Incidence Of AEs Research Articles

Adverse Events Associated With Bevacizumab and Chemotherapy in Older Patients With Metastatic Colorectal Cancer

BackgroundThe safety of bevacizumab in older mCRC patients is poorly understood. The purpose of this analysis was to determine the prevalence, incidence, and risk factors for treatment-related AEs in older bevacizumab recipients. Patients and MethodsPatients age ≥65 were identified from SEER–Medicare and categorized by mCRC diagnosis pre and post bevacizumab approval (2001-2003 vs. 2005-2007). Preexisting conditions known to increase bevacizumab-related AE risk were identified in the year before diagnosis. Factors associated with bevacizumab receipt were identified using logistic regression. Incidence rates for all AEs and specific serious AEs were determined. Risk factors for first AE were determined by competing risks regression. ResultsOf 6821 patients, 3282 (48%) were diagnosed in 2005-2007 of whom 19% received first-line bevacizumab. Likelihood of bevacizumab receipt was lower in patients age ≥ 75 (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.36-0.47), nonwhite patients (OR, 0.67; 95% CI, 0.55-0.81), patients with higher comorbidity index (OR, 0.52; 95% CI, 0.43-0.62), and patients with preexisting cerebrovascular disease (OR, 0.49; 95% CI, 0.33-0.73). AE incidence rate was not increased among first-line bevacizumab recipients relative to first-line chemotherapy recipients. In a competing risk regression adjusting for potential confounders, bevacizumab receipt (2005-2007) was not associated with an increased risk of first AE compared with chemotherapy alone (2001-2007) (hazard ratio, 0.97; 95% CI, 0.87-1.08). ConclusionIn an older mCRC population, bevacizumab receipt was less likely in older (age ≥ 75) nonwhite patients with preexisting cerebrovascular comorbidities. First-line bevacizumab was not associated with increased AE incidence or risk of first AE compared with chemotherapy alone.

A phase 1, randomized, placebo‐controlled, dose‐escalation study of an anti‐IL‐13 monoclonal antibody in healthy subjects and mild asthmatics

IL-13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti-IL-13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586. In this randomized, double-blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg(-1)) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg(-1)) or placebo. GSK679586 displayed approximately linear pharmacokinetics (based on AUC and C(max)) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL-13 concentrations, indicative of GSK679586-IL-13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg(-1) doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment-related SAEs. GSK679586 demonstrated dose-dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half-life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.

High Dose Plerixafor Is Safe and Mobilizes Higher Numbers of CD34+ Cells Compared with Standard Dose Plerixafor

AbstractAbstract ▪585▪This icon denotes a clinically relevant abstract IntroductionPlerixafor is a bicyclam compound that inhibits the binding of stromal cell derived factor-1 (SDF-1) to its cognate receptor CXCR4. This results in therapid release of CD34+ cells into circulation, which can then be collected by apheresis. Plerixafor is FDA approved at the 240 μg/kg dose to be used in conjunction with G-CSF to mobilize autografts for transplantation. Allogeneic grafts can also be mobilized using single agent plerixafor without G-CSF, and following transplantation, result in sustained donor derived hematopoiesis. However, when the 240 μg/kg dose is used, 1/3 of donors fail to mobilize minimally acceptable doses of CD34+ cells. Recently, we demonstrated the safety of administration of a single dose of 480 μg/kg of subcutaneous (sc) plerixafor in humans. We subsequently conducted a randomized cross-over trial comparing CD34+ mobilization in healthy subjects mobilized with a single dose of sc plerixafor given at either a high dose (480 μg/kg) or a conventional dose (240 μg/kg). MethodsTwenty normal healthy volunteers were randomized and received either a 240 or 480 μg/kg dose of sc plerixafor followed by at least a 2 week wash out period then were administered the other dose of plerixafor. Circulating numbers of leukocytes and CD34+ cells/μlwere measured at multiple time points for 24 hours following each plerixafor injection and the CD34+ AUC over 24 hours was calculated for each subject at each dose level. Peripheral blood colony forming unit (CFU) assays were performed at baseline and 6 hours after plerixafor dosing. Adverse events were graded using CTCAE version 3.A sample size of 20 subjects was determined to have over 90% power to detect an absolute CD34+ count difference of 10/μl using this crossover design and a two-sidedpaired t-test at the 0.05 level. ResultsTwenty-three subjects were enrolled and 20 completed administration of both doses. Peak circulating CD34+ cell numbers (median 31.5 vs 25, p=0.0009), circulating CD34+ cell numbers at 24hrs (median 15.5 vs 9, p<0.0001), and the CD34+ AUC over 24 hours (median 543 vs 411, p<0.0001) were all significantly higher following the administration of the 480 μg/kg plerixafor dose compared to the 240 μg/kg dose. The time to peak CD34+ was also slightly longer after the 480 μg/kg dose (median 10 vs 8 hrs, p=0.011). These differences were not related to the order of administration of the 2 different plerixafor doses. Although GM-CFUs from the peripheral blood at 6hrs following plerixafor were significantly higher compared to baseline levels at both plerixafordoses, there was no dose-effect relationship observed between drug dose and fold increase in GM-CFUs. The incidence and severity of AE’s did not differ between lower and higher doses of plerixafor and no grade 3 or greater adverse events occurred at either dose level. ConclusionThese preliminary data suggest high dose plerixafor can be administered safely and may mobilize more CD34+ cells than standard dose plerixafor. Furthermore, these data suggest mobilization following a single dose of plerixafor and a single apheresis procedure would result in graft collections containing higher CD34+ cell numbers when allogeneic stem cell donors are mobilized with high-dose plerixafor compared to standard-dose. Disclosures:Off Label Use: Plerixafor, a hematopoietic stem cell mobilizer, is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM).

Randomized Double-blind, Active-controlled Phase 3 Study to Assess 12-Month Safety and Efficacy of Mirabegron, a β3-Adrenoceptor Agonist, in Overactive Bladder

BackgroundDespite several antimuscarinic treatment options for overactive bladder (OAB), there is still a need for distinct treatment approaches to manage this condition. Mirabegron, a β3-adrenoceptor agonist, has demonstrated efficacy and tolerability for up to 12 wk in phase 3 trials. ObjectiveTo assess the 12-mo safety and efficacy of mirabegron. Design, setting, and participantsPatients ≥18 yr of age with OAB symptoms for ≥3 mo. InterventionsAfter a 2-wk single-blind placebo run-in, patients with eight or more micturitions per 24h and three or more urgency episodes in a 3-d micturition diary were randomized 1:1:1 to once-daily mirabegron 50mg, mirabegron 100mg, or tolterodine extended release (ER) 4mg for 12 mo. Outcome measurements and statistical analysisPrimary variable: incidence and severity of treatment-emergent AEs (TEAEs). Secondary variables: change from baseline at months 1, 3, 6, 9, and 12 in key OAB symptoms. Results and limitationsA total of 812, 820, and 812 patients received mirabegron 50mg, mirabegron 100mg, and tolterodine ER 4mg, respectively. Baseline demographic and OAB characteristics were similar across groups. TEAEs were reported in 59.7%, 61.3%, and 62.6% of patients, respectively; most were mild or moderate. Serious TEAEs were reported in 5.2%, 6.2%, and 5.4% of patients, respectively. The most common TEAEs were similar across groups. Dry mouth was reported by 2.8%, 2.3%, and 8.6% of patients, respectively. Adjusted mean changes from baseline to final visit in morning systolic blood pressure were 0.2, 0.4, and −0.5mm Hg for mirabegron 50mg, 100mg, and tolterodine ER 4mg, respectively. Mirabegron and the active control, tolterodine, improved key OAB symptoms from the first measured time point of 4 wk, and efficacy was maintained throughout the 12-mo treatment period. The study was not placebo controlled, which was a limitation. ConclusionsThe safety and tolerability of mirabegron was established over 1 yr, with sustained efficacy observed over this treatment period. Trial registrationClinicalTrials.gov identifier: NCT00688688.

Influence of psoriatic arthritis on the efficacy of adalimumab and on the treatment response of other markers of psoriasis burden: subanalysis of the BELIEVE study

Adalimumab is a fully human anti-TNF monoclonal antibody with demonstrated efficacy and safety in patients with moderate to severe psoriasis and psoriatic arthritis (PsA). This study examined the effect of PsA on adalimumab treatment response in patients from the Phase IIIb BELIEVE trial (NCT00574249, ClinicalTrials.gov registry), and response of other markers of disease burden to adalimumab treatment. In this post hoc analysis, patients with or without a history of PsA and with moderate to severe psoriasis were randomized to adalimumab plus adjunctive topical therapy (calcipotriol/betamethasone dipropionate) or monotherapy (adalimumab plus matching topical vehicle). Regardless of baseline PsA, improvement at Week 16 was seen in PASI 75, pruritus, PSSI, and DLQI (all patients), and mean NAPSI scores. Patients with PsA had HAQ improvement at Week 16, and compared to patients without PsA, had higher VAS pain scores. This analysis represents the first publication of the influence of PsA and PsA plus body weight on patient response to adalimumab, and response of scalp psoriasis, nail psoriasis, and patient-reported outcomes to adalimumab. The incidence of AEs was similar among all patients (62%), those with PsA (65%) and without PsA (60%). The most common AEs were infections (27%); 4.2% of all patients reported serious AEs. Adalimumab treatment resulted in comprehensive, clinically relevant improvements from baseline PsA status, in skin, nails, quality of life, pain and pruritus. Despite having more severely affected disease and quality of life, patients with PsA did not respond to adalimumab significantly differently from patients without PsA.

SINGLE-PILL COMBINATION OF TELMISARTAN 80 MG/AMLODIPINE 5 MG PROVIDES SUPERIOR BLOOD PRESSURE REDUCTIONS TO AMLODIPINE 5 MG IN HYPERTENSIVE PATIENTS WHO WERE UNCONTROLLED ON AMLODIPINE 5 MG MONOTHERAPY

ObjectivesTo investigate the efficacy and safety of the single-pill combination of telmisartan 80 mg plus amlodipine 5 mg (T80/A5 SPC) versus amlodpine 5 mg (A5) in hypertensive Asian patients who...

An observational study to evaluate the efficiency and safety of ioversol pre-filled syringes compared with ioversol bottles in contrast-enhanced examinations

The use of pre-filled syringes for contrast media (CM) administration allows efficient and optimized workflow during radiologic diagnostic procedures, and reduces the risk of contamination, providing benefits for both patients and healthcare workers. To compare the efficiency and safety of ioversol (Optiray(TM)) bottles and pre-filled syringes in clinical practice. This was an observational, non-interventional, prospective, multicenter study conducted at 72 centers in Germany. Patients undergoing contrast-enhanced computed tomography (CT) examinations with ioversol were enrolled. The use of ioversol bottles and pre-filled syringes in the diagnostic procedure was recorded in terms of efficiency (residual volume, re-use of CM) and safety (adverse events [AEs]). A total of 10,836 patients were enrolled and included in this study. Ioversol bottles and syringes were used in 72% and 28% of cases, respectively. Analysis of the volume of CM in bottles before and after examinations, together with the volume used during the examination, suggested that in 22.5% of cases a new bottle was connected during the procedure. Further analysis revealed that in 80.2% of cases, the remaining volume of CM in the bottles could potentially be used for subsequent investigations, compared with <1% of cases for pre-filled syringes. For the total study population, AEs and serious AEs were reported in 30 (0.28%) and four (0.037%) patients, respectively, with no significant difference observed between ioversol bottles and syringes. Administration of ioversol for contrast-enhanced CT examinations is associated with a low incidence of AEs and is generally safe and well tolerated. Ioversol pre-filled syringes were associated with lower residual volumes and less potential re-use compared with bottles.

Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study

Objective:To demonstrate non-inferior/superior efficacy of flupirtine modified release (MR) compared with tramadol/placebo for the management of moderate to severe chronic low back pain (LBP).Research design:Randomized, double-blind, active-/placebo-controlled double-dummy multicenter study, performed in 31 German study centers. LBP patients (n = 363) with moderate pain intensity were randomized 1:1:1 to receive flupirtine MR 400 mg, tramadol extended release (ER) 200 mg, or matching placebo (each given OD in the evening) over 4 weeks.Clinical trial registration:EudraCT 2009-013268-38.Main outcome measures:Primary endpoint was change from baseline in the LBP intensity index (LBPIX; 11-point NRS) at week 4; last observation carried forward was used to impute missing scores.Results:Least square (LS) mean ± SD LBPIX changes from baseline at week 4 were clinically significant for all three treatment groups of the intent-to-treat (ITT) and the per-protocol (PP) population (n = 326/276): placebo (n = 110/96): −1.81 ± 1.65/−1.77 ± 1.59; flupirtine MR (n = 109/95): −2.23 ± 1.73/−2.28 ± 1.68; and tramadol ER (n = 107/85): −1.92 ± 1.84/2.03 ± 1.83 (p < 0.001 for each). ITT/PP treatment effects for flupirtine MR were non-inferior when compared with tramadol ER and superior when compared with placebo (p = 0.003/0.033). Significantly more ITT patients treated with flupirtine MR (59.6/37.6 showed a ≥30/50% LBPIX relief in comparison to placebo (46.4/24.6%; p vs. flupirtine MR: 0.049/0.037). Treatment contrasts for tramadol failed to reach significance vs. placebo. Within the safety population (n = 355), flupirtine MR (n = 119) was associated with a significantly lower incidence of treatment emergent AEs (TEAEs; 21.0%) and TEAE-related study discontinuations (3.4%) than tramadol ER (n = 116; 34.5/12.0%; p = 0.039/0.017) and exhibited an overall safety/tolerability profile non-inferior to placebo (n = 120; 15.8/3.3%; p = ns for each). Major limitations of this study were the short treatment duration, the comparison of different drug classes and the lack of a titration phase.Conclusions:The analgesic efficacy of flupirtine MR 400 mg OD was comparable to that of tramadol ER 200 mg OD and superior to that of placebo.

Bupivacaine liposome injectable suspension compared with bupivacaine HCl for the reduction of opioid burden in the postsurgical setting

Objective:Assess comparative efficacy of liposome bupivacaine administered at doses ≤266 mg and bupivacaine HCl administered at doses ≤200 mg for postsurgical analgesia.Research design and methods:Analysis of pooled efficacy and safety data from nine double-blind, placebo or active (bupivacaine HCl) controlled multimodal analgesia studies using a single dose of liposome bupivacaine or comparator, given via administration into the surgical site before end of surgery (i.e., inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation, or bunionectomy). Data from study arms that received liposome bupivacaine doses ≤266 mg were included.Clinical trial registration:Pooled data analysis includes nine studies: Study 1 – NCT01203644; Study 2 – NCT00485433; Study 3 – NCT00485693; Study 4 – NCT00529126; Study 5 – NCT00745290; Study 6 – NCT00744848; Study 7 – NCT00813111; Study 8 – NCT00890721; Study 9 – NCT00890682.Main outcome measures:Outcome measures included area under the curve (AUC) of pain intensity scores assessed by numeric rating scale (NRS) through 72 h postsurgery, time to first use of rescue opioid medications, total amount (mg) of opioid medications used, and occurrence of opioid-related adverse events (ORAEs). Incidence of overall AEs was also assessed.Results:Mean cumulative pain score (AUC of NRS through 72 h) was significantly lower with liposome bupivacaine (283) compared with bupivacaine HCl (329, p = 0.039). Median time from administration of study drug to first use of opioid rescue medication was significantly longer for liposome bupivacaine (10 h vs 3 h, p < 0.0001). Liposome bupivacaine was associated with a significant reduction in opioid use (12 mg vs 19 mg; p < 0.0001) and incidence of ORAEs (20% vs 36%; p < 0.0001), compared with bupivacaine HCl.Conclusions:In this pooled analysis from nine studies representing five different surgical procedures, liposome bupivacaine administered at doses ≤266 mg in a multimodal setting was associated with statistically significant and clinically meaningful lower cumulative pain score at 72 h, delayed and less consumption of opioids, and fewer ORAEs than bupivacaine HCl.

596P - Adverse Events (AES) Associated with Bevacizumab (BV) In Older Patients (PTS) With Metastatic Colorectal Cancer (MCRC)

ABSTRACT Background The relative safety of BV in older mCRC pts is understudied. The objectives of this analysis are to investigate treatment-related AE incidence and to determine factors associated with AEs in a population-based sample of older mCRC pts. Methods Pts age ≥ 65 diagnosed (Dx) with mCRC in 2001-7 were identified from SEER-Medicare. First-line (1L) chemotherapy (CTx) was identified by claims within 3 months of Dx; pts were categorized as receiving no 1L CTx, 1L CTx alone, or 1L CTx + BV. Pts were also categorized by Dx period (2001-3 vs. 2005-7); pts Dx in 2004 were excluded as BV use could not be reliably identified in that year. Preexisting conditions (PCs) identified in the year prior to Dx were grouped into 5 categories (cardiovascular (CV), cerebrovascular (CNS), gastrointestinal (GI), tissue integrity (TI), and pulmonary (Pulm). Claims for these conditions between start of 1L CTx and end of follow-up were identified as AEs. AE incidence rates were determined by Dx year and 1L CTx cohort. We used a competing risks regression model to compare time to 1st AE for pts who received 1L CTx + BV in 2005-7 to pts who received 1L CTx alone in 2001-7. Similar models were constructed for specific serious AEs (stroke, DVT/PE, GI bleed, GI perforation). Results 6,899 pts (median age 77) were identified. In 2001-3, 37% of pts received 1L CTx alone; in 2005-7, 21% and 19% of pts received 1L CTx alone and 1L CTx + BV. AE incidence was similar between pts receiving 1L CTx alone in 2001-3 (135 AEs / 100,000 person-days (PD)) and 1L CTx + BV in 2005-7 (140 AEs / 100,000 PD). Time to 1st AE was not shorter in pts receiving 1L CTx + BV in 2005-7 compared with 1L CTx alone in 2001-7 (HR 0.99, p = 0.90). Similarly, receipt of 1L CTx + BV was not associated with a shorter time to specific AE. (Table) Conclusions Older pts who received 1L CTx + BV had neither increased AE incidence nor decreased time to 1st AE compared with pts who received 1L CTx alone. BV utilization may not increase AE risk among elderly mCRC pts. Time to 1st AE: BV vs. 1L CTx alone AE Type HR 95% CI Any AE 0.99 0.90-1.10 Stroke 1.04 0.95-1.15 DVT/PE 1.03 0.94-1.14 GI bleed 1.03 0.94-1.14 GI perforation 1.05 0.95-1.15 Models adjusted for: age, comorbidity, race, gender, CTx backbone, PC Disclosure V. Shankaran: This research activity received industry funding from Genentech, Inc. D. Mummy: This research activity received industry funding from Genentech, Inc. L. Koepl: This research activity received industry funding from Genentech, Inc. D. Blough: This research activity received industry funding from Genentech, Inc. Y.M. Yim: Financial interests include employment at Genentech, Inc. as as health economist and ownership in Genentech stocks. E. Yu: Financial interests include employment at Genentech, Inc. as Associate Director and stock ownership in Roche. S. Ramsey: This research activity received industry funding from Genentech, Inc.

271P - Additional Safety Results of Hannah: A Phase III Randomised, Open-Label, International Study of the Subcutaneous Formulation of Trastuzumab (H) in HER2-Positive Early Breast Cancer Patients

ABSTRACT Background HannaH demonstrated non-inferiority of the fixed-dose subcutaneous (SC) formulation of H compared with the intravenous (IV) formulation, based on co-primary endpoints of pharmacokinetics (Ctrough) and efficacy (pCR) (Jackisch et al, EBCC 2012). Methods Pts with HER2-positive, operable, locally advanced or inflammatory BC were randomised to receive 8 cycles of chemotherapy (4x docetaxel 75 mg/m2 followed by 4x FEC 600/75/600 mg/m2) concurrently with 3-wkly H, either SC (600 mg/5 mL) or IV (8 mg/kg to 6 mg/kg). After surgery, pts continued H-SC or IV to complete 1 year of treatment. Safety has been monitored until 24 mths after last dose of H, including cardiac monitoring. Results Safety data from 298 (IV) /297 (SC) HannaH pts were analysed. At a median F/U of 12.3 months, 116 pts had completed adjuvant treatment and received a median of 17.5 (IV) and 17.0 (SC) H cycles. Pt characteristics were balanced at baseline. Overall, safety was comparable between arms. Most common AEs (>25% in either arm) were alopecia, nausea, neutropenia, diarrhoea, asthenia, and fatigue, with similar incidence in the two arms. Incidence of severe AEs (≥ grade 3) was comparable between arms (both 52%); the most common of which were haematologic (36.9 [IV] v 35.4% [SC]), GI (6.4 v 5.7%) and infections (5.0 v 6.7%). Serious AEs (SAEs) were reported in 12.4% (IV) v 20.9% (SC) of pts. The imbalance was largely driven by increased reporting of SAEs in the “infections” disease category in the SC v the IV arm (38.7 v 35.1%). Multiple logistic regression analyses did not reveal interactions between route of H treatment, body weight, and exposure (AUC) for SAEs or grade 3–5 AEs. AEs led to the withdrawal of 2.3% (IV) and 5.7% (SC) pts, with a contribution from cardiac AEs (3.0% [SC] v 1.3% [(IV]). Grade 1/2 AEs were reasons for withdrawal in 43% (IV) v 61% (SC) of pts. Grade 1/2 cardiac AEs led to withdrawal in 1.0% (IV) v 2.0% (SC) of pts. Incidence of cardiac AEs was similar in both arms: 12.1% % (IV) v 11.4% (SC). Conclusions The safety profile of H-SC was comparable to that of H-IV. Detailed analyses of observed imbalances in SAEs and withdrawals will be provided. Disclosure C. Jackisch: I have participated in an advisory board for Roche. M. Johnston: I am currently an employee of Genentech Inc. D. Heinzmann: I am currently an employee of F. Hoffmann-La Roche. H. Weber: I am currently an employee of F. Hoffmann-La Roche. G. Ismael: I declare that my institute has received research funding from Roche and honoraria for attendance at conferences. All other authors have declared no conflicts of interest.

578 Single-pill combination of telmisartan 80 mg/amlodipine 5 mg provides superior blood pressure reductions to amlodipine 5 mg in hypertensive patients whowere uncontrolled on amlodipine 5 mg monotherapy

Objectives: To investigate the efficacy and safety of the single-pill combination of telmisartan 80 mg plus amlodipine 5 mg (T80/A5 SPC) versus amlodpine 5 mg (A5) in hypertensive Asian patients who were uncontrolled on amlodipine 5 mg (A5) monotherapy. Design and Methods: After a 6-weekopen-label run-in period with amlodipine 5 mg monotherapy, patients, who failed to respond adequately to A5 (defined as seated DBP ≥90 mmHg), underwent double-blind randomization with 160 and 164 patients assigned to receive either T80/A5 SPC or A5 monotherapy daily. The primary endpoint was change from baseline in mean seated trough DBP after 8 weeks of randomized treatment. Treatment groups were compared using an Analysis of Covariance (ANCOVA) model including treatment, country and the baseline measurement as a covariate. Results: In the full population (n = 314), seated trough mean ± SE BP reductions (mmHg) with T80/A5 vs A5 from baseline to Week 8 were –16.2 ± 1.3 vs –11.7 ± 1.3 for SBP (p < 0.001) and −12.4 ± 0.95 vs –10.2 ± 0.93 for DBP (p = 0.007). T80/A5 provided DBP goal attainment (<140/90 mmHg) in 64.5% vs 45.3% with A5 alone (p = 0.007) and DBP response rate (<90 mmHg or ≥10 mmHg reduction) was 80.0% vs 63.5% (p = 0.0017). The incidence of related AEs (including peripheral edema) was 1.9% with T80/A5 and 2.4% with A5. Conclusions: In Asian patients T80/A5 SPC provided superior BP reductions and goal rate achivement vs A5 monotherapy after 8 weeks of treatment, T80/A5 was well-tolerated and had a safety profile comparable to A5 monotherapy.

AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).

LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. Methods: Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or &gt;2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life. The design provided 80% power to detect a PFS hazard ratio (HR) of 0.7 with 2-sided log-rank test and α=0.05 after 247 events, assuming median PFS of 4.0 mo with CT and 5.7 mo with CT + BEV. Results: Between Oct 2009 and Apr 2011, 361 pts were randomized to receive selected CT (PLD: 126; PAC: 115; TOP: 120) alone or with BEV. Median follow-up after 301 PFS events was 13.5 mo. Conclusions: In PT-resistant OC, BEV + CT provides statistically significant and clinically meaningful improvement in PFS and ORR vs CT alone. Strict inclusion criteria minimized the incidence of BEV AEs. This is the first phase III trial in PT-resistant OC to show benefit with a targeted therapy and improved outcome with a combination vs monotherapy. [Table: see text]

P-0073 GIDEON (Global Investigation of Therapeutic Decisions in HCC and of its Treatment eith Sorafenib): European Interim Safety and Dosing Subanalysis

IntroductionGIDEON (Global Investigation Of Therapeutic Decisions In Hepatocellular Carcinoma (HCC) And Of Its Treatment With Sorafenib) is an ongoing, global, prospective, non-interventional study of patients with HCC eligible for and receiving sorafenib under real-life practice conditions. It aims to assess safety and efficacy of sorafenib in different settings and patient subgroups where data are limited. Findings from the second interim analysis (1571 patients treated for ≥4 months) have been reported. Here we report details of AEs in the European subset. MethodsPatient demographics, medical, disease and treatment history are recorded at enrolment; sorafenib dose, performance status, liver function, AEs and efficacy are recorded at follow-up. Results588 of the 1571 patients were treated in Europe: 59.4% aged ≥65 years, ECOG performance status (PS) 0/1, 45.9/38.9%, and BCLC stage A/B/C/D, 9.0/24.3/52.9/4.9%. Treating physicians’ predominant specialty was hepatology/gastroenterology (56.5% of patients) and medical oncology (32.1%). Most patients (80.6%) were started on sorafenib 800mg daily. Sorafenib dose was modified for 40.8% of patients; 29.8% due to AEs. The dose was increased in 13.8% of patients and decreased in 33.7%. Treatment was interrupted in 20.1% of patients; 16.2% due to AEs. Median treatment duration was 14.3 weeks. Median daily dose was 746mg. A total of 84.5% of patients experienced a treatment-emergent AE. The overall incidence was similar in patients aged <65 or ≥65 years, although the incidence of grade 3/4 AEs was higher in the ≥65 age group; 24.7 vs. 34.7%. The proportion of AEs occurring in the 400mg group was numerically higher than in the 800mg group (92.3% vs. 84.4%), including the grade 3/4 AE subgroup; 35.1% and 30.6% respectively. Incidence appeared lower in BCLC-A patients at start of therapy (66%) vs BCLC B–D (87.4–89.7%). The most frequent AEs were diarrhoea (31.8%; 5.3% Grade ≥3), fatigue (28.2%, 10.4% Grade ≥3), hand-foot skin reaction (HFSR; 18.2%; 4.9% Grade 3). The most common serious AEs were liver dysfunction (8%), encephalopathy (3.4%), fatigue (2.2%), and ascites (2.4%). Most AEs occurred within the first 30 days of treatment. A similar number of drug-related serious AEs were experienced regardless of initial dose. 30.3% of patients discontinued sorafenib due to AEs. Fewer patients started on 800mg daily (29.3%) discontinued treatment vs those started on 400mg (40.7%). AEs leading to permanent discontinuation seemed less frequent in patients treated by medical oncologists, where 68.3% were Child-Pugh A status, albeit with more advanced malignant disease. Medical oncologists treated a greater proportion of patients with sorafenib 800mg daily than hepatologists/gastroenterologists (88.9% vs. 78.6%). The most frequent AEs leading to permanent discontinuation were liver dysfunction (5.3%), fatigue (4.9%), HFSR (2.0%), ascites (1.9%), diarrhoea (1.9%), anorexia (1.5%), encephalopathy (1.5%), and rash (1.2%). ConclusionThe results did not reveal any unexpected AEs and indicate that the incidence of AEs among patients treated with sorafenib in routine clinical practice appears similar to those treated in randomized clinical trials. Furthermore, these data suggest that a modified dosing strategy did not improve upon the incidence of AEs associated with the standard 800mg daily dose of sorafenib.

Phase I safety and tolerability of once daily oral afatinib (A) in combination with docetaxel (D) in patients (pts) with relapsed or refractory advanced solid tumors.

e13010 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability, and PK of A, in two parallel dose cohort expansion parts, in combination with either gemcitabine (Part A) or D (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part B are presented here. Methods: Eligible pts (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once daily, oral dosing of A in combination with D, given iv on Day 1 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. Primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 pts using a 3+3 design. Initial starting dose level was A 30 mg/day and D 60 mg /m², escalating up to A 50 mg/day and D 75 mg/m² until the MTD was reached, and followed by a PK expansion cohort of 12 pts at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 21 pts have been treated with A (30–50 mg/day) and D (60–75 mg/m2), with baseline characteristics: mean age (55.4 years), women (42.9%) and number of prior chemotherapies (≤2: 57%; &gt;2: 43%). Fourteen pts received 2–4 cycles of treatment and five patients received 4 or more cycles. In Cycle 1, DLT was experienced by one out of six pts receiving 30 mg afatinib + 60 mg/m² docetaxel (Grade 3 diarrhea). No DLT was observed during the subsequent dose levels up to A 50 mg/day and D 75 mg/m². AEs observed in most pts were diarrhea (76.2%) and asthenia (66.7%). Conclusions: In pts with relapsed or refractory advanced solid tumors, the combination of A and D is well tolerated. AEs were manageable and the MTD was not reached in the tested dose range up to A 50 mg/day and D 75 mg/m². Considering the potential for diarrhea and rash during later cycles, the recommended dose for the expansion cohort was A 40 mg/day in combination with D 75 mg/m². Enrollment is ongoing (nine pts to date) and additional safety data and preliminary evidence of activity are anticipated to be available at the time of presentation.

A phase Ib study of CUDC-101, a multitargeted inhibitor of EGFR, HER2, and HDAC, in patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer.

e13101 Background: CUDC-101 is a small molecule EGFR/HER2 receptor tyrosine kinase and HDAC inhibitor that has shown promising activity in cancer cell lines and tumor xenograft models. A previous Phase 1 study showed 275 mg/m2 to be the maximum tolerated dose when given daily for 5 days every 2 weeks (QDx5). Dose limiting toxicity included transient creatinine elevation. This expansion Phase 1b study was conducted to further evaluate safety and tolerability of the QDx5 and of a three dose per week (3x/week) schedule for 3 weeks every 4 weeks. Methods: Eligible patients (pts) ≥18 years with advanced breast, gastric, head and neck, NSCLC or liver cancer (n = 10/tumor type); adequate marrow and organ function; and an ECOG PS ≤2 were assigned to receive CUDC-101 (275 mg/m2) on QDx5 or 3x/week schedule. NSCLC patients required documented EGFR exon 19 or 21 mutation/deletion with recent acquired resistance to erlotinib. Study parameters included safety (CTCAE v.3), antitumor response (RECIST v1.1), PK (blood and urine) and PD (tumor biopsy and CTC) assessments. Results: A total of 46 pts were treated (23/dose schedule), including 25 (54%) males, mean age 62 yrs, PS 0/1/2 (33/56/11%), and a median of 3 prior regimens (range, 0-7). The overall incidence and severity of treatment-related AEs were similar between the 2 dose schedules, including fatigue, transiently increased creatinine, nausea, vomiting, decreased appetite, anemia and asthenia, each occurring in &lt;20% of all pts and mostly Grade ≤ 2. Grade 3 AEs were reported in 4 pts. Overall, 15 (33%) pts had SD as their best response: 4 pts had SD for &gt;14 weeks, including 1 with head and neck (QDx5), and 2 with liver (1 lasting 47 weeks) and 1 gastric cancer (all 3 on 3x/week). Paired tumor biopsies were available for one pt showing target inhibition. CTC and PK analyses are ongoing. Conclusions: CUDC-101 was well tolerated using either dosing schedule, with preliminary evidence of antitumor activity. The more convenient 3x/week schedule was selected for an ongoing Phase 1 combination study.

Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma.

8018^ Background: Preclinical studies of siltuximab (S), a chimeric anti-IL-6 mAb, in combination with bortezomib (B) indicate an additive to synergistic effect in multiple myeloma (MM) cell lines. This randomized study evaluated the safety and efficacy of S+B compared with placebo (plc)+B in pts with relapsed/refractory MM after 1−3 prior tx lines, measurable disease but no prior B exposure. Methods: 286 pts were randomized 1:1 to S+B: B+plc. S 6 mg/kg or plc was given IV q2w. B 1.3 mg/m2 was given IV on d 1, 4, 8, 11, 22, 25, 29, 32 for a max of 4 of 42-d cycles and then reduced to q1w for 35-d cycles. B was stopped for pts with PD/intolerability, and high dose oral dexamethasone (dex) 40 mg could then be started qd on d 1−4, 9−12, 17−20 for a max of 4 of 28-d cycles and on d 1−4 of subsequent cycles until PD, while S/plc continued. Primary endpoint was PFS by EBMT criteria censored at the start of dex/subsequent tx. Secondary endpoints included overall response rate (ORR), OS, and safety before dex. Results: 142 and 144 pts received S+B and B+plc, respectively. Baseline demographics and disease characteristics were well balanced across S+B and B+plc, except for age (median 64 vs. 61 yrs) and myeloma type (IgG 65 vs. 71%, IgA 27 vs. 20%). Median tx duration was 5.1 mo in both grps. Median PFS was 8.1 mo in S+B and 7.6 mo in B+plc (HR 0.869, p = 0.345). ORR (CR+PR) was 55% in pts on S+B and 47% on B+plc (p = 0.213); CR rates were 11 and 7% (p = 0.342), respectively. With 24.5 mo median follow up, median OS was 30.8 mo for S+B and 36.9 mo for B+plc (HR 1.353 for S+B, p = 0.103). Fewer pts on S+B than B+plc moved to dex (23 vs. 31%) and had subsequent SCT (5 vs. 11%). Gr ≥3 AEs occurred in 91% on S+B and 74% on B+plc. Common gr ≥3 AEs in S+B were neutropenia (49%), thrombocytopenia (48%), leukopenia (14%). SAEs occurred in 29% on S+B and 24% on B+plc. Death occurred within 30 d of last study agent administration pre-dex in 8% on S+B and 5% on B+plc. Conclusions: The combination of S+B had higher response rates but did not prolong survival compared with B+plc. A negative survival trend heavily influenced by differences in dex and SCT rescue was noted. S+B appears to be generally well tolerated but had a higher incidence of hematologic AEs.

Phase I safety and tolerability of once daily oral afatinib (A) in combination with gemcitabine (G) in patients with advanced solid tumors.

e13009 Background: A is an orally bioavailable, irreversible, ErbB Family Blocker. This open label, Phase I, dose escalation trial investigated the safety, tolerability and pharmacokinetics of A in two parallel dose cohort expansion parts, in combination with either G (Part A) or docetaxel (Part B) in patients with relapsed or refractory solid tumors. Preliminary results from Part A are presented here. Methods: Eligible patients (confirmed diagnosis of advanced solid tumors, ECOG PS 0–1) received once-daily, oral dosing of A in combination with G, given intravenously at Day 1 and at Day 8 of every 3 week cycle. Dosing of A started on Day 2 of Cycle 1. The primary objective was to establish the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLTs) observed in Cycle 1. Dose escalation was performed with cohorts of 3–6 patients using a 3+3 design. Initial starting dose level was A 30 mg/day and G 1000mg /m², escalating up to A 50 mg/day and G 1250 mg/m², until the MTD was reached, and followed by a PK expansion cohort of 12 patients at the MTD level. Incidence and severity of AEs were recorded. Results: To date, 19 patients have been treated on study with the following baseline characteristics: mean age (53.7 years), women (63.2%) and number of prior chemotherapies (≤2: 26%, &gt;2: 74%). Twelve patients received 2–4 cycles of treatment and five patients received 4 or more cycles. AEs observed in most patients were diarrhea (89.5%) and rash (63.2%). In Cycle 1, DLTs were experienced by one patient out of six receiving A 30 mg and G 1250 mg/m². MTD was exceeded at a dose level of at least A 40 mg/day and G 1250 mg/m². An intermediate dose level of A 40 mg/day and G 1000 mg/m² is currently under evaluation. Conclusions: In patients with relapsed or refractory advanced solid tumors, the combination of A with G is well tolerated, with manageable AEs. Dose finding is ongoing and MTD, safety profile and preliminary evidence of activity are anticipated to be reported at time of presentation.

Efficacy and safety of bosutinib (BOS) for Philadelphia chromosome–positive (Ph+) leukemia in older versus younger patients (pts).

6511 Background: BOS is an oral dual Src/Abl kinase inhibitor with potent activity in Ph+ leukemia. Methods: Efficacy and safety of BOS 500 mg/d was evaluated in older (≥65 y; n = 119) and younger (&lt;65 y; n = 451) pts in 3 cohorts: chronic phase chronic myeloid leukemia (CP CML) after imatinib (IM; CP2L cohort; n = 287); CP CML after IM + dasatinib (DAS) and/or nilotinib (NIL; CP3L cohort; n = 119); and accelerated/blast phase (AP/BP) CML or acute lymphoblastic leukemia after IM ± DAS and/or NIL (ADV cohort; n = 164). Results: Baseline events (≥65 y vs &lt;65 y) included respiratory disorders (35% vs 13%), cardiac disorders (29% vs 9%), and diabetes (4% vs 4%). Median baseline medications were 3 (≥65 y) and 5 (&lt;65 y). Median BOS duration was 11 mo and median follow-up was 31 mo for all pts. 80% of ³65 y and 67% of &lt;65 y pts discontinued BOS, including 32% and 18% due to an adverse event (AE; most commonly thrombocytopenia [6% vs 3%]). Rates of response were similar or lower in older versus younger pts (Table). On-treatment transformation to AP/BP CML was similar between groups. Incidences of nonhematologic treatment-emergent AEs were generally similar between older and younger pts, notably (all grades/grade ≥3 for ≥65 y vs &lt;65 y): diarrhea (85%/9% vs 81%/8%), infection (56%/15% vs 49%/10%), and edema (8%/0% vs 4%/&lt;1%). Common grade ≥3 lab abnormalities (≥65 y vs &lt;65 y) were thrombocytopenia (35% vs 35%), neutropenia (21% vs 25%), and anemia (19% vs 19%). Conclusions: BOS demonstrated similar efficacy and acceptable safety in both older and younger pts across Ph+ leukemia cohorts. [Table: see text]

Second interim analysis of the Global Investigation of Therapeutic Decisions in Unresectable HCC (uHCC) and of Its Treatment with Sorafenib (GIDEON): Differences in AE reporting across physician specialties.

286 Background: GIDEON is an ongoing, global, prospective, non-interventional study of patients (pts) with uHCC receiving sorafenib (Sor) in real-life practice. Differences in pt management across physician specialties can be explored. Methods: The 2nd interim analysis was pre-planned when ~1500 treated pts were followed for ≥4 months. The predefined descriptive subgroup analysis by specialty is presented. Results: Median days between visits varied across specialties: medical oncologists (Med Oncs) had the shortest. Sor dosing was broadly similar across specialties, with hepatologists/gastroenterologists (Hep/GIs) having the greatest incidence of dose reductions. Most commonly reported (&gt;20% of pts) adverse events (AEs; e.g. diarrhea, hand-foot skin reaction [HFSR], fatigue) were similar across specialties, but the incidences varied. These AEs and grade 3/4 AEs were reported by more Hep/GIs and Med Oncs than by surgeons. The incidences of liver-related AEs varied across specialties. Interval-specific AE rates by specialty will be presented. Conclusions: Interim data from GIDEON highlight variations in the assessment and management of uHCC pts across specialties. The reporting of AEs and dose reductions may reflect the frequency of visits with physicians. Findings support the importance of a multidisciplinary team approach to optimize pt care. [Table: see text]