Search

Summary X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model., Highlights • hiPSC-derived retinal organoid model recapitulates key features of XLRS • CRISPR/Cas9 correction normalizes RS1 secretion and retinal development • Transcriptome analysis links XLRS to other hereditary retinopathies, Chiou, Schlaeger, and colleagues use hiPSC-derived retinal organoids to model X-linked juvenile retinoschisis. They show that patient hiPSC-derived retinal organoids replicate key pathologies observed in patients, including retinal splitting and photoreceptor deficit. The observed abnormalities were normalized in organoids derived from isogenic CRISPR/Cas9 gene-corrected hiPSCs. This validated XLRS in vitro model could be used to test and optimize therapeutic approaches.

For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight P interaction =0.005), but more preterm birth ( P interaction =0.043), and no effect on perinatal death or high-level neonatal care >48 hours ( P interaction =0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks ( P interaction =0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes. Clinical Trial Registration— URL: https://www.isrctn.com . Unique identifier: ISRCTN71416914.

Background In global phase III ASCEND-4 study (NCT01283516), ceritinib 750 mg/day (fasted), demonstrated statistically significant and clinically meaningful improvement in PFS by BIRC (median, 16.6 mos [95% CI: 12.6, 27.2] vs 8.1 mos [95% CI: 5.8, 11.1]; HR = 0.55; p Methods Pts with stage IIIB/IV, ALK + (centrally tested IHC), nonsquamous NSCLC, ≥1 measurable lesion per RECIST v1.1, and WHO PS 0–2 were eligible. Efficacy and safety were evaluated in Asian pts who had not received prior systemic anticancer therapy except neo-/adjuvant therapy. Data cutoff: June 24, 2016. Results Among 376 pts randomized (1:1) in the study, 158 pts were Asian, with 76 in ceritinib arm and 82 in chemotherapy arm. Of these, 25 pts (32.9%) in ceritinib arm and 21 (25.6%) in chemotherapy arm had brain metastases at baseline. Median duration of treatment exposure: 64.5 wks (ceritinib, N = 76) and 35.0 wks (chemotherapy, N = 75). Median duration from randomization to data cutoff: 18.3 mos. Ceritinib demonstrated superior PFS by BIRC (median, 26.3 mos; 95% CI: 8.6, NE; HR = 0.66) compared to chemotherapy (Table). Most common (≥50%; all grades; all-causality) AEs in ceritinib arm: diarrhea (85.5%), ALT increased (73.7%), vomiting (73.7%), AST increased (69.7%), and nausea (69.7%). Incidence of grade 3/4 AEs was Table . 1473P By BIRC (N * =158) Ceritinib 750mg N = 76 Chemotherapy N = 82 Overall response rate (ORR), % [95% CI] 65.8 [54.0, 76.3] 29.3 [19.7, 40.4] Best overall response, n (%) Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Non-CR/Non-PD Unknown 0 50 (65.8) 11 (14.5) 11 (14.5) 2 (2.6) 2 (2.6) 0 24 (29.3) 38 (46.3) 6 (7.3) 3 (3.7) 11 (13.4) Disease control rate (DCR), % [95% CI] 82.9 [72.5, 90.6] 79.3 [68.9, 87.4] M ‡ =50 M ‡ =24 Median DOR, months [95% CI] NE [24.7, NE] 16.4 [7.8, NE] n/N (%) 14/50 (28.0) 8/24 (33.3) % Event-free probability estimates [95% CI] 9 months 81.2 [67.0, 89.8] 76.1 [48.0, 90.4] 12 months 79.0 [64.5, 88.1] 50.8 [22.5, 73.5] 15 months 70.4 [54.0, 81.9] 50.8 [22.5, 73.5] Median PFS, months [95% CI] 26.3 [8.6, NE] 10.6 [6.7, 15.0] n/N (%) 32/76 (42.1) 45/82 (54.9) % Event-free probability estimates [95% CI] 9 months 61.0 [48.4, 71.5] 54.7 [41.8, 65.8] 12 months 61.0 [48.4, 71.5] 49.8 [37.1, 61.2] 15 months 55.9 [43.2, 66.9] 39.0 [26.9, 51.0] * Total number of patients included in the full analysis set. ‡ Total number of patients with confirmed complete response or partial response. n: Total number of events included in the analysis. N: Total number of patients included in the analysis. Conclusions In Asian pts with ALK+ NSCLC, ceritinib demonstrated durable and clinically meaningful efficacy and a safety profile consistent with overall ASCEND-4 study results. Clinical trial identification NCT01828099. Editorial acknowledgement Shilpa Garg, Novartis Healthcare Pvt Ltd. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure D.S. Tan: Honoraria (self): Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli-lily, Loxo; Research grant / Funding (self): Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer; Travel / Accommodation / Expenses: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche,Takeda. S. Geater: Advisory / Consultancy: Boehringer Ingelheim; Honoraria (institution): AstraZeneca, Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Roche, Novartis, Boehringer Ingelheim; Full / Part-time employment: Prince of Songkla Univerisity. C.J. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim. T.C. Hsia: Advisory / Consultancy: Norvatis, Lilly, AZ, Roche local speaker. M.C. Lin: Advisory / Consultancy: AZ, Novartis, BI, Roche. V. Sriuranpong: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Novartis, Roche, Pfizer, Eisai, Boehringer, Taiho, MSD, BMS, Amgen; Research grant / Funding (institution): AstraZeneca, Novartis, Roche, Pfizer, Boehringer, Eisai, Taiho, Lilly, MSD. P. Sen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. F. Branle: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Shi: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Y.L. Wu: Honoraria (self): AZ, Roche, Eli Lilly, Pfizer, MSD, BMS, BI; Advisory / Consultancy: AZ, Roche, BI; Research grant / Funding (institution): AZ, Roche. All other authors have declared no conflicts of interest.

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated. A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (Ctrough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC0–24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study. In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC0–∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC0–24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing. Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

According to the official health statistics, Taiwan has the highest prevalence of end stage renal disease (ESRD) in the world. Each year, around 60,000 ESRD patients in Taiwan consume 6% of the national insurance budget for dialysis treatment. The prevalence of chronic kidney disease (CKD) has been climbing during 2008–2012. However, the spatial disparities and clustering of CKD at the public health level have rarely been discussed. The aims of this study are to explore the possible population level risk factors and identify any clusters of CKD, using the national health insurance database. The results show that the ESRD prevalence in females is higher than that in males. ESRD medical expenditure constitutes 87% of total CKD medical expenditure. Pre-CKD and pre-ESRD disease management might slow the progression from CKD to ESRD. After applying ordinary least-squares regression, the percentages of high education status and the elderly in the townships are positively correlated with CKD prevalence. Geographically weighted regression and Local Moran’s I are used for identifying the clusters in southern Taiwan. The findings can be important evidence for earlier and targeted community interventions and reducing the health disparities of CKD.

Purpose: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial. Experimental Design: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule). Results: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort. Conclusions: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients. Clin Cancer Res; 19(5); 1257–68. ©2012 AACR.

Pump thrombosis (PT) remains a life-threatening complication of LVAD therapy. Lactate dehydrogenase (LDH) levels, used to aid in the diagnosis of PT, may rise prior to overt clinical thrombosis. We investigated the predictive power of 30-day post implant LDH to predict future PT. Between 2006 and

Chronic obstructive pulmonary disease (COPD) causes a high disease burden among the elderly worldwide. In Taiwan, the long-term temporal trend of COPD mortality is declining, but the geographical disparity of the disease is not yet known. Nationwide COPD age-adjusted mortality at the township level during 1999–2007 is used for elucidating the geographical distribution of the disease. With an ordinary least squares (OLS) model and geographically weighted regression (GWR), the ecologic risk factors such as smoking rate, area deprivation index, tuberculosis exposure, percentage of aborigines, density of health care facilities, air pollution and altitude are all considered in both models to evaluate their effects on mortality. Global and local Moran’s I are used for examining their spatial autocorrelation and identifying clusters. During the study period, the COPD age-adjusted mortality rates in males declined from 26.83 to 19.67 per 100,000 population, and those in females declined from 8.98 to 5.70 per 100,000 population. Overall, males’ COPD mortality rate was around three times higher than females’. In the results of GWR, the median coefficients of smoking rate, the percentage of aborigines, PM10 and the altitude are positively correlated with COPD mortality in males and females. The median value of density of health care facilities is negatively correlated with COPD mortality. The overall adjusted R-squares are about 20% higher in the GWR model than in the OLS model. The local Moran’s I of the GWR’s residuals reflected the consistent high-high cluster in southern Taiwan. The findings indicate that geographical disparities in COPD mortality exist. Future epidemiological investigation is required to understand the specific risk factors within the clustering areas.

Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer that accounts for 3 to 5% of all invasive breast tumors in the United States. IBC possesses an increase of proangiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) as compared with non-IBC. In particular, FGF family receptors play a critical role in tumorigenesis, morphogenesis, and inducers of angiogenesis. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor with in vitro IC50 values of approximately 10 nmol/L against FGFR1-3, VEGFR1-3, and PDGFR. These structurally related receptors are important for the growth and survival of endothelial cells during tumor angiogenesis. Trial Design: This is a single institution, single arm phase II study. Patients receive a single daily oral dose of dovitinib 500 mg for 5 consecutive days, followed by a 2-day rest period (5 days on/2 days off schedule). Eligibility: Patients have histological confirmation of breast carcinoma with a clinical diagnosis of IBC based on presence of inflammatory changes in the involved breast, including diffuse erythema and edema (peau d’orange). Pathological evidence of dermal lymphatic invasion should be noted but is not required for diagnosis. HER2-negative. ECOG PS 0-2. Baseline MUGA or echocardiogram scans with LVEF of > 50%. Normal hematology, liver and kidney function laboratory studies. Patients must have received at least 2 chemotherapy lines for metastatic disease and have relapsed. Research Hypothesis: Dovitinib has antitumor activity in patients with HER2-negative advanced IBC. Specific Aims: Primary objective: to determine the disease control rate (CR, PR, and SD). Secondary objective: to evaluate safety profile. Exploratory biomarkers: circulating tumor cells (CTC), CTC undergoing EMT, and cancer stem cells Statistical Methods: The primary endpoint is the six-month disease control rate (ORR) as defined by RECIST 1.1. A response is anyone who experiences SD, CR or PR in the first 6 months. We will conduct this study with Simon’s two-stage design using the mini-max criterion and the response rate will be estimated accordingly. It is assumed that dovitinib will have a target ORR of 30%. An ORR of 10% or lower is considered a failure based on the typical ORR with a second line regimen for IBC and the new regimen will be rejected under this circumstance. When the probability of accepting a "bad" regimen (i.e. response rate < 10%) is 0.05 and the probability of rejecting a "good" regimen (i.e. response rate > 30%) is also 0.10, Simon’s design to minimize the maximum sample size requires 22 patients in the first stage. If two or less patients respond to the treatment, the trial will be stopped and the regimen will be declared as ineffective. If at least three of the first 22 patients respond to the treatment, 11 additional patients will be entered in the study to reach a total of 33 patients. By the end of the study, the new regimen will be rejected if response rate is less than or equal to 6 out of 33 patients and will be accepted otherwise. Present Accrual and Target Accrual: A total of 22 patients were accrued. Target accrual is 33 patients. Citation Format: Ricardo H Alvarez, Mariana Chavez-MacGregor, Joe Ensor, James L Murray, Kimberly Koenig, Savitri Krishnamurty, Antony Lucci, Gildy V Babiera, Wendy Woodward, Gary J Whitman, Summer A Jackson, Michael Shi, Kenneth Culver, James L Reuben, Naoto T Ueno, Vicente Valero. A phase II study of dovitinib as salvage therapy in patients with stage IV inflammatory breast cancer HER2-negative with local or distant relapse [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-15.

473 Background: In the GOLD trial, Dov did not improve progression-free survival (PFS) or overall survival (OS) over Sor. An exploratory objective of the study was to investigate plasma and tumor biomarkers to predict outcome. Methods: Plasma samples were obtained longitudinally throughout the study, and biomarkers were assessed by immunoassay. Primary archival tumor samples were assessed by immunohistochemistry. Log-rank tests, stratified by baseline MSKCC risk group, for difference in Kaplan-Meier curves between biomarker category (low/high based on

Abstract 4055 Introduction: Approximately 15% of patients (pts) with multiple myeloma (MM) exhibit a t(4;14) translocation that results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3) in the absence of ligand. This translocation has been strongly linked with a poor prognosis and short survival compared with pts without this translocation. Dovitinib (TKI258) is an RTK inhibitor that has demonstrated in vitro inhibitory activity against FGFR (including FGFR3), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), with IC50values of approximately 10 nM. Tumor growth inhibition was observed in xenograft tumor models of MM treated with dovitinib. This study was designed to evaluate the efficacy and safety of dovitinib in pts with relapsed or refractory MM that is either t(4;14) positive or negative. Patients and Methods: Adult pts who had received at least 2 prior antimyeloma regimens and who had relapsed or were refractory to their last treatment regimen were enrolled in this multicenter, open-label, 2-stage, phase 2 trial. Pts were evaluated for t(4;14) status at the baseline visit and classified according to the result into either a t(4;14)-positive or a t(4;14)-negative group. Dovitinib was administered at a dose of 500 mg/day on a 5-days-on/2-days-off schedule. Response was characterized as per the International Myeloma Working Group (IMWG) criteria. The primary endpoint was extended overall response rate as defined by the rate of pts with best overall response of complete response, very good partial response, partial response, or minor response. Secondary endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. After disease progression, pts had the option to continue treatment with the addition of low-dose dexamethasone (40 mg every 7 days) with M-protein levels at the time of progression considered as the new baseline. Results: A total of 43 pts were enrolled in this study; 26 pts were t(4;14) negative, 13 were t(4;14) positive, and 4 pts had unknown/indeterminate t(4;14) status. Median age was 63 years. Most pts (86%; n = 37) had received ≥ 3 prior lines of therapy. No objective responses were observed in either group of pts. Due to the apparent lack of efficacy, the study did not proceed to stage 2. The following observations are based on the preliminary data. In the t(4;14)-negative group, median duration of exposure to the study drug was 4.0 weeks, and 9 of the 26 pts (35%) had stable disease, 13 (50.0%) had progressive disease, and 4 (15%) were not evaluable. Due to slow enrollment and lack of efficacy among the earlier enrolled t(4;14)-positive pts, enrollment for the t(4;14)-positive group was closed prematurely. Among the 13 enrolled t(4;14)-positive pts, median duration of exposure to the study drug was 8.7 weeks. Best responses were stable disease for 8 pts (62%), disease progression for 3 pts (23%), and unknown for 2 pts (15%). Among both groups, the most common adverse events of any grade, regardless of study drug, were nausea (67%), diarrhea (58%), vomiting (51%), fatigue (47%), thrombocytopenia (33%), and anemia (28%). Most of the nonhematologic events were mild. The most common grade 3/4 adverse events were thrombocytopenia (26%) and anemia (23%). The principal reasons for discontinuation of dovitinib monotherapy were disease progression (72%) and adverse events (19%). Six pts continued on the dovitinib plus dexamethasone regimen; 1 pt is ongoing, and 5 pts discontinued due to disease progression (n = 4) and adverse events (n = 1). Conclusion: Dovitinib was found to have no or minimal single-agent activity in relapsed/refractory myeloma irrespective of t(4;14) status. Although the patient numbers are small, the rate of patients with stable disease during study treatment who may have had a clinical benefit was higher in the t(4;14)-positive group, suggesting that this subgroup may be a candidate to explore combination treatment of dovitinib with other agents, such as proteasome inhibitors. Gastrointestinal toxicity, while mostly mild, remains a challenge, and timely monitoring and supportive care during dovitinib treatment may alleviate these symptoms. Dovitinib may be a promising agent for combination therapies to improve prognosis of patients with t(4;14)-positive MM. Disclosures: Scheid: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Reece:Millennium Pharmaceuticals: Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria. Callander:Millennium Pharmaceuticals: Research Funding. Sonneveld:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding. Kalimi:Novartis Pharmaceuticals: Employment. Cai:Novartis: Employment. Shi:Novartis: Employment, Equity Ownership. Scott:Novartis: Employment. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

TPS4683 Background: Standard first- and second-line treatments in metastatic renal cell carcinoma (mRCC) target the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways. However, signaling through other pathways, including the fibroblast growth factor receptor (FGFR) pathway, may account for tumor resistance to these standard therapies. Dovitinib (TKI258) is an oral FGF, VEGF, and platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor, with IC50 values of ≈ 10 nM. In a phase II study of 59 RCC patients, many of whom had failed prior VEGF-targeted and mTOR inhibitor therapies, dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) was well tolerated and demonstrated promising anti-tumor effects, with progression-free survival (PFS) of 5.5 months (Angevin et al, ASCO 2011). Methods: Approximately 550 patients from over 26 countries will be randomized 1:1 in this multicenter, open-label, randomized phase III trial (NCT01223027) to receive dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) or sorafenib (400 mg twice daily). Eligible mRCC patients must have failed 1 VEGF-targeted therapy and 1 mTOR inhibitor (disease progression on or within 6 months of stopping the prior treatment). Patients will remain on study until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover is planned. The primary endpoint is PFS as determined by central radiology assessment according to RECIST v1.1, with evaluations performed every 8 weeks. Secondary endpoints include overall survival, overall response rate, safety, patient-reported outcomes, and pharmacokinetics. The pharmacodynamic effects of dovitinib on plasma/serum biomarkers will also be explored. The data monitoring committee last reviewed the trial on 20 December 2011 and recommended that the trial continue as planned. This is the first third-line randomized clinical trial in mRCC to evaluate a multitargeted inhibitor of FGFR.

TPS4147 Background: Hepatocellular carcinoma (HCC) is a highly vascularized tumor that may rely on tumor angiogenesis for growth, invasion, and metastasis. Inhibition of the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) pathways temporarily prevents HCC tumor progression. However, because the fibroblast growth factor receptor (FGFR) pathway can serve as an escape pathway for these tumors, simultaneous inhibition of FGFR may be required to provide a sustainable antitumor response. Dovitinib (TKI258) has been shown to be a potent oral tyrosine kinase inhibitor that inhibits multiple angiogenic factors, including FGFR, VEGFR, and PDGFR, with IC50 values of < 20 nM. Preclinical studies in HCC xenograft models have demonstrated that the antitumor effects of dovitinib are superior to those of the kinase inhibitor sorafenib, which is approved for use in advanced HCC. These data support additional testing of dovitinib in advanced HCC patients. Methods: This study (NCT01232296) is an open-label, randomized phase II trial being conducted at multiple centers in the Asia-Pacific region. Adult patients are eligible if they have advanced HCC (Barcelona Clinic Liver Cancer stage C) with Child-Pugh class A cirrhotic status. Patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and cannot be eligible for (or have had disease progression after) surgical or locoregional therapies. Patients are randomized 1:1 to receive dovitinib (500 mg/day on a 5-days-on/2-days-off dosing schedule) or sorafenib (400 mg twice daily). Patients will be treated until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover will be permitted. The primary end point of this trial is overall survival. Secondary end points include time to tumor progression, disease control rate, time to definitive deterioration in ECOG status, safety, and pharmacokinetics. The pharmacodynamic effects of dovitinib and sorafenib on plasma/serum biomarkers will also be explored. As of 30 January 2012, 93 of the planned 150 patients have been enrolled.

Background: Adenoid Cystic Carcinoma (ACC) is an uncommon cancer of the head and neck which typically originates in the salivary glands. We and others have previously performed preclinical and clinical screens of FDA-approved and investigational agents in an attempt to identify useful therapies for ACC. However, to date no approved standard of care drug therapy exists. Fibroblast growth factors (FGF) and their receptors (FGFR 1–4) are a highly conserved group of functional proteins involved in cell migration, proliferation and survival and have been found important in initiation and progression of certain cancer types. Recently FGFR1 has been found over-expressed and phosphorylated in a majority of ACC tumors and FGF2, a known ligand of FGFR1, is a known downstream target of MYB which is rearranged in most ACC tumors. These data provide the rationale for testing the efficacy of FGFR inhibitors in ACC. Dovitinib (TKI-258) is an orally bioavailable multi-tyrosine kinase inhibitor (TKI) selectively targeting a number of proteins including VEGFR, PDGFR and FGFR. Preclinical and clinical activity of this agent has been demonstrated in solid tumors including breast and renal cancers. However, whether dovitinib is active towards ACC is unclear. Methods: We have developed and characterized a panel of patient-derived ACC tumor models including ACC×5M1, ACC×6, ACC×9, ACC×14 and ACC×16. To evaluate potential activity of dovitinib towards ACC we tested this agent alone and in combination with docetaxel, a taxane previously found active in our preclinical ACC screens, in these five models. Single agent and combination tumor growth inhibition was evaluated with a mean control tumor volume of 1cm3 or seventy-days following treatment initiation as study endpoints. Results: In these studies dovitinib was well tolerated at the evaluated treatment regimens. Dovitinib alone demonstrated statistically significant (p58%) and combination with docetaxel resulted in additive tumor growth inhibition in sensitive models, including partial and compete tumor responses in some models. Dose and schedule-dependent activity was also demonstrated with dovitinib in these studies. Conclusion: These results identify dovitinib as a potential treatment for ACC and suggest combination benefit with docetaxel. Based on these studies and correlative molecular characterization data clinical trials have been initiated to evaluate dovitinib in patients with ACC. These studies further demonstrate the utility of patient derived tumor models as translational tools for improved identification of potential anticancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B120.

Background: Endometrial carcinoma is the most common gynecological malignancy in the western world. Activating mutations of the fibroblast growth factor receptor 2 (FGFR2) have been described in 12-16% of endometrial cancers. Moreover, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their receptors are involved in the neovascularization, invasiveness, and metastatic potential of endometrial cancer. Therefore, suppression of FGFR/VEGFR/PDGFR signaling by TKI258 may represent a novel approach for treatment of endometrial cancer. Experimental Design: The aims of this study were 1.) to assess the effect of TKI258 on tumor cell growth in two-dimensional (2D) and three-dimensional (3D) culture assays using a panel of 20 human endometrial cancer cell lines, 2.) to identify candidate molecular markers predicting sensitivity using baseline gene expression profiling and mutational analyses, and 3.) to determine the in vivo antineoplastic activity of TKI258 in endometrial cancer xenograft models. In addition, we screened 200 fresh frozen endometrial cancer specimens to comprehensively assess the distribution pattern of PI3K, PTEN, and FGFR mutations in endometrial cancer. Results: Concentration-dependent anti-proliferative effects of TKI285 using 2D assays were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC50 range: 0.42µM – 3.06 µM). The three most sensitive endometrial cancer cell lines demonstrated activating FGFR2 mutations (MFE296: N549K, IC50 0.42µM; AN3CA: N549K and K310R, IC50 0.50µM; MFE280: S252W, IC50 0.66µM). Assessment of TKI258 responses in 3D assays demonstrated similar results to those observed in 2D culture assays in that the 3 cell lines harboring FGFR2 mutations were the most sensitive to TKI258 achieving 100% growth inhibition at a concentration of 1µM. AN3CA and MFE296 endometrial cancer cells formed xenografts in nude mice and antitumor activity was studied in both models. Inhibition of p-FGFR, p-PDGFR, p-VEGFR-2, pAKT and p-ERK1/2 were observed. Comprehensive data on the pattern of PI3K, PTEN and FGFR mutations in endometrial cancer will be provided. Conclusion: TKI258 demonstrates significant antitumor activity in endometrial cancer cells with FGFR2 mutations. This study provides a strong rationale for the clinical evaluation of TKI258 in patients with endometrial cancer, specifically in those harboring FGFR2 mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3589. doi:10.1158/1538-7445.AM2011-3589

e18035 Background: ASA404 (vadimezan, DMXAA) is a flavonoid, non-tubulin-binding tumor-vascular disrupting agent (Tumor- VDA) that causes irreversible tumor vasculature disruption and extensive hemorrhagic necrosis of the tumor core. In combination with paclitaxel and carboplatin (P/C), ASA404 increased the median overall survival of previously untreated NSCLC patients from 8.8 to 14.0 months in a phase II clinical trial. Methods: A phase I trial assessed the safety profile and tolerability of three dose levels of ASA404 (600, 1,200, and 1,800 mg/m2) administered in combination with P/C (P, 200 mg/m2; C, AUC 6) every 3 weeks in Japanese patients with NSCLC. A panel of plasma biomarkers of angiogenesis and cytokines were evaluated to investigate the pharmacodynamic effect and mechanism of action (MOA) of ASA404. Plasma VEGF and basic FGF (bFGF) were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma IL-8 and macrophage chemotactic protein (MCP)1 were analyzed by Luminex beads plat...

Undifferentiated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and ubiquitously associated with Epstein-Barr virus (EBV) infection. AKT is frequently activated in NPC and PIK3CA amplification can be found in 40% of NPC tissues. BEZ235 is a dual inhibitor of PI3K and mTOR, which results in inhibition of downstream effectors AKT, S6 ribosomal protein and 4EBP1. The preclinical activity of BEZ235 was evaluated in 6 NPC cell lines (Table 1). Western Blot analysis showed all 6 NPC cell lines showed basal activation of AKT and mTOR. The effect of BEZ235 on cell growth was evaluated by exposing NPC cell lines to increasing concentrations of BEZ235 (0.1nM, 0.5nM, 1nM, 10nM, 100nM, 1µM& 10µM) for up to 72 hrs followed by MTT assay. Over 80% of growth inhibition was achieved in all NPC cell lines except C666-1 (∼70% inhibition), with the respective IC50 concentrations in the nanomolar range (Table 1). Two representative cell lines (HONE1-LMP-1 and CNE-2 cells) were selected for assessing the effect of BEZ235 on AKT-mTOR signaling, apoptosis, cell cycle and synergism with chemotherapy. Treatment of HONE1-LMP-1 and CNE-2 cells with BEZ235 at 5nM and 50nM for 24-48 hours, resulted in cell cycle arrest at G1 phase, apoptosis (indicated by the induction of PARP cleavage), and moderate reduction of cyclin D1 expression. After BEZ235 treatment, the expression level of phosphorylated (p-)AKT, pS6K, p4EBP-1 and p-mTOR were reduced, but the level of p-p44/42 MAPK was increased in both HONE1-LMP-1 and CNE-2 cells. No synergistic effect on growth inhibition was observed when HONE1-LMP-1 and CNE-2 cells were treated with concomitant BEZ235 and chemotherapy (cisplatin, or paclitaxel). Our preliminary result suggests that BEZ235 has promising activity in most NPC cells, while the increase in p-p44/42 MAPK observed in some cell lines suggest the presence of compensatory MAPK activation that have been previously described with mTORC1 inhibitors in other cancer types. Further investigations are warranted.Table 1: IC50 (growth)% growth inhibition by BEZ235% cells at G1 arrest after BEZ235 (5nM) treatment for 24hrsEBV-associated NPC cell linesHK1-LMP14.1nM∼85%-HONE-1-LMP14.9nM∼75%62%C666-19.5nM∼70%-Poorly-differentiated NPC cell linesHONE-16.4nM∼85%-CNE-25.7nM∼90%58%Well-differentiated NPC cell lineHK14.7nM∼90%- Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1638.

3563 Background: TKI258 is a potent receptor tyrosine kinase inhibitor (TKI) that selectively targets VEGFR, PDGFR, FGFR, CSF1R, c-KIT, RET, TrKA, and FLT3. Compared to other TKI agents, TKI258 additionally targets FGFR. FGF has been reported as an important escape mechanism of anti-VEGFR therapies. Methods: The primary objective of this phase I was to determine the maximum tolerated dose (MTD) of TKI258, administered orally on a 5 days on / 2 days off schedule in repeated 28 day cycles, in mRCC pts refractory to standard therapies. A two-parameter Bayesian logistic regression model and safety data for at least 21 pts will be used to determine MTD. Results: A phase I study is ongoing. As of December 2008, 11 pts (9 m, 2 f), median age: 55 (29–66 yrs) have been enrolled. Four pts have been treated at 500 mg/day (start dose): 2 are ongoing at cycle (C) 7; 1 pt discontinued due to PD and 1 due to sinus bradycardia. Five pts received 600 mg/day: 2 DLTs (G4 hypertension and G3 fatigue - pts discontinued) leading to dose reduction of all patients to 500mg/day; 2 pts in C5 and C4, 1 pt discontinued for PD. Two pts just entered the extension cohort at 500 mg. Other toxicities ≥G2 included fatigue, nausea, vomiting, diarrhea, neutropenia, folliculitis and dizziness. PK data showed CMax range (180–487 ng/mL, n = 8), and AUC range (2200–8251 ng/mL*h). Preliminary biomarker data indicated pts had high baseline VEGF (506 ± 203 pg/ml, n=6) and bFGF (220 ± 185 pg/ml, n = 6) levels, which may reflect failure of previous anti-VEGF agents. Induction of plasma FGF23 levels, a pharmacodynamic biomarker of FGFR1 inhibition, was observed in pts from the first 500 mg/day dosing cohort. Preliminary evidence of efficacy is observed with one minor response (-17% at C4), 4 stable disease and 1 dramatic shrinkage/necrosis of some target lesions (lymph node & suprarenal mass). Conclusions: TKI258 500mg/day seems a feasible schedule in heavily pre-treated mRCC patients with some indications of clinical benefit. These preliminary findings will be confirmed in the extension cohort. [Table: see text]