SummaryBackground Circulating tumor cells (CTCs) and chemokine (C-X-C motif) receptor 4 (CXCR4) expression in CTCs and tumor tissue were evaluated as prognostic or predictive markers of CXCR4 peptide antagonist LY2510924 plus carboplatin-etoposide (CE) versus CE in extensive-stage disease small cell lung cancer (ED-SCLC). Methods This exploratory analysis of a phase II study evaluated CXCR4 expression in baseline tumor tissue and peripheral blood CTCs and in post-treatment CTCs. Optimum cutoff values were determined for CTC counts and CXCR4 expression in tumors and CTCs as predictors of survival outcome. Kaplan-Meier estimates and hazard ratios were used to determine biomarker prognostic and predictive values. Results There was weak positive correlation at baseline between CXCR4 expression in tumor tissue and CTCs. Optimum cutoff values were H-score ≥ 210 for CXCR4+ tumor, ≥7% CTCs with CXCR4 expression (CXCR4+ CTCs), and ≥6 CTCs/7.5 mL blood. Baseline H-score for CXCR4+ tumor was not prognostic of progression-free survival (PFS) or overall survival (OS). Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTCs ≥6 at baseline and cycle 2, day 1 were prognostic of shorter PFS and OS. None of the biomarkers at their respective optimum cutoffs was predictive of treatment response of LY2510924 plus CE versus CE. Conclusions In patients with ED-SCLC, baseline CXCR4 expression in tumor tissue was not prognostic of survival or predictive of LY2510924 treatment response. Baseline CXCR4+ CTCs ≥7% was prognostic of shorter PFS. CTC count ≥6 at baseline and after 1 cycle of treatment were prognostic of shorter PFS and OS.

OBJECTIVES:This multicenter, open-label, randomized phase II study evaluated the efficacy and safety of LY2510924 (LY) added to first-line standard of care (SOC) chemotherapy for extensive-disease small cell lung cancer (ED-SCLC) and explored the predictive value of C-X-C motif receptor 4 (CXCR4) tumor response. MATERIALS AND METHODS:Patients with treatment-naïve ED-SCLC were randomized (1:1) to receive up to six 21-day cycles of carboplatin/etoposide alone (SOC) or in combination with 20mg LY2510924 administered subcutaneously on days 1-7 of each cycle (LY+SOC). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Response relative to CXCR4 expression on baseline tumor was an exploratory endpoint. RESULTS:Of 94 patients randomized, 90 received treatment (LY+SOC, n=47; SOC, n=43). Median PFS (95% confidence interval [CI]) was 5.88 (4.83, 6.24) months for LY+SOC versus 5.85 (4.63, 5.51) months for SOC (hazard ratio [95% CI], 1.01 [0.62, 1.63]; p=0.9806). Median OS (95% CI) was 9.72 (6.64, 11.70) months for LY+SOC versus 11.14 (8.25, 13.44) months for SOC. ORR was 74.5% for LY+SOC versus 81% for SOC. Safety results between arms were similar, although the following adverse events were more frequent on the LY+SOC arm: anemia (61.7% vs 46.5%), neutropenia (61.7% vs 53.5%), leukopenia (27.7% vs 9.3%), vomiting (27.7% vs 16.3%), and pneumonia (10.6% vs 2.3%). In patients whose baseline CXCR4 expression was above the optimal cutoff (H-score 210), the hazard ratio (95% CI) was 1.27 (0.51, 3.15). CONCLUSION:LY2510924 did not improve efficacy but had an acceptable toxicity profile when added to SOC for ED-SCLC.

The chemokine (C-X-C Motif) receptor 4 (CXCR4) and its ligand, stromal-cell derived factor-1 (SDF-1), are frequently overexpressed in a variety of solid tumors, and are believed to play important roles in the regulation of organ-specific metastasis, tumor growth, invasion, and survival. In this randomized Phase 2 trial, we evaluated the safety and efficacy of LY2510924 (LY), a peptide antagonist of CXCR4, combined with sunitinib (SUN) in the first-line treatment of advanced renal cell carcinoma (RCC).

Background Data quality issues in clinical trials can be caused by a variety of behaviors including fraud, misconduct, intentional or unintentional noncompliance, and significant carelessness. Regardless of how these behaviors are defined, they may compromise the validity of the study results. Reliable study results and quality data are needed to evaluate products for marketing approval and for decisions that are made on the use of medicine. This article focuses on detecting data quality issues, irrespective of origin or motive. Early detection of data quality issues are important so that corrective actions taken can be implemented during the conduct of the trial, recurrence can be prevented, and data quality can be preserved. Methods A survey was distributed to TransCelerate member companies to assess current strategies for detecting and mitigating risks involving fraud and misconduct in clinical trials. A review of literature across many industries from 1985 to 2014 was conducted using multiple platforms. Results Eighteen TransCelerate member companies anonymously responded to the survey. All of the respondents had one or more existing strategies for fraud and misconduct detection. The literature search identified current practices and methodologies across many industries. Conclusions TransCelerate recommends the creation of an integrated, multifaceted approach to proactively detect data quality issues. Detection methods should include a strategy tailored to the characteristics of the study. Some sponsors are taking advantage of more advanced methods and integrated processes and systems to proactively detect and address issues, relying on advances in technology to more efficiently review data in real time. Further research is underway to assess statistical data quality detection methodology in clinical trials.

7567 Background: Small cell lung cancer (SCLC) can express CXCR4 chemokine receptor, and inhibition potentially synergizes with cytotoxic and targeted therapeutics in vitro in SCLC. Baseline CXCR4 ...

4547 Background: Sunitinib is a standard first-line treatment for patients (pts) with metastatic renal cell carcinoma (RCC). CXCR4 and its only known ligand, SDF-1, are both overexpressed in tumor and vascular cells of clear cell RCC. LY2510924 is a selective peptide antagonist of CXCR4. We compared the results of open-label treatment with LY2510924 + sunitinib vs sunitinib alone. Methods: Previously untreated metastatic clear cell RCC pts were randomized (2:1) to receive standard-dose sunitinib (50 mg qd for 4 weeks [wk], then 2 wk off) + LY2510924 (20 mg sc, qd) (Arm A) or sunitinib alone (Arm B). Pts were evaluated (per RECIST v.1.1) every 8 wk. The primary analysis was done when all pts completed 72 wk of treatment, discontinued, progressed, or died and compared progression-free survival (PFS) between arms using a Bayesian time to event analysis incorporating prior information about sunitinib along with the trial data. PFS was also analyzed using the hazard ratio (HR) with only trial data. The Bayesian design was simulated to size the trial. The objective response rates (ORR) in each arm were compared using the chi-squared test. Results: 72 and 36 pts were treated in Arms A and B, respectively. Key pt characteristics (ECOG PS, Motzer risk score, prior nephrectomy) were similar in Arms A and B. Median number of cycles administered in each arm was 5. Median PFS was 8.1 and 12.3 months in Arms A and B, respectively (HR [95% CI]: 1.19 [0.73, 1.94]). The ORR (95% CI) was 30.6% (19.9%, 41.2%) in Arm A and 38.9% (23.0%, 54.8%) in Arm B. The most frequent ( > 5% Arm A) grade 3/4 AEs (Arm A, Arm B) were hypertension (13.9%, 19.4%), fatigue (9.7%, 13.9%), diarrhea (6.9%, 16.7%), thrombocytopenia (8.3%, 5.6%), and anemia (8.3%, 2.8%). Of interest, there were more bleeding-related events (mostly grade 1 or 2) in Arm A than B (39%, 14%). More pts in Arm A discontinued treatment due to AE (18.1%, 8.3%). Two deaths in Arm A were due to adverse events (pulmonary edema/respiratory arrest/cardiac arrest and intracranial tumour hemorrhage). Conclusions: Adding the CXCR4 inhibitor LY2510924 to sunitinib as first-line treatment for metastatic RCC was tolerated but did not improve efficacy. Clinical trial information: NCT01391130.

Purpose: Overexpression of C-X-C motif receptor 4 (CXCR4) is implicated in tumor progression. LY2510924 is a peptide antagonist, which blocks stromal cell–derived factor-1 (SDF1) from CXCR4 binding. Experimental Design: This phase I study included two parts: a 3+3 dose escalation (part A) and dose confirmation (part B). LY2510924 was administered as a daily subcutaneous injection on a 28-day cycle. The primary objective was to determine the recommended phase II dose. Secondary objectives included safety, pharmacokinetics, efficacy, and pharmacodynamic response, including mobilization of CD34+ hematopoietic stem cells into the peripheral blood. Results: Forty-five patients were enrolled, 25 in part A and 20 in part B. Patients were administered increasing doses of LY2510924: 1.0, 2.5, 5.0, 10, 20, and 30 mg/day for part A and 2.5 or 20 mg/day for part B. Two patients (30-mg/day cohort) experienced dose-limiting toxicities of grade 3 increased neutrophil count. The maximum tolerated dose (MTD) was 20 mg/day. The most common drug-related treatment-emergent adverse events were fatigue (9%), injection-site reaction (9%), injection site pruritus (7%), and nausea (7%). The best response was stable disease for nine patients (20%). At the end of cycle 1, mean peak LY2510924 plasma concentration and the 24-hour area under the plasma concentration versus time curve increased slightly more than dose proportionally. LY2510924 dose dependently increased CD34+ cell counts in peripheral blood up to 18-fold. Conclusions: LY2510924 demonstrated CD34+ cell mobilization at doses ≥2.5 mg/day with a tolerable safety profile up to an MTD of 20 mg/day. Clin Cancer Res; 20(13); 3581–8. ©2014 AACR.

OBJECTIVE Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients. RESEARCH DESIGN AND METHODS Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications. RESULTS LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: −0.27, −0.38 and −0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated. CONCLUSIONS Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM.

Type 2 diabetes occurs when pancreatic b-cell function fails to compensate for insulin resistance (1,2). As the duration of diabetes increases, b-cell function progressively deteriorates, partly as a result of apoptotic cell death (3–5). Inflammation is associated with pancreatic b-cell apoptosis and reduced insulin sensitivity, supporting the notion that inflammation plays a key role in aggravating or even causing type 2 diabetes specifically or the metabolic syndrome generally (6). Interleukin (IL)-1b is an inflammatory mediator that may contribute to this pathophysiology. IL-1b expression has been observed in b-cells of patients with type 2 diabetes (7). Moreover, production and secretion of IL-1b from b-cells is induced by high glucose levels and inhibits the function and promotes the apoptosis of b-cells (7–10). The IL-1 receptor antagonist (IL-1ra) protects human b-cells from glucose-induced functional impairment (7) and apoptosis, and its expression is decreased in patients with type 2 diabetes (11). The hypothesis that blocking IL-1b activity could be therapeutic in type 2 diabetes was tested clinically with anakinra, a recombinant IL-1ra (12,13). Results from a proof-of-concept study indicated that anakinra modestly improved hemoglobin A1c (HbA1c) relative to placebo, reduced circulating inflammatory cytokines, and showed signs of improved b-cell secretory function after 13 weeks of daily subcutaneousdosing (13).Ninemonths after treatment completion, anakinratreated patients continued to have improved proinsulin/insulin ratios and reduced inflammatory cytokines; anakinra responders required less exogenous insulin than did nonresponders (14). Clinical evaluation of a neutralizing IL-1b monoclonal antibody (XOMA 052) in type 2 diabetic patients showed similar results. XOMA 052 improved HbA1c relative to placebo after a single intravenous infusion and after repeated subcutaneous dosing; improvements in fasting blood glucose and insulin sensitivity after subcutaneous dosing were also noted (15). Typically only a small percentage of cytokine receptors require engagement to activate downstream signaling pathways, and cytokines are typically labile proteins expressed at low concentrations. Because anakinra binds to the IL-1 receptor and has a short half-life (4–6 h) (16), it is unclear whether the modest nature of the response in type 2 diabetes was related to compound-specific properties or a reflection of the role of this cytokine pathway in the disease pathogenesis. Although XOMA 052 binds and neutralizes IL-1b directly and has a longer half-life, it was dosed in a limited number of subjects and for short duration. Further evaluation c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c

Background: The over-expression of C-X-C motif receptor 4 (CXCR4), a chemokine receptor implicated in tumor progression, tumor cell growth, migration, and invasion, correlates with a worse prognosis. LY2510924 is a selective peptide antagonist to CXCR4. This peptide blocks stromal cell-derived factor-1 (SDF-1), the only known ligand to CXCR4, from binding to the receptor. Disruption of the CXCR4/SDF-1 axis with CXCR4 antagonists is known to mobilize WBC, neutrophils, and CD34+ cells. The primary objective of this study was to determine the maximum tolerated dose (MTD). Secondary objectives were to determine safety, pharmacokinetics, efficacy, and pharmacodynamic response, which included mobilization of CD34+ hematopoietic stem cells into the peripheral blood. Material & Methods: This phase I study in patients (pts) with advanced cancer included two Parts: a 3+3 dose escalation (Part A) and dose confirmation (Part B). LY2510924 was administered as a daily injection subcutaneously (s.c.) on a 28-day cycle. Results: Forty-five pts, 98% with solid tumors, were enrolled onto study, 25 in Part A and 20 in Part B. The median age was 67.0 years (range: 39-86), 51.1% were male, and 80.0% were Caucasian. The Eastern Cooperative Oncology Group performance status was 1 for 73.3% of pts. In Part A, pts in 6 cohorts were treated with doses of LY2510924: 1.0 (n=3), 2.5 (n=5), 5.0 (n=3), 10 (n=3), 20 (n=4), and 30 mg/day (n=7). Two pts in the 30 mg/day cohort experienced dose-limiting toxicities, grade 3 neutrophil count increase. The MTD was determined to be 20 mg/day. Pts in Part B were treated with either 2.5 (n=10) or 20 mg/day (n=10). For Parts A and B combined, the most frequently reported (≥15%) treatment emergent adverse events (TEAE), regardless of causality, included fatigue, nausea, constipation, anemia, and anorexia. The most common grade 3 TEAE were increased neutrophil count, anemia, asthenia, and dypsnea (all occurring in 4.4% of pts). There were no grade 4 TEAE. The best response was stable disease for 9 pts (20.0%). At the end of Cycle 1, mean peak LY2510924 plasma concentration (Cmax) and the 24-hour area under the plasma concentration vs. time curve (AUC) increased slightly more than dose proportionally. Mean Cmax and AUC ranged from 18.8 ng/mL to 1250 ng/mL, and 61.5 ng•h/mL to 5720 ng•h/mL, respectively, in the 1-30 mg dose range. Median time to Cmax was 0.5 hours independent of dose. Receptor occupancy was consistently high with median values of 96.9-100% for 2.5 mg, 20 mg and 30 mg, between 0.5 hours through 24 hours after dosing. There was an up to 18-fold mean increase from baseline in CD34+ cell count in peripheral blood, with an apparent dose-response relationship between 1mg and 10 mg, and little additional response with 20 mg or 30 mg. The increase persisted to the end of Cycle 1, but was somewhat blunted. Conclusions: LY2510924 demonstrated CD34+ cell mobilization with an acceptable safety profile up to an MTD of 20 mg/day (s.c.). Citation Format: Nicholas Vogelzang, Mansoor Saleh, Paul Conkling, Eyas J. Abu-Raddad, John P. Polzer, Stephanie Roberson, John R. Stille, Donald E. Thornton. A phase I study of the CXCR4 peptide antagonist LY2510924 in patients with advanced cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1419. doi:10.1158/1538-7445.AM2013-1419

Objective: The present work examined suicide-related events in acute, double-blind, and placebo- or active comparator-controlled trials with atomoxetine. Method: Fourteen trials in pediatric patients were included. Potential events were identified in the adverse events database using a text-string search. Potential suicide-related events were categorized according to U.S. Food and Drug Administration-defined codes using blinded patient summaries. The meta-analyses used the Mantel-Haenszel incidence difference and Mantel-Haenszel risk ratio methods. Results: No patient in atomoxetine attention-deficit/hyperactivity disorder (ADHD) trials committed suicide. The frequency of suicidal ideation was 0.37% (5/1357) in pediatric patients taking atomoxetine versus 0% (0/851) for the placebo group; Mantel-Haenszel incidence difference of 0.46 (95% confidence interval 0.09-0.83; p = .016) and Mantel-Haenszel risk ratio of 2.92 (95% confidence interval 0.63-13.57; p = .172). Frequencies of suicide-related events in pediatric patients with ADHD did not differ between methylphenidate and atomoxetine treatments (Mantel-Haenszel incidence difference of -0.12 (95% confidence interval -0.62 to 0.38; p = .649). The number needed to harm in pediatric patients for an additional suicide-related event is 227 compared to the number needed to treat of five to achieve remission of ADHD symptoms. Conclusions: Although uncommon, suicidal ideation was significantly more frequent in pediatric ADHD patients treated with atomoxetine compared to those treated with placebo. Retrospective analysis has limitations in ascertaining intent.

Background: We systematically examined potential aggression/hostility-related events in a meta-analysis of acute clinical trials of atomoxetine for attention-deficit/hyperactivity disorder (ADHD).Methods: Pediatric patients from 14 trials of atomoxetine were subdivided into a placebo-controlled (atomoxetine n = 1308, placebo n = 806) or active comparator databases (atomoxetine n = 566, methylphenidate n = 472). A third database comprised adult patients from placebo-controlled studies (atomoxetine n = 541, placebo n = 405). A computerized search of adverse events and comments identified patients with potential aggression/hostility events. Mantel-Haenszel incidence differences (MHID) were calculated.Results: In the placebo-controlled database, we observed 21 atomoxetine and 9 placebo patients with reported aggression/hostility events, MHID of .6% (95% confidence interval [Cl]: -.4,1.7). In the active comparator database, there were seven events in atomoxetine and four in methylphenidate patients, MHID = .2% (95% CI: -1.0,11.3). In the adult database, there were no events in 0 atomoxetine and one placebo patient, MHID = -.3% (95% CI: -.8,.2).Conclusions: Aggression/hostility-related events occurred in less than 2% of patients and were more frequent in pediatric patients treated with atomoxetine versus placebo (risk ratio of 1.33; not statistically significant). The risk of aggression/hostility events was similar inpatients treated with atomoxetine or methylphenidate.

Selective serotonin reuptake inhibitor treatments have been suggested by some to induce emergence of suicidality (ideation and behaviors). The objective of this study was to assess suicidality emergence by adverse event and rating scale data in the largest available, adult, major depression, double-blind, placebo-controlled, fluoxetine trial database (18 trials). Adverse event reports and comments for patients (fluoxetine, n = 2200; placebo, n = 1551) were searched for suicide-related events that were then classified into Food and Drug Administration categories. For 16 trials, suicidality was also examined by Hamilton Depression Scale item 3 (suicide) scores, and these data were analyzed along with the combination of event-based data and scale-based data. Comparisons between treatments were made for various estimates of worsening (risk) and improvement (benefit) of suicidality. Fluoxetine treatment did not result in greater worsening but was associated with greater improvement and faster resolution of ideation (P ≤ 0.05 vs placebo). Data sources were differentially sensitive in detecting changes in suicidal ideation and behaviors. Fluoxetine treatment led to greater benefit rather than risk for suicidality.