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Introduction In the phase 3 ASCEND-4 study, ceritinib exhibited improved progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) assessment versus the standard first-line chemotherapy in patients with advanced ALK-rearranged NSCLC. Here, we assessed the efficacy and safety of ceritinib in the subgroup of Asian patients from the ASCEND-4 trial. Methods Treatment-naive patients with stage IIIB or IV ALK-rearranged nonsquamous NSCLC were randomized in a one-to-one ratio to receive either oral ceritinib 750 mg/day (fasted) daily or intravenous chemotherapy ([cisplatin 75 mg/m2 or carboplatin area under the curve 5–6 plus pemetrexed 500 mg/m2] every three wk, followed by pemetrexed maintenance). The primary end point was PFS by BIRC assessment. Results Of 376 randomized patients, 158 (42.0%) were Asian (ceritinib arm: N = 76; chemotherapy arm: N = 82). The median time from randomization to the cutoff date (June 24, 2016) was 18.3 months (range = 13.5–34.2) in the Asian subgroup. The median PFS (by BIRC assessment) was 26.3 months (95% confidence interval [CI]: 8.6–not estimable) and 10.6 months (95% CI: 6.7–15.0), with an estimated 34% risk reduction in PFS (hazard ratio = 0.66, 95% CI: 0.41–1.05) in the ceritinib arm versus chemotherapy arm. The most common adverse events of any grade were diarrhea (85.5%), increased alanine aminotransferase and vomiting (73.7% each), and increased aspartate aminotransferase and nausea (69.7% each) in the ceritinib arm, and nausea (49.3%), vomiting (42.7%), and anemia (40.0%) in the chemotherapy arm. Conclusion Ceritinib was effective and safe in treatment-naive Asian patients with advanced ALK-rearranged NSCLC. The findings were largely consistent with that of the overall study population.

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.

Background Second-line treatment options for patients with advanced urothelial carcinoma (UC) are limited. Fibroblast growth factor receptor 3 (FGFR3) is dysregulated in UC by activating mutations or protein overexpression in non-mutant tumours. In this study, the efficacy, pharmacodynamics and safety of dovitinib—a broad-targeted inhibitor of tyrosine kinases, including FGFR3—were evaluated in patients with previously treated advanced UC with and without FGFR3 mutations. Methods Forty-four adults with advanced UC who had progressed after one to three platinum-based and/or combination chemotherapy regimens were classified as having mutant ( FGFR3 MUT ; n =12), wild-type ( FGFR3 WT ; n =31), or unknown ( n =1) FGFR3 status. Patients received 500mg dovitinib once daily on a 5-days-on/2-days-off schedule. The primary end-point of this two-stage study was the investigator-assessed overall response rate (ORR). Results Most of the patients were men (75%) and over half of the patients were aged ⩾65years (61%). All patients had received ⩾1 prior antineoplastic therapy for UC. The study was terminated at the end of stage 1, when it was determined by investigator review that the ORR of both the FGFR3 MUT (0%; 95% confidence interval [CI], 0.0–26.5) and FGFR3 WT (3.2%; 95% CI, 0.1–16.7) groups did not meet the criteria to continue to stage 2. The most common grade 3/4 adverse events, suspected to be study-drug related, included thrombocytopenia (9%), fatigue (9%), and asthenia (9%). Conclusion Although generally well tolerated, dovitinib has very limited single-agent activity in patients with previously treated advanced UC, regardless of FGFR3 mutation status. clinicaltrials.gov NCT00790426.

Background Published data from UNOS demonstrated that donor hearts with transient LV dysfunction can be used without increasing the risk of poor transplant outcomes, but account for less than 3% of allocated donors. Our organ procurement organization (OPO) utilizes a centralized treatment and recovery facility allowing for aggressive protocol driven management and frequent assessment of organ function early after brain death declaration. Methods We retrospectively reviewed our OPO experience with cardiac allograft donors from 2013-2017. Clinical data (patient demographics, cause of death, medical management, biomarkers, and serial echocardiographic imaging) were extracted from the OPO EMR for all 168 allocated cardiac donors during this time period. Improved LV systolic function was defined as an initial LVEF ≤40% which later improved to ≥50% consistent with the definition used in the prior UNOS analysis. Results We found that 23% (38/168) of allocated cardiac allografts from our OPO had transient LV dysfunction with an EF ≤40% on the initial echocardiogram. This rate was consistent over the years examined. Moreover 55% of donors had an initial echocardiogram with an EF of less than 50%. Comparison of donors with an initial EF ≤40% to donors with normal LV function on initial examination revealed minimal differences. There was no difference in the average age or sex between the two groups. No differences were found in the dose of vasopressors used either at the time of arrival to the facility or at organ harvest. The average amount of blood transfused was not different between the two groups. Although peak ALT was significantly higher in donors with transient LV dysfunction (402 vs 175 Units/L), there was no differences found in peak AST, troponin, lactate, or creatinine. Conclusion We found a markedly higher percentage of cardiac donors with transient LV dysfunction in allografts coming from our OPO facility compared to the UNOS database. The extent to which this reflects increased recognition versus increased organ yield is unknown at this time. These donors did not differ significantly from donors with normal LV function on initial examination. Coupled with prior data that showed equivalent outcomes in donors with recovered LV function, these data suggest that additional efforts to recover cardiac allografts initially found to have LV dysfunction could be an important means of increasing the donor pool and further work is ongoing to understand the most important factors in the recovery process.

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.

Background: In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo in patients with sickle cell disease (SCD), crizanlizumab 5.0 mg/kg significantly reduced the frequency of vaso-occlusive crises (VOCs) leading to healthcare utilization versus placebo (Ataga KI et al. N Engl J Med 2017;376:429-39). The overall incidences of adverse events and serious adverse events were similar among the patients treated with crizanlizumab and placebo. Aims: This post-hoc analysis from SUSTAIN evaluated key VOC-related endpoints in crizanlizumab 5.0 mg/kg and placebo groups in the per protocol (PP) population, as a way to assess the effect in patients who are able to follow the standard treatment regimen; data from the intention-to-treat (ITT) population will also be shown for context. Methods: The SUSTAIN study was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361) that enrolled patients aged 16-65 years with SCD who had experienced 2-10 VOC events in the previous 12 months. Patients were randomized 1:1:1 to receive crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo 14 times intravenously over 52 weeks; here we focus on the 5.0 mg/kg dose of crizanlizumab versus placebo. The number and time of VOCs leading to healthcare utilization (e.g., hospital admission, emergency department visit) from randomization to end of treatment were measured for each individual patient. Analyses were conducted on the ITT population (i.e., all patients randomized) and PP population (i.e., all patients randomized who received at least 12/14 planned doses of treatment, and completed the study without major protocol violations that impacted the efficacy assessments). Results: In the crizanlizumab 5.0 mg/kg and placebo groups, there were 67 and 65 patients in the ITT population, and 40 and 41 patients in the PP population, respectively; the main reasons for exclusion from the PP population were associated with violations of the visit schedule. As shown previously (Ataga KI et al. N Engl J Med 2017;376:429-39), the median annual rate of VOCs was 1.63 in the crizanlizumab 5.0 mg/kg group versus 2.98 in the placebo group (stratified Wilcoxon Rank-Sum test, P=0.01; Table) in the ITT population. The median time to first on-treatment VOC was 4.07 versus 1.38 months (stratified log-rank test, P=0.001), respectively, in the crizanlizumab 5.0 mg/kg and placebo groups. Overall, 24/67 (35.8%) and 11/65 (16.9%) patients in the crizanlizumab 5.0 mg/kg and placebo groups (stratified Cochran-Mantel-Haenszel test, P=0.013), respectively, did not experience any VOCs during treatment. In the PP population, the median annual rate of VOCs was 1.04 with crizanlizumab 5.0 mg/kg versus 2.18 with placebo (P=0.02; Table). The median time to first on-treatment VOC was 6.55 months with crizanlizumab 5.0 mg/kg and 1.58 months in the placebo group (P Conclusions: This post-hoc analysis of SUSTAIN shows that crizanlizumab 5.0 mg/kg provided benefit over placebo: nearly halving the median annual rate of VOCs, doubling the time to first VOC, and doubling the number of patients with no VOCs during treatment in the ITT population. The effect was even more pronounced in the PP population. This suggests that the superior VOC-related treatment outcomes of crizanlizumab 5.0 mg/kg versus placebo are further improved in patients who are able to follow the standard crizanlizumab treatment regimen. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Sancilio: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kutlar:Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding; Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member. Bruederle:Novartis: Employment. Shi:Novartis: Employment, Other: Stock owner of Novartis. Campigotto:Novartis: Employment. Ataga:Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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

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.

6597 Background: Gan (2013) reported that approximately 27% of 120 randomized phase III trials with a primary endpoint of OS had statistically significant outcomes. Ratain (2005) suggests that the ...

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

255 Background: Increased signaling through mutational activation of fibroblast growth factor receptor 3 (FGFR3) contributes to tumor development and vascularization of urothelial carcinoma (UC). Dovitinib (TKI258), an oral investigational inhibitor of angiogenic factors including FGFR3, has demonstrated inhibition of tumor growth and proliferation in preclinical UC models with FGFR3-activating mutations or protein overexpression. Methods: Advanced UC patients (pts) with 1-3 prior regimens received dovitinib 500 mg/day on a 5-days-on/2-days-off schedule. Pts were stratified into 2 groups based on presence (mut) or absence (non-mut) of FGFR3 gene mutation in archival tissue (initially analyzed by SNaPshot; later by Sanger sequencing for screening and confirmation). The primary objective was overall response rate (ORR) in each group using a Simon’s 2-stage design (20 pts planned for stage 1 and 20 for stage 2 if ≥ 2 responses seen in stage 1). Results: A total of 44 pts (median age, 67 years) were treated in stage 1: 12 FGFR3 mut, 31 FGFR3 non-mut, and 1 unknown mutation status. Over-recruitment of non-mut pts was due to rapid enrollment of non-mut pts with invasive bladder tumors and some tumors initially classified as mut by SNaPshot but reclassified as non-mut after sequencing. Most pts (77%) had metastases in ≥ 2 organs. ORR (local review) was 0% in the FGFR3 mut group and 3% in the FGFR3 non-mut group (1 partial response). Median progression-free survival was 3 months in the FGFR3 mut group and 1.8 months in the FGFR3 non-mut group. There were insufficient non-mut responders to proceed to stage 2. Since most pts in the mut group did not receive > 6 months of treatment and meeting the response threshold to proceed to stage 2 was highly unlikely, the study was terminated. Common adverse events were diarrhea (73%), nausea (61%), and asthenia (50%) and were similar in both groups. Conclusions: Although there were difficulties in evaluating mutation status, dovitinib had limited single-agent activity in pts with advanced bladder cancer regardless of FGFR3 mutation status. Further studies are needed to understand the role of FGFR3 inhibition in advanced UC treatment. Clinical trial information: NCT00790426.

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.

2543 Background: Fridlyand (2011) retrospectively compared PFS vs. change in tumor burden as a primary endpoint in phase II non-small cell lung cancer (NSCLC) trials to inform phase III decision making and found the use of PFS was superior. Since the classic tumor burden model only uses measurements of target lesions, we investigated whether the model could be strengthened by incorporating new and non-target lesion progression. The ability to use a strong tumor burden model has the benefit of potentially earlier decision making and considerable timeline savings. Methods: We analyzed five phase III trials of combination chemotherapy ± targeted therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, -2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards model to OS using the covariates of baseline tumor burden, 1st tumor assessment percentage change from baseline, new lesions, and non-target PD. Results: See table. Conclusions: We show that predictive models for OS should consider new and non-target lesions for PD, as well as target lesion tumor burden, findings independently corroborated by Suzuki (2011). We propose a longitudinal rank-based randomized phase II design, ranking a patient’s risk of death, differentially weighting PDs by type and time of PD, and percentage change in tumor burden. This may be more informative for phase II decision making for phase III trials based on OS, than PFS which only uses time of PD. Further studies with other tumor types and treatment modalities are warranted. [Table: see text]

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

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]

9020 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, and c-KIT. A phase I study was conducted to determine the maximum tolerated dose (MTD), the biological activity and the preliminary efficacy of TKI258 in patients with advanced melanoma. A panel of plasma biomarkers of angiogenesis and soluble receptors were evaluated to determine the pharmacodynamic effect of TKI258. Methods: Patients were treated orally with 200, 300, 400 or 500 mg/day on a once daily continuous dose schedule. The MTD was defined at 400 mg/day. Plasma samples from 43 patients were collected. Plasma concentration of TKI258 was measured by LC/MS/MS. Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2), and c-Kit were measured by multiplex assays using the Meso-Scale Discovery platform. Plasma FGF23 was evaluated by ELISA as a pharmcodynamic marker of FGFR1 inhibition. Results: Following 400 mg or 500 mg continuous daily dosing, the mean plasma exposure (AUC24hr) was approximately 3000 ng/mL*h and 4100 ng/mL*h, respectively. No accumulation in TKI258 plasma exposure was observed at doses of 400mg or below, while accumulation up to 2.5-fold was observed on day 15 following the 500 mg daily dose. At the end of the first treatment cycle, mean plasma VEGF, PLGF and FGF23 levels increased over baseline by 100%, 198% and 68%, respectively, while mean plasma sVEGFR2 levels decreased by 15% in patients treated with 400 and 500 mg/day TKI258. Further analysis of correlations with pharmacokinetic and clinical parameters is ongoing. Conclusions: TKI258 therapy is associated with increases of plasma VEGF and PLGF as well as decreases of sVEGFR2 suggesting VEGFR inhibition. Induction of plasma FGF23 suggest that FGFR may be inhibited at doses of 400 mg/day and above. This panel of circulating proteins may have utility as pharmacodynamic biomarkers of TKI258 activity in patients with advanced melanoma. [Table: see text]