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This open-label, randomized, 3-treatment, 3-period, 6-sequence, crossover study in healthy subjects compared the pharmacokinetic and pharmacodynamic properties of a lipid-based (soft gelatin capsule) prototype final market image (pFMI) formulation of tropifexor (90-µg) to its clinical service form (CSF) and assessed the food effect for the pFMI formulation. In the fasted state, drug exposure was higher for the pFMI. The geometric mean ratios for pFMI versus CSF of peak concentration and area under the concentration-time curve were 2.0 and 1.5, respectively. No food effect was apparent for the pFMI formulation, and the geometric mean ratios for pFMI fed versus pFMI fasted of peak concentration and area under concentration-time curve were 1.0 and 1.0 respectively. Despite having lower systemic exposure, the CSF formulation provided a higher pharmacological response for the gut biomarker fibroblast growth factor 19. Under fasted conditions, fibroblast growth factor 19 maximum change from baseline serum concentration after drug administration and area under the change from baseline serum concentration-time curve from time 0 to 24 hours were 36% for CSF and 12% for FMI. For a second biomarker, serum 7-alpha hydroxy-4-cholest-3-one, the pharmacological activity was comparable between CSF (fasted) and pFMI (both fasted and fed states). The pFMI offers advantages over the CSF in terms of insensitivity to food effect, lower intersubject variability, and overcoming solubility limitations.

Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5'-diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug-drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (C

This cohort study assesses whether higher levels of family member–reported palliative care needs are observed among those whose critically ill loved ones meet a clinical palliative care trigger compared with those who do not meet such a trigger., Key Points Question Does clinical palliative care trigger status accurately identify individuals with the most serious unmet palliative care needs? Findings In this cohort study including 257 dyads (1 patient in an intensive care unit [ICU] and 1 family member of each patient), there was no significant difference in self-reported palliative care needs between those with and without a clinical trigger (median Needs at the End-of-Life Screening Tool scores, 21.0 vs 22.5). Clinical triggers’ 45% sensitivity and 55% specificity suggested that they were no better than chance at identifying serious needs. Meaning The findings suggest that using clinical trigger status to prompt palliative care consultation in ICU settings may be an inefficient use of this limited resource; incorporating direct measures of unmet need in care may be a promising alternative strategy., Importance Palliative care consultations in intensive care units (ICUs) are increasingly prompted by clinical characteristics associated with mortality or resource utilization. However, it is not known whether these triggers reflect actual palliative care needs. Objective To compare unmet needs by clinical palliative care trigger status (present vs absent). Design, Setting, and Participants This prospective cohort study was conducted in 6 adult medical and surgical ICUs in academic and community hospitals in North Carolina between January 2019 and September 2020. Participants were consecutive patients receiving mechanical ventilation and their family members. Exposure Presence of any of 9 common clinical palliative care triggers. Main Outcomes and Measures The primary outcome was the Needs at the End-of-Life Screening Tool (NEST) score (range, 0-130, with higher scores reflecting greater need), which was completed after 3 days of ICU care. Trigger status performance in identifying serious need (NEST score ≥30) was assessed using sensitivity, specificity, positive and negative likelihood ratios, and C statistics. Results Surveys were completed by 257 of 360 family members of patients (71.4% of the potentially eligible patient–family member dyads approached) with a median age of 54.0 years (IQR, 44-62 years); 197 family members (76.7%) were female, and 83 (32.3%) were Black. The median age of patients was 58.0 years (IQR, 46-68 years); 126 patients (49.0%) were female, and 88 (33.5%) were Black. There was no difference in median NEST score between participants with a trigger present (45%) and those with a trigger absent (55%) (21.0; IQR, 12.0-37.0 vs 22.5; IQR, 12.0-39.0; P = .52). Trigger presence was associated with poor sensitivity (45%; 95% CI, 34%-55%), specificity (55%; 95% CI, 48%-63%), positive likelihood ratio (1.0; 95% CI, 0.7-1.3), negative likelihood ratio (1.0; 95% CI, 0.8-1.2), and C statistic (0.50; 95% CI, 0.44-0.57). Conclusions and Relevance In this cohort study, clinical palliative care trigger status was not associated with palliative care needs and no better than chance at identifying the most serious needs, which raises questions about an increasingly common clinical practice. Focusing care delivery on directly measured needs may represent a more person-centered alternative.

Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics (PK) and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's PK, safety, and tolerability following a 200-μg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percent free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf, u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf, u = 1.64 [90% CI, 1.25-2.16]; Cmax,u = 1.30 [0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf, u (1.61 [1.04-2.49]) and comparable Cmax,u (1.02 [0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment. This article is protected by copyright. All rights reserved.

ObjectiveBecause the heterogeneity of patients in intensive care units (ICUs) and family members represents a challenge to palliative care delivery, we aimed to determine if distinct phenotypes of palliative care needs exist.MethodsProspective cohort study conducted among family members of adult patients undergoing mechanical ventilation in six medical and surgical ICUs. The primary outcome was palliative care need measured by the Needs at the End-of-Life Screening Tool (NEST, range from 0 (no need) to 130 (highest need)) completed 3 days after ICU admission. We also assessed quality of communication, clinician–family relationship and patient centredness of care. Latent class analysis of the NEST’s 13 items was used to identify groups with similar patterns of serious palliative care needs.ResultsAmong 257 family members, latent class analysis yielded a four-class model including complex communication needs (n=26, 10%; median NEST score 68.0), family spiritual and cultural needs (n=21, 8%; 40.0) and patient and family stress needs (n=43, 31%; 31.0), as well as a fourth group with fewer serious needs (n=167, 65%; 14.0). Interclass differences existed in quality of communication (median range 4.0–10.0, pConclusionsFour novel phenotypes of palliative care need were identified among ICU family members with distinct differences in the severity of needs and perceived quality of the clinician–family interaction. Knowledge of need class may help to inform the development of more person-centred models of ICU-based palliative care.

Tropifexor (NVP-LJN452) is a highly potent, selective, non-steroidal, non-bile acid farnesoid X receptor (FXR) agonist for the treatment of nonalcoholic steatohepatitis (NASH). Its absorption, metabolism, and excretion was studied following a 1-mg oral dose of [14C]tropifexor to four healthy male subjects. Mass balance was achieved with ~94% of the administered dose recovered in excreta through 312 hours collection period. Fecal excretion of tropifexor-related radioactivity played a major role (~65% of the total dose). Tropifexor reached a maximum blood concentration (Cmax) of 33.5 ng/mL with a median Tmax of 4 hours and was eliminated with a plasma elimination half-life (T1/2) of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (~92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out, based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Due to these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study.

Background: Chronic hypersensitivity pneumonitis (cHP) is a disease caused by exposure to inhaled environmental antigens. Diagnosis of cHP is influenced by the awareness of the disease prevalence, which varies significantly in different regions, and how clinicians utilize relevant clinical information. We conducted a retrospective study to evaluate how clinicians in the Southeast United States, where the climate is humid favoring mold growth, diagnosed cHP using items identified in the international modified Delphi survey of experts, i.e., environmental exposure, CT imaging and lung pathology, Methods: We searched Duke University Medical Center database for patients over the age of 18 with a diagnosis of cHP (ICD-9 code: 495) between Jan. 1, 2008 to Dec. 31, 2013 using a query tool, Duke Enterprise Data Unified Content Explorer (DEDUCE). Results: Five hundred patients were identified and 261 patients had cHP confirmed in clinic notes by a pulmonologist or an allergist. About half of the patients lived in the Research Triangle area where our medical center is located, giving an estimated prevalence rate of 6.5 per 100,000 persons. An exposure source was mentioned in 69.3% of the patient. The most common exposure sources were environmental molds (43.1%) and birds (26.0%). We used Venn diagram to evaluate how the patients met the three most common cHP diagnostic criteria: evidence of environmental exposures (history or precipitin) (E), chest CT imaging (C) and pathology from lung biopsies (P). Eighteen patients (6.9%) met none of three criteria. Of the remaining 243 patients, 135 patients (55.6%) had one (E 35.0%, C 3.3%, P 17.3%), 81 patients (33.3%) had two (E+C 12.3%, E+P 17.3%, C+P 4.9%), and 27 patients (11.1%) had all three criteria (E+C+P). Overall, 50.6% of patients had pathology from lung biopsy compared to 31.6% with CT scan. Conclusions: Environmental mold was the most common exposure for cHP in the Southeast United States. Lung pathology was available in more than half of cHP cases in our tertiary care center, perhaps reflecting the complexity of referrals. Differences in exposure sources and referral patterns should be considered in devising future diagnostic pathways or guidelines for cHP.

9058 Background: Datopotamab deruxtecan (Dato-DXd; DS-1062) is an ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a topoisomerase I inhibitor via a tetrapeptide-based cleavable linker. Methods: TROPION-PanTumor01 (NCT03401385) is a multicenter dose-escalation/expansion study evaluating Dato-DXd administered Q3W in patients (pts) with advanced NSCLC (since expanded to other tumor types, excluded from this analysis). Efficacy and safety were evaluated in 175 pts for dose analysis. Pharmacometric analyses (population pharmacokinetics [popPK] and exposure-response modeling) were conducted across doses to inform dose selection for further development. Results: At data cutoff (Sept 4, 2020), median follow-up was 7.4 mo (range, 0.10-21.7 mo). Select all-grade TEAEs were 1.5- to 2-fold higher in the 8 mg/kg vs 4 and 6 mg/kg cohorts: vomiting (34% vs 12% and 18%), anemia (28% vs 4% and 16%), diarrhea (20% vs 6% and 11%), and mucositis (29% vs 6% and 13%). Rates of grade ≥3 drug-related TEAEs and serious drug-related TEAEs were ≥2-fold higher with the 8 mg/kg dose (n = 80; 34% and 20%) relative to the 4 mg/kg (n = 50; 10% and 8%) and 6 mg/kg (n = 45; 16% and 9%) doses. Rates of drug-related interstitial lung disease (ILD), as determined by an independent adjudication committee, were higher in the 8 mg/kg cohort (15% vs 2% and 2% in the 4 and 6 mg/kg cohorts); 3 pts in the 8 mg/kg cohort experienced grade 5 ILD. Dose interruptions and reductions due to TEAEs increased with dose (4 mg/kg: 4% and 2%; 6 mg/kg: 20% and 9%; 8 mg/kg: 20% and 31%). More pts in the 8 mg/kg cohort discontinued Tx early due to AEs (15%) compared with those in the 4 mg/kg (4%) and 6 mg/kg (7%) cohorts. ORRs determined by blinded independent central review were similar: 8 mg/kg, 25% (20/80); 6 mg/kg, 21% (8/39); and 4 mg/kg, 23% (9/40). Preliminary median PFS (95% CI) was 5.4 mo (4.1-7.1 mo) in the 8 mg/kg cohort, 8.2 mo (1.5-11.8 mo) in the 6 mg/kg cohort, and 4.3 mo (2.0 mo-NE) in the 4 mg/kg cohort. PFS was limited by early censoring due to immature duration of follow-up, with the majority of pts having ≤3 mo of follow-up in the 4 (66%) and 6 mg/kg (67%) cohorts vs 8 mg/kg (46%) cohort. In pharmacometric analyses, tumor-size change from baseline and probability of complete response/partial response positively correlated with exposure (AUC) of Dato-DXd. Incidences of dose reduction and grade ≥2 stomatitis/mucositis were also positively correlated with exposure; projected probabilities in a virtual population bootstrapped from pts with NSCLC in the popPK data confirmed these trends. Updated results will be presented. Conclusions: A Dato-DXd dose of 6 mg/kg was selected for the randomized, phase 3, TROPION-Lung01 trial (NCT04656652) based on better tolerance and improved efficacy, including a trend toward increased PFS. Clinical trial information: NCT03401385.

TPS9127 Background: Treatment options are limited for patients with advanced/metastatic NSCLC without driver genomic alterations after failure of a platinum-based chemotherapy and immunotherapy; median survival is < 1 year. Datopotamab deruxtecan (Dato-DXd; DS-1062) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. Results from the ongoing phase 1 study (TROPION-PanTumor01; Spira, WCLC 2020) demonstrated an overall response rate (ORR) of 21%, a disease control rate (DCR) of 67%, and a preliminary median progression-free survival (PFS) of 8.2 months (all by blinded independent central review [BICR]), with a manageable safety profile, in patients with NSCLC who were treated with 6 mg/kg of Dato-DXd. This phase 3 study (NCT04656652) will compare the efficacy of Dato-DXd with that of docetaxel as 2/3L therapy in patients with advanced/metastatic NSCLC. Methods: TROPION-Lung01 is an open-label, phase 3, randomized study of Dato-DXd vs docetaxel in patients with advanced/metastatic NSCLC without EGFR, ALK, or other actionable genomic alterations. Patients must have been previously treated with platinum-based chemotherapy and a PD-(L)1 monoclonal antibody in combination or sequentially and have radiographic disease progression on or after the most recent therapy. Those with asymptomatic and stable/treated brain metastases are eligible. A tumor specimen is required for biomarker analyses. Patients (N = 590) are randomized 1:1 to either Dato-DXd 6 mg/kg or docetaxel 75 mg/m2 given intravenously on day 1 of each 3-week cycle. Randomization is stratified by histology (squamous vs nonsquamous), immunotherapy in last regimen (yes vs no), and region (US/Japan/Western Europe vs rest of world). Treatment continues until disease progression or intolerance or other discontinuation criteria are met. The study will be conducted globally at approximately 184 study sites. Dual primary endpoints are PFS by BICR and overall survival. Secondary outcome measures include PFS by investigator, ORR, duration of response, DCR, and time to response (all assessed by BICR and by investigator per RECIST version1.1), patient-reported outcomes, safety, pharmacokinetics, and proportion of patients who develop antidrug antibodies. Biomarkers will be evaluated for potential associations with efficacy. Clinical trial information: NCT04656652.

GD2 and GD3 are the tumor-associated glycolipid antigens found in a broad spectrum of human cancers. GD2-specific antibody is currently a standard of care for high-risk neuroblastoma therapy. In this study, the pattern of GD2 and GD3 expression among pediatric/adolescent or young adult tumors was determined, providing companion diagnostics for targeted therapy.Ninety-two specimens of human osteosarcoma (OS), rhabdomyosarcoma (RMS), Ewing family of tumors, desmoplastic small round cell tumor (DSRCT), and melanoma were analyzed for GD2/GD3 expression by immunohistochemistry. Murine monoclonal antibody 3F8 was used for GD2 staining, and R24 for GD3. Staining was scored according to both intensity and percentage of positive tumor cells from 0 to 4.Both gangliosides were highly prevalent in OS and melanoma. Among other tumors, GD3 expression was higher than GD2 expression. Most OS samples demonstrated strong staining for GD2 and GD3, whereas expression for other tumors was highly variable. Mean intensity of GD2 expression was significantly more heterogeneous (P0.001) when compared to GD3 across tumor types. When assessing the difference between GD2 and GD3 expression in all tumor types combined, GD3 expression had a significantly higher score (P = 0.049). When analyzed within each cancer, GD3 expression was significantly higher only in DSRCT (P = 0.002). There was no statistical difference in either GD2 or GD3 expression between primary and recurrent sarcomas.GD2/GD3 expression among pediatric solid tumors is common, albeit with variable level of expression. Especially for patients with sarcoma, these gangliosides can be potential targets for antibody-based therapies.

Outsourcing and multi-site testing has increased for ligand binding assays supporting protein therapeutic measurement. It is common to combine and compare data across studies with data from multiple bioanalytical sites. We designed a prospective study to determine the benefits of increasing control over the transfer process to improve ruggedness. The experiment involved the testing of 30 incurred samples at 3 stages with incremental laboratory harmonization in standard/quality controls and assay components: Stage I represented a transfer of a detailed protocol and critical reagents. Stage II, a single source of standards and quality controls were provided to each site. Stage III, standards and quality controls plus a ready-to-use kit were provided. The results indicated that all testing facilities failed agreement testing using the stage I procedure. The introduction of standards from a single source improved the agreement. The modification reduced variation by 33% compared to the stage I approach. There was no additional benefit when a packaged kit was provided. In conclusion, introduction of a single source of standards and quality controls reduced the inter-site component of variation and should allow for combinability of data.

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Gene expression profiling by microarrays is a powerful tool for identification of genes that may encode key proteins involved in molecular mechanisms underlying epileptogenesis. Using the Affymetrix oligonucleotide microarray, we have surveyed the expression levels of more than 26,000 genes and expressed sequence tags (ESTs) in the amygdala-kindling model of temporal lobe epilepsy. Furthermore, the effect of the antiepileptic drug levetiracetam (LEV) on kindling-induced alterations of gene expression was studied. Treatment of rats with LEV during kindling acquisition significantly suppressed kindling development. For gene expression profiling, six groups of rats were included in the present study: (i) and (ii) sham-operated rats treated with saline or LEV; (iii) and (iv) electrode-implanted but non-kindled rats treated with saline or LEV; (v) and (vi) kindled rats treated with saline or LEV. Treatment was terminated after 11 or 12 daily amygdala stimulations, when all vehicle-treated rats had reached kindling criterion, i.e. a stage 5 seizure. Twenty-four hours later, the ipsilateral temporal lobe was dissected for mRNA preparation. Six temporal lobe preparations from each group were analysed for differential gene expression. In control (non-kindled) rats, LEV treatment was devoid of any significant effect on gene expression. In saline-treated kindled rats, a large number of genes were observed to display mRNA expression alterations compared with non-kindled rats. LEV treatment induced marked effects on gene expression from kindled rats. Previously described epilepsy-related genes, such as neuropeptide Y (NPY), thyrotropin-releasing hormone (TRH) and glial fibrillary acidic protein (GFAP) were confirmed to be up-regulated by kindling and partially normalized by LEV treatment. Real-time quantitative polymerase chain reaction confirmed NPY, TRH and GFAP expression data from chip experiments. Furthermore, a number of novel genes were identified from the gene chip experiments. A subgroup of these genes demonstrated correlation between expression changes and kindled phenotype measurements. In summary, this study identified many genes with potentially important roles in epileptogenesis and highlighted several important issues in using the gene chip technology for the study of animal models of CNS disorders.

Tangier disease (TD) is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of high density lipoprotein (HDL) cholesterol and, in some cases, peripheral neuropathy and premature coronary heart disease (CHD). Homozygotes are further characterized by cholesteryl ester deposition in various tissues throughout the body, most notably in those of the reticuloendothelial system. Several studies have demonstrated that the excess lipid deposition in TD is due to defective apolipoprotein-mediated efflux of cellular cholesterol and phospholipids. Although much progress has been made in our understanding of the metabolic basis of TD, the precise molecular defect had remained elusive until very recently. By positional cloning methods, we: 1) confirm the assignment of TD to chromosome 9q31, 2) provide evidence that human ATP-binding cassette-1 (hABC-1) maps to a 250 kb region on 9q31, and 3) describe novel deletion, insertion, and missense mutations in the gene encoding hABC-1 in four unrelated TD kindreds. These results establish a causal role for mutations in hABC-1 in TD and indicate that this transporter has a critical function in the regulation of intracellular lipid trafficking that dramatically affects plasma HDL cholesterol levels. —Brousseau, M. E., E. J. Schaefer, J. Dupuis, B. Eustace, P. Van Eerdewegh, A. L. Goldkamp, L. M. Thurston, M. G. FitzGerald, D. Yasek-McKenna, G. O'Neill, G. P. Eberhart, B. Weiffenbach, J. M. Ordovas, M. W. Freeman, R. H. Brown, Jr., and J. Z. Gu. Novel mutations in the gene encoding ATP-binding cassette 1 in four Tangier disease kindreds. J. Lipid Res. 2000. 41: 433–441.

We have developed a panel of radiation hybrids containing fragments of chromosome 8 as the only human material. The human chromosome content of each cell line was determined relative to an ordered map of sequence tagged sites (STSs) specific to chromosome 8. Between one and four fragments of chromosome 8 were identified in each cell line, with an average of 25% of the STSs retained in each line. Subclones of one radiation hybrid were examined to determine whether all cells within a line are homogeneous with respect to chromosome 8 sequence content. There was considerable variability between subclones, with retention rates for individual STSs ranging from 5 to 100% in different clones. Furthermore, a gradient of retention of sequences along the length of one large chromosome fragment was found, suggesting that sequence loss involved deletions from one end of the fragment at early stages in the establishment of the cell line. We have also made use of the radiation hybrids to develop novel sequence tagged sites for the pericentromeric region of chromosome 8.

Introduction: Marked lowering of low-density-lipoprotein cholesterol (LDL-C) levels (≤50%) with intensive statin therapy is associated with major reduction in cardiovascular risk, but is limited by a potential increase in adverse effects, thereby justifying optimization of LDL-C reduction with minimal risk. The organic anion transporting polypeptide-1B1 encoded by the SLCO1B1 gene is implicated as a major transporter in cellular uptake of statins, and notably fluvastatin. We postulated that genetic variation in SLCO1B1 might affect statin bioavailability, and might therefore influence drug response and potential adverse effects. Materials & methods: Elderly hypercholesterolemic subjects (n = 724), whose plasma lipid profile was determined before and 2 months after fluvastatin extended-release treatment (80 mg/day, n = 420), or placebo (n = 304), were genotyped for the most frequent nonsynonymous polymorphisms (SNP) in the SLCO1B1 gene (c.388A>G, c.463C>A and c.521T>C). Results: Due to linkage disequilibrium, only four alleles (*1b, *5, *14 and *15) of SLCO1B1 were detected in addition to the wild-type allele (*1a). The c.463A genotype, which was systematically associated with the c.388G SNP corresponding to the *14 allele was significantly associated with percentage LDL-C reduction from baseline (p = 0.005) and with mean post-treatment LDL-C values (p = 0.0005). Subjects homozygous for the c.463C genotype (n = 294) exhibited significantly less LDL-C reduction and higher post-treatment LDL-C levels (-31.5%, 138 mg/dl) relative to heterozygous C/A patients (-36.2%, 126 mg/dl; n = 111), and to homozygous A/A subjects (-41%, 115 mg/dl; n = 15). Conclusions: These results reveal that OATP1B1 is implicated in the pharmacological action and efficacy of fluvastatin. Indeed, the common *14 allele, which is distinguished by the presence of the c.463C>A polymorphism, was associated with enhanced lipid-lowering efficacy in this study.

8519 Background: PI3K-delta signaling is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3Kδ. Initial response rate of 42% was previously reported in MCL (Kahl, ICML 2011). Long-term follow-up is now presented. Methods: This phase 1 study evaluated the activity of continuous (48 weeks) idelalisib monotherapy in pts with relapsed or refractory hematologic malignancies. Doses ranged from 50 mg BID to 350 mg BID in 8 cohorts. Response was based on investigator assessments using standard criteria (Cheson et al, 2007). Patients who continued to benefit were able to enroll in an extension study. Results: 40 patients with recurrent MCL enrolled. Patients were 88% male, median age [range] of 69 [52-83] years, 43% with refractory disease. The median [range] number of prior therapies was 4 [1E14]. The median [range] duration of idelalisib treatment was 3.5 [1-26+] months, with 6 (15%) patients continuing on treatment in the extension protocol. Overall response rate (ORR) was 16/40 (40%), with 2/40 CR (5%). The median duration of response (mDOR) was 2.7 months, and median PFS (mPFS) was 3.7 months. The 1-year PFS was 22%. For patients dosed with ≥100 mg BID, ORR was 12/23 (52%), for patients dosed with ≥150 mg BID, ORR was 11/16 (69%) including both CR (12.5%). Most common adverse events included (total%/≥G3%); diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (25/3), decreased appetite (20/15), URI (20/0), and pneumonia (13/13). Abnormal lab values included (total%/≥G3%) ALT/AST elevations (65/20). 6/40 (15%) patients discontinued therapy due to AEs, potentially treatment related. Conclusions: The oral PI3Kδ inhibitor idelalisib (GSE1101) is active and well tolerated in heavily pre-treated pts with MCL. A proportion of patients have long-term (>1 year) clinical benefit. These data support further clinical evaluation of idelalisib in MCL. Clinical trials with idelalisib in combination with other agents are in progress. Clinical trial information: NCT00710528.

7005 Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective oral inhibitor of PI3Kδ. When combined with R in 19 relapsed/refractory patients with CLL, the ORR was 78% (Coutre, ASH 2012). Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m2 weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 wks w/o progression could continue to receive idelalisib on an extension study. Responses and progression were based on investigator assessment using IWCLL criteria (Hallek, Blood 2008). Results: Data is presented here on the first 50 of 64 pts enrolled, 48 CLL/2 SLL, median age 71 yrs (range: 65-89), M/F 70/30 (%), Rai stage III/IV 10/32 (%), nodes ≥5 cm in 16%, WHO 0/1/2 in 34/64/2 (%); del(17p) in 6 pts and del(11q) in 13 pts. 32 pts completed 48 wks (18 discontinued, 11 due to AE, 4 due to death and 3 other); 30 pts entered the extension study and 26 remain on treatment. The median time on treatment was 16 months (range 0.8-27.5). The ORRwas 96% with 4% nonevaluable; median time to response was 1.9 mos (range 1.0-6.5). There have been no on-study relapses. The Kaplan-Meier estimated PFS is 91% at 24 mos. Of note, 6/6 pts with del(17p) responded (1 CR, 5 PR) and 3 remain on treatment for more than 21 months. 13/14 (93%) pts with thrombocytopenia and 12/12 (100%) pts with anemia at baseline responded. Of 20 pts with B symptoms at baseline, 13 (65%) were asymptomatic by 8 wks. Most frequent AEs (total%/ ≥G3%) were diarrhea (including reported as colitis) (46/16), pyrexia (42/4), chills (34/0), fatigue (34/2), rash (34/10), pneumonia (30/20) and nausea (28/0). Elevated ALT/AST was seen in 60%, Gr ≥3 in 22%. Conclusions: Idelalisib + R is highly active, resulting in durable disease control in treatment-naïve older pts with CLL. These results support the further development of idelalisib in frontline CLL. Clinical trial information: NCT01203930.