESULTS: Median telaprevir Ctrough plasma concentrations were 2579 ng/mL and 2233 ng/mL for the pharmacologically more active S, and R, enantiomers, respectively, with median S/R plasma ratio of 1.11. In PBMC, the medians were 6863 ng/mL and 1096 ng/mL for S and R, respectively, with median S/R being 5.73. The PBMC:plasma ratio for S was 2.59 for R. Plasma ribavirin concentrations were directly correlated with plasma S-telaprevir concentrations. In linear regression analysis, only CYP24A1_rs2585428 SNP (p=0.003) and body mass index (p=0.038) were able to predict S-telaprevir PBMC concentrations. CONCLUSIONS: Our preliminary data could increase the understanding of mechanisms underlying telaprevir intracellular and plasma exposure, suggesting the implementation of pharmacogenetics in these drug kinetic studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3827-3834 ◽  
Author(s):  
Nita A. Limdi ◽  
Mia Wadelius ◽  
Larisa Cavallari ◽  
Niclas Eriksson ◽  
Dana C. Crawford ◽  
...  
Keyword(s):  
Linear Regression ◽  
Warfarin Dose ◽  
Population Level ◽  
Racial Groups ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Dose Prediction ◽  
Similar Dose ◽  
Warfarin Dosing ◽  
Dose Variability

Abstract Warfarin-dosing algorithms incorporating CYP2C9 and VKORC1 −1639G>A improve dose prediction compared with algorithms based solely on clinical and demographic factors. However, these algorithms better capture dose variability among whites than Asians or blacks. Herein, we evaluate whether other VKORC1 polymorphisms and haplotypes explain additional variation in warfarin dose beyond that explained by VKORC1 −1639G>A among Asians (n = 1103), blacks (n = 670), and whites (n = 3113). Participants were recruited from 11 countries as part of the International Warfarin Pharmacogenetics Consortium effort. Evaluation of the effects of individual VKORC1 single nucleotide polymorphisms (SNPs) and haplotypes on warfarin dose used both univariate and multi variable linear regression. VKORC1 −1639G>A and 1173C>T individually explained the greatest variance in dose in all 3 racial groups. Incorporation of additional VKORC1 SNPs or haplotypes did not further improve dose prediction. VKORC1 explained greater variability in dose among whites than blacks and Asians. Differences in the percentage of variance in dose explained by VKORC1 across race were largely accounted for by the frequency of the −1639A (or 1173T) allele. Thus, clinicians should recognize that, although at a population level, the contribution of VKORC1 toward dose requirements is higher in whites than in nonwhites; genotype predicts similar dose requirements across racial groups.

Prognostic Significance Of TP53 mutations and Single Nucleotide Polymorphisms In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4971-4971
Author(s):  
Simon B. Zeichner ◽  
Sarah Alghamdi ◽  
Gina Elhammady ◽  
Robert Poppiti ◽  
Amilcar Castellano-Sanchez
Keyword(s):  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
De Novo ◽  
Performance Status ◽  
Nucleotide Polymorphisms ◽  
Complex Karyotype ◽  
Single Nucleotide ◽  
Tp53 Mutations ◽  
Significant Difference ◽  
De Novo Aml

Abstract Background The response to treatment and overall survival (OS) of patients with acute myeloid leukemia (AML) is variable, with a median OS ranging from several months to more than 10 years. Age at diagnosis, performance status (PS), and karyotype expression have long been established in prognostication. Loss of TP53, a tumor suppressor gene located on the short arm of chromosome 17, is one of the most frequent genetic abnormalities in human cancer and is one of the more promising prognostic markers for AML. Studies have shown that TP53 mutations are present in 5-25% of all AML patients, in 70% of those with complex karyotypes, and are associated with old age, chemotherapy resistance, and worse OS. Single nucleotide polymorphisms (SNPs), changes in DNA seen in an appreciable amount of the population, have been examined in AML and studies have suggested a possible correlation with worse outcomes. Using genetic sequencing, we set out to look at our own experience with AML, and hypothesized TP53 mutations and SNPs would mimic the literature, occurring in a minority of patients, and conferring a worse OS. Methods We performed a pilot study of randomly selected, newly diagnosed AML patients at Mount Sinai Medical Center, diagnosed from 2005-2008 (n =10). Immunohistochemical (IHC) analysis of bone marrows and peripheral blood smears was assessed via DO-1 antibody on paraffin embedded tissue. Conventional cytogenetic analyses were performed on short-term cultured bone marrow and peripheral blood cells with the use of the GTG-banding technique. TP53 PCR sequencing was performed using DNA from bone marrow smears using the Sanger sequencing platform and resolved by capillary electrophoresis. Analysis was performed using Mutation Surveyor software with confirmation of the variants using the COSMIC and dbSNP databases. Descriptive frequencies and median survivals were calculated for demographic information, prognostic factors, and treatment variables. A univariate analysis was performed. Results The majority of patients in our pilot study were older than age 60 (80%), male (60%), Hispanic (60%), and had a poor PS (ECOG 2-3: 60%). Most patients had de-novo AML (50%) with an intermediate (50%) non-complex (70%) karyotype and a TP53 P72R SNP (50%). Fewer than half of these patients harbored TP53 mutations (40%). There was no significant difference in OS based on sex, AML history, risk-stratified karyotype, or TP53 mutation. There was a trend toward improved survival among patients younger than age 60 (11, 4 mo, p = 0.09), of Hispanic ethnicity (8, 1 mo, p = 0.11), and those not harboring P72R (8, 2, p = 0.10). There was a significant improvement in survival among patients with a better PS (28, 4 mo, p = 0.01) and those who did not have a complex karyotype (8, 1 mo, p = 0.03). Among patients with a TP53-mutation, there were a larger number of individuals who were younger than age 60 (25.0, 16.7%), who were male (75.0, 50.0%), had a good performance status (ECOG 0-1: 50.0, 16.7%), had de-novo AML (50.0, 66.7%), and who had an adverse karyotype (50.0, 33%). Patients with a P72R SNP were more often male (80, 40%) and had a worse PS (ECOG 2-3: 80, 40%) with AML secondary to MDS (60, 20%) and a complex karyotype (40, 0%). The most commonly observed TP53 mutation was a missense N310K (40%) and the most commonly observed SNP was P72R (100.0%). Patients with more than one TP53 mutation had a worse clinical course than those with only a single mutation. Conclusion Our study demonstrated that poor PS and the presence of a complex karyotype were associated with a decreased OS. TP53 mutations were relatively uncommon, occurring more frequently in male patients with an adverse karyotype. Although there was no significant difference in survival between TP53 mutated and un-mutated patients, there was a trend toward worse OS among patients with a specific SNP. These results suggest that different TP53 mutations and SNPs should not be treated the same, and that some may confer a worse prognosis than others. Larger studies are needed to validate these findings. Disclosures: No relevant conflicts of interest to declare.

A phase I-II and pharmacodynamic (PD) study of the combination of the proteasome inhibitor bortezomib (B) and paclitaxel (P) in patients with taxane-sensitive solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13029-13029
Author(s):  
E. Gallerani ◽  
S. Cresta ◽  
D. Tosi ◽  
C. Sessa ◽  
G. Capri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Phase I ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Peripheral Blood Mononuclear

13029 Background: Proteasome inhibition blocks the chemotherapy-induced activation of NF-кB increasing chemosensitivity to anticancer agents due to increased apoptosis. NF-кB is frequently aberrantly activated in primary human carcinomas and over-expressed in aggressive breast cancer lines1 supporting the rationale for combining B with P. We designed a phase I-II and PD trial to determine the recommended dose (RD) of the B&P combination, to screen for antitumor activity in patients with potentially taxane-sensitive tumors, to search for drug-induced changes and to identify potential surrogate markers of drug activity and toxicity in peripheral blood mononuclear cells (PBMC). Methods: Eligibility included ECOG performance status < 2, neurotoxicity < 2 and adequate organ functions. Treatment was given Q21 days: B on days 1,4, 8 and 11 and P on days 1 and 8. PBMC for gene expression profiling have been collected on day 1 and 4 before and after therapy. RECIST for response was applied. Results: Twenty-nine patients (20 female, median age 60 yrs) were accrued and 25 are evaluable (breast cancer: 13, ovarian cancer: 7, prostate cancer 1, other 4) ; 16 pts were treated in 4 escalation levels and the RD defined respectively at 1.3 mg/m2/dose & 100 mg/m2/dose for B&P. Neurotoxicity was the main toxicity (G1 36%, G2 20% and 1 case G3) requiring treatment discontinuation in 2 pts at cy 6 & 7. Other toxicities (all grades) were nausea and vomiting (68%), diarrhea (56%, G3 12%), alopecia (52%), asthenia (36%, G2 4%), and myalgia (32%, G2 8%). Antitumor activity consisted of 3 PR in pts with ovarian cancer lasting respectively 14, 8+ and 16 wks; 2 PRs in pts with breast cancer (12+ wks,14+ wks) and 1 PR in a pt with prostate cancer. Conclusions: Thus far the regimen has acceptable toxicity with evidence of antitumor activity. The trial will continue until accrual of four additional patients as planned. Footnotes 1 Adams J Current Opin Oncol 2002, 14:628–634. [Table: see text]

A phase II trial of capecitabine (C) in combination with the farnesyltransferase (FT) inhibitor (FTI), tipifarnib (T), in patients (pt) with metastatic breast cancer (MBC): ECOG trial 1103

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1036-1036
Author(s):  
M. Wang ◽  
W. J. Gradishar ◽  
J. A. Sparano ◽  
E. A. Perez ◽  
G. Sledge
Keyword(s):  
Mononuclear Cells ◽  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Human Tumor ◽  
Metastatic Breast ◽  
Type I ◽  
Post Translational Modification ◽  
Ras Genes ◽  
Previously Treated

1036 Background: Approximately 30% of human cancers have mutated Ras genes that produce proteins that remain in an active state causing uncontrolled proliferative signals. Post-translational modification of Ras include farneyslation catalyzed by FT. Tipifarnib (R115777) is an oral FTI active against human tumor cell lines and exhibiting modest single agent activity in pts with previously treated MBC. A previous phase I trial reported that CT inhibited farneyslation in peripheral blood mononuclear cells without affecting the pharmacokinetics of either agent. Objective: To evaluate objective response rate (ORR) of CT in taxane refractory MBC and to secondarily evaluate associated toxicity and progression-free survival (PFS). Methods: Pt with measurable MBC, previously treated (rx) with an anthracycline and relapse on a taxane or within 30 days (d). Study rx: T- 300 mg, po BID × 14 d plus C- 1,000 mg/m2, po BID × 14 d, followed by 7 d rest. Tumor reassessment was repeated q 3 cycles. The study was designed to detect improvement in ORR from 25% with C alone to 40% for the CT combination (90.5% power; type I error rate of 9.9%; 21 responses in 64 eligible pt needed to be promising. Results: 66/71 pt are available for primary analysis. Median age 50 yrs. Performance status: 0–1, 100%. ORR: PR-4.8% (3/62) [95% CI 0.01, 0.13], SD - 21% (13/62) [ 95% CI 0.12, 0.33]. Median survival - 10.6 months. Toxicity (%): anemia - 8(G3/4), neutropenia - 30 (G3/4), thrombocytopenia - 8 (G3/4), HFS-8 (G3), nausea/vomiting - 11(G3), diarrhea - 8 (G3), sensory neuropathy - 5 (G3). Conclusion: CT in taxane -refractory MBC has low antitumor activity without excessive toxicity. More mature data, including PFS, will be presented. No significant financial relationships to disclose.

BEZ235 in combination with everolimus for advanced solid malignancies: Preliminary results of a phase Ib dose-escalation study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13518-e13518 ◽  
Author(s):  
Mohamad Adham Salkeni ◽  
Olivier Rixe ◽  
Nagla Abdel Karim ◽  
Sue Ogara ◽  
Monica Feiler ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dose Escalation ◽  
Mtor Inhibitor ◽  
Mononuclear Cells ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Dose Escalation Study ◽  
Peripheral Blood Mononuclear ◽  
Phase Ib ◽  
Solid Malignancies

e13518 Background: The mammalian target of rapamycin (mTOR) is a critical signaling pathway in many tumors including cancers of the breast and colon, glioblastoma multiforme, and hepatocellular carcinoma (HCC). Preclinical studies demonstrated the combination of BEZ235, a competitive dual phosphatidylinositide 3-kinase (PI3K)/mTOR inhibitor, and the mTOR inhibitor, everolimus led to greater regression of a carcinogen-induced HCC than treatment with higher doses of either drug alone. Based on this, we initiated a study of BEZ235 combined with everolimus in patients with advanced solid tumors. Methods: A single institution phase Ib dose-escalation study. Patients with advanced solid malignancies, no available standard of care treatment option, and ECOG performance status 0-2 were eligible. Prior treatment with PI3K inhibitors was not allowed. Sequential cohorts of 3-6 patients were treated. The starting dose was everolimus 2.5 mg and BEZ235 200 mg daily in an oral sachet formulation. Cohort 2 received everolimus 2.5 mg and BEZ235 400 mg daily. Pharmacokinetic and pharmacodynamic studies were performed during the first cycle. The phosphorylation of specific downstream effectors of the mTOR pathway was assessed in peripheral blood mononuclear cells (PBMC). Results: Eleven patients, median age 58 (36-73 years) were treated. Tumors included non-small cell lung cancer, colon cancer, and glioblastoma, hepatocellular carcinoma, pancreatic cancer, esophageal cancer, adenoid cystic carcinoma of the larynx, and appendiceal carcinoma. Four patients were treated on cohort 1. None experienced dose-limiting toxicity. Seven patients were treated on the second dose cohort. One patient withdrew necessitating replacement and another developed grade 3 stomatitis from herpes virus requiring cohort expansion. The most common adverse events were thrombocytopenia, lymphopenia, transaminitis, diarrhea, nausea and fatigue. No tumor responses were noted. PBMC showed a decrease in 4E-BP1S65 phosphorylation on day 28 in 2 of 3 patients in cohort 1. Conclusions: The combination of BEZ235 and everolimus was well tolerated at these doses. The trial remains open to accrual. Clinical trial information: NCT01508104.

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