Severity Of AEs Research Articles

Lamotrigine-induced sexual dysfunction and non-adherence: case analysis with literature review.

BackgroundOptimal anti-epileptic drug (AED) treatment maximises therapeutic response and minimises adverse effects (AEs). Key to therapeutic AED treatment is adherence. Non-adherence is often related to severity of AEs. Frequently, patients do not spontaneously report, and clinicians do not specifically query, critical AEs that lead to non-adherence, including sexual dysfunction. Sexual dysfunction prevalence in patients with epilepsy ranges from 40 to 70%, often related to AEDs, epilepsy or mood states. This case reports lamotrigine-induced sexual dysfunction leading to periodic non-adherence.AimsTo report lamotrigine-induced sexual dysfunction leading to periodic lamotrigine non-adherence in the context of multiple comorbidities and concurrent antidepressant and antihypertensive pharmacotherapy.MethodCase analysis with PubMed literature review.ResultsA 56-year-old male patient with major depression, panic disorder without agoraphobia and post-traumatic stress disorder was well-controlled with escitalopram 20 mg bid, mirtazapine 22.5 mg qhs and alprazolam 1 mg tid prn. Comorbid conditions included complex partial seizures, psychogenic non-epileptic seizures (PNES), hypertension, gastroesophageal reflux disease and hydrocephalus with patent ventriculoperitoneal shunt that were effectively treated with lamotrigine 100 mg tid, enalapril 20 mg qam and lansoprazole 30 mg qam. He acknowledged non-adherence with lamotrigine secondary to sexual dysfunction. With lamotrigine 300 mg total daily dose, he described no libido with impotence/anejaculation/anorgasmia. When off lamotrigine for 48 h, he described becoming libidinous with decreased erectile dysfunction but persistent anejaculation/anorgasmia. When off lamotrigine for 72 h to maximise sexual functioning, he developed auras. Family confirmed patient’s consistent monthly non-adherence for 2–3 days during the past year.ConclusionsSexual dysfunction is a key AE leading to AED non-adherence. This case describes dose-dependent lamotrigine-induced sexual dysfunction with episodic non-adherence for 12 months. Patient/clinician education regarding AED-induced sexual dysfunction is warranted as are routine sexual histories to ensure adherence.Declaration of interestNo financial interests. K.R.K. is Editor of BJPsych Open; he took no part in the peer-review of this work.Copyright and usage© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

SUVN-G3031, A SELECTIVE H3 RECEPTOR INVERSE AGONIST: ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

SUVN-G3031, a potent and selective histamine H3 receptor inverse agonist is being developed for the treatment of cognitive deficits associated with Alzheimer's disease. SUVN-G3031 demonstrated cognitive enhancement and relevant neurochemical modulation without affecting the sleep in rodent models. SUVN-G3031 was studied in a single-center, multi-faceted, phase 1 clinical study (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single and multiple ascending doses in healthy adult subjects. For single dose evaluation, subjects dosed with 0.1 mg to 20 mg of SUVN-G3031 tablets. For multiple ascending dose evaluation, once daily doses of 1 mg to 6 mg were administered for 14 days. Effect of food on pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-G3031 was administered under fasted conditions in healthy female and elderly subjects. SUVN-G3031 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was assessed throughout the study by incidence and severity of AEs, abnormalities in vital signs, ECG and clinical laboratory assessments. SUVN-G3031 was well tolerated up to the highest tested dose of 20 mg single dose or 12 mg/ day repeated dose in healthy adult subjects. During single ascending dose studies, exposures were observed to be dose-proportional at the tested doses between 0.1 mg to 20 mg. During multiple ascending dose studies, SUVN-G3031 has shown an excellent pharmacokinetic profile. SUVN-G3031 achieved the projected efficacy concentrations and attained steady state on day 6. At a tested dose of 6 mg, food, gender and age had no effect on human pharmacokinetics of SUVN-G3031. SUVN-G3031 was well tolerated and there were no clinically relevant or serious adverse events observed in different population. SUVN-G3031 has excellent safety and pharmacokinetic profile in healthy human volunteers after single and multiple dose administration for 14 days. Food, gender and age had no effect on SUVN-G3031 pharmacokinetics in human. Long term safety studies are completed and SUVN-G3031 is ready for phase-2 clinical evaluation.

SUVN-D4010: A POTENT AND SELECTIVE 5-HT4 RECEPTOR PARTIAL AGONIST— ASSESSMENT OF SAFETY, TOLERABILITY AND PHARMACOKINETICS IN HEALTHY HUMAN VOLUNTEERS

SUVN-D4010 is a potent, selective and orally bioavailable 5-HT4 receptor partial agonist being developed for the treatment of Alzheimer's disease (AD). SUVN-D4010 has shown to improve the memory in preclinical animal models. SUVN-D4010 also produced significant increase in the brain acetylcholine levels and cortical sAPPα with simultaneous decrease in amyloid-β protein levels. SUVN-D4010 was studied in a single-center, multi-faceted, phase 1 clinical trial (US IND) to evaluate its safety, tolerability, and pharmacokinetics after single or multiple ascending doses in healthy male subjects. For single dose evaluation, subjects were dosed with 5 mg, 15 mg, 30 mg or 45 mg of SUVN-D4010 tablets, once. For multiple ascending dose evaluation, the once daily doses of 10, 25 and 40 mg SUVN-D4010 were administered for 14 days. SUVN-D4010 was administered at a dose of 25 mg for evaluation of food, gender and age effect. Effect of food on SUVN-D4010 pharmacokinetics was evaluated under fed and fasted conditions in healthy adult male subjects. For evaluation of gender and age effect, SUVN-D4010 was administered under fasted conditions in healthy female and elderly subjects. SUVN-D4010 was quantified in plasma using a validated LC-MS/MS method. Safety and tolerability was assessed by incidence and severity of AEs, abnormalities in vital signs, ECG and laboratory assessments. SUVN-D4010 was well tolerated up to the highest tested dose of 45 mg single dose or 40 mg/day multiple doses in healthy male subjects. There were no clinically relevant or serious adverse events reported. During single ascending dose studies, the absorption of SUVN-D4010 was rapid and exposures (Cmax and AUC) were dose proportional. During multiple ascending dose studies, SUVN-D4010 achieved steady state on day 3 in the tested population. SUVN-D4010 has excellent safety and pharmacokinetic profile following single or multiple dose administration for 14 days in healthy male subjects. Projected efficacy concentrations of SUVN-D4010 achieved during multiple ascending dose studies. SUVN-D4010 is currently being evaluated for long term safety in animal models.

A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients

BackgroundThe aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer.MethodsPatients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2 gemcitabine combined or 1000 mg/m2 gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated.ResultsNinety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3–18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-∞) ≥21,000 ng∙hr/mL and Cmax ≥2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618.ConclusionsLY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer.Trial RegistrationNCT00839332. Clinicaltrials.gov. Date of registration: 6 February 2009

New Film-Coated Tablet Formulation of Deferasirox Is Well Tolerated in Patients with Thalassemia or MDS: Results of the Randomized, Phase II E.C.L.I.P.S.E. Study

▪Background: Patients (pts) compliant with iron chelation therapy (ICT) experience improved organ function and survival (Delea et al. Transfusion 2007;47:1919-29). Once-daily deferasirox (DFX) dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater adherence, pt satisfaction, and quality of life (Cappellini et al. Clin Ther 2007;29:909-17). However, barriers exist to pt adherence to DFX DT, including GI tolerability and palatability, leading to development of a film-coated tablet (FCT) that can be taken with or without a light meal. The FCT contains the same active substance as DT but different excipients (lactose and sodium lauryl sulfate removed). Here we present results of the randomized, open-label, Phase II ECLIPSE study that evaluated safety of DFX FCT and DT formulations in pts with transfusion-dependent thalassemia (TDT) or IPSS-R very low-, low- or intermediate-risk MDS.Methods: ICT-naïve or pre-treatedpts aged ≥10 yrs, requiring ICT at DFX DT ≥30 mg/kg/day (TDT) or ≥20 mg/kg/day (MDS), with serum ferritin (SF) >1000 ng/mL, were enrolled. Exclusion criteria: creatinine clearance below contraindication limit per local label (<60 mL/min or <40 mL/min), serum creatinine >1.5xULN, alanine aminotransferase >5×ULN, urine protein/urine creatinine ratio (UPCR) >0.5 mg/mg, or impaired GI function. ICT-naïve pts received DFX DT 20 mg/kg/day or DFX FCT 14 mg/kg/day. ICT pre-treated pts received a DT or FCT dose equivalent to their pre-washout dose. FCT doses are 30% lower than DT doses due to improved bioavailability, conversion factor 1.43. Dose was adjusted based on SF and investigator’s judgment after wk 4 for ICT-naïve pts and after 3 months for ICT pre-treated pts (DT ±5-10 mg/kg/day, max 40 mg/kg/day; FCT ±3.5-7 mg/kg/day, max 28 mg/kg/day); dose adjustments for safety reasons were permitted at any time. Primary endpoint was overall safety, measured by frequency and severity of AEs and changes in laboratory values from baseline (BL) over 24 wks. A secondary endpoint was evaluation of selected GI AEs.Results: 173 pts were randomized 1:1 to DT or FCT (Table 1). Mean actual daily DFX dose ± SD over 24 wks was 27.5 ± 7.7 mg/kg/day (DT) and 20.8 ± 5.4 mg/kg/day (FCT). More FCT pts were started on a dose higher than the protocol-specified dose than DT pts (26.4% vs 9.3%). Mean/median duration of exposure was 155/168 days with DT and 163/169 days with FCT. 73 (84.9%; DT) and 77 (88.5%; FCT) pts completed 24 wks. Relative consumed tablet count was high, but lower with DT (85.3%) than FCT (92.9%). Absolute median (range) change in SF at end of treatment was -85.5 (-2146 to 8250) ng/mL (from 2485 [915-8250] ng/mL at BL) with DT, and -350 (-4440 to 3572) ng/mL (from 2983 [939-8250] ng/mL at BL) with FCT, corresponding to a median relative change of -4.1% (DT) and -14.0% (FCT) at end of treatment.AEs regardless of causality were reported in similar proportions of pts for each formulation (Table 2). Fewer severe AEs were observed in FCT pts. The most common AEs with either formulation were consistent with the known DFX safety profile. Notable laboratory evaluation frequencies were similar with both formulations (Table 3).61.6% (95% CI, 50.5-71.9%) of DT pts and 58.6% (95% CI, 47.6-69.1%) of FCT pts reported ≥1 GI AEs. Similar proportions of pts had diarrhea, nausea, and abdominal pain. Fewer FCT pts had constipation and vomiting than pts receiving DT. Fewer pts had severe GI AEs with FCT than with DT. In pts receiving DT prior to study entry, fewer FCT pts had GI AEs (53.5%, FCT; 60.3%, DT), particularly diarrhea, vomiting and constipation. Increased UPCR was reported in more FCT pts (12.8%, DT; 20.7%, FCT), which could be attributed to more FCT pts receiving a higher than recommended starting dose. Renal event frequency was similar when patients were started on a correct starting dose (30.9%, DT; 33.3%, FCT). 23 pts discontinued, 10 because of AEs (n=6, DT; n=4, FCT).Conclusions: These results in pts with TDT or very low-, low- or int-risk MDS demonstrate comparable FCT and DT safety profiles, consistent with the known DFX profile. In patients with prior DT exposure, fewer GI AEs were seen with FCT than DT. Pts receiving FCT had better compliance, continued longer on treatment and experienced greater SF reduction. DFX FCT may improve pt experience with ICT resulting in greater compliance and reduced frequency and severity of iron overload-related complications. [Display omitted] [Display omitted] [Display omitted] DisclosuresTaher:Novartis: Honoraria, Research Funding; Celgene: Research Funding. Origa:Novartis: Honoraria; Apopharma: Honoraria. Kouraklis:Gilead: Consultancy; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Consultancy; Celegene: Consultancy. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Cortoos:Novartis: Employment. Huang:Novartis: Employment. Weill:Novartis: Employment. Herranz:Novartis: Employment. Porter:Novartis: Consultancy, Honoraria, Research Funding; Celegene: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Bluebird Bio: Consultancy.

1090P - Identification of patients at risk for severe toxicity under PD1 inhibitors: role of sarcopenic overweight

PD-1 checkpoint inhibitors are associated with a specific spectrum of immune-related adverse events (irAEs). Body composition has been proven to influence the pharmacokinetics of many anti-neoplastic drugs. We evaluated the effect of decreased muscle mass (sarcopenia) on PD-1 inhibitors toxicity. Pre-therapeutic biological and clinical assessments were prospectively performed for patients (pts) treated with anti-PD1. Muscle mass was estimated using Creatinine/Cystatine C (Cr/CysC) clearance ratio (Kim SW, 2016). Univariate and multivariate analysis tested the association between anti-PD1 induced severe toxicity and age, sex, Performans Status (PS), (Cr/CysC) clearance ratio, body mass index (BMI), lymphocytes, C-Reactive Protein (CRP) and albuminemia. The severity of AEs was graded according to the NCI CTC for AE V4. From July 2015 to April 2016, 74 pts, median age 65 years (41-84), 58.1% men, received at least one infusion of nivolumab (85%) or pembrolizumab (15%), for lung cancer (n = 44), melanoma (n = 13), renal carcinoma (n = 9) and others (n = 8). A total of 418 cycles (median per pt: 4, range 1-20) were analyzed. Median Cr/CysC clearance ratio was 1.17. Twenty pts (27%) had both Cr/CysC clearance ratio >1.17, reflecting low lean body mass and a BMI > 25 kg.m-2. Fifteen pts (20.2%) developed grade 3-5 AEs, some rare, such as insipid diabetes with hypophysitis (n = 1) after 1st cycle (C1), pulmonary arterial hypertension (n = 3, C1, C1, C5), polymyositis (n = 2, C2, C2) and thrombocytopenia (n = 1, C6). In univariate analysis, gr 3-5 AE was associated with Cr/CysC clearance ratio >1.17 (p = 0.006), high CRP (p = 0.036) and the combination of Cr/Cyst clearance ratio >1.17 with BMI > 25 kg/m2 (p= 0.024). In multivariate analysis, Cr/CysC clearance ratio >1.17 (p = 0.03) and the combination of Cr/CysC clearance ratio >1.17 with BMI >25 kg/m2 (p = 0.014) remained significant. The Creatinine/Cystatine C clearance ratio associated with BMI helps to identify sarcopenic overweight pts who are at high risk of severe PD-1 inhibitors induced toxicity. To date, it is unknown if the development of irAEs is an inherent component of checkpoint blockade with anti–PD-1 or if modifying the dosage can decrease the rates of these events.

Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study

Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study

Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program.

BackgroundOnartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program.MethodsAdverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards. The severity of AEs was assessed using the NCI Common Toxicity Criteria, Version 4. Medical Dictionary for Regulatory Activities (MedDRA) AEs were grouped using the standardized MedDRA queries (SMQs) “gastrointestinal (GI) perforation”, “embolic and thrombotic events, venous (VTE)”, and “embolic and thrombotic events, arterial (ATE)”, and the Adverse Event Group Term (AEGT) “edema.” The safety evaluable populations (patients who received at least one dose of study treatment) for each study were included in this analysis.ResultsA total of 773 onartuzumab-treated patients from seven studies (phase II, n = 6; phase III, n = 1) were included. Edema and VTEs were reported in onartuzumab-treated patients in all seven studies. Edema events in onartuzumab arms were generally grade 1–2 in severity, observed more frequently than in control arms and at incidences ranging from 25.4−65.7% for all grades and from 1.2−14.1% for grade 3. Hypoalbuminemia was also more frequent in onartuzumab arms and observed at frequencies between 77.8% and 98.3%. The highest frequencies of all grade and grade ≥3 VTE events were 30.3% and 17.2%, respectively in onartuzumab arms. The cumulative incidence of all grade ATE events ranged from 0−5.6% (grade ≥3, 0−5.1%) in onartuzumab arms. The frequency of GI perforation was below 10% in all studies; the highest estimates were observed in studies with onartuzumab plus bevacizumab for all grades (0−6.2%) and grade ≥3 (0−6.2%).ConclusionsThe frequencies of VTE, ATE, GI perforation, hypoalbuminemia, and edema in clinical studies were higher in patients receiving onartuzumab than in control arms; these are considered to be expected events in patients receiving onartuzumab.

Phase 1 Study Results of a Novel Controlled-Release Formulation of Anagrelide (GALE-401) for the Treatment of Thrombocytosis

Introduction: Despite recent advances in the diagnosis and management of myeloproliferative neoplasms (MPNs), treatment of essential thrombocythemia (ET) has remained largely unchanged since the introduction of anagrelide in the US during 1997. Anagrelide is indicated for the treatment of thrombocythemia, to reduce the elevated platelet count and risk of thrombosis, and to ameliorate symptoms including thrombohemorrhagic events. The primary pharmacological effect of anagrelide is inhibition of megakaryocyte hypermaturation leading to reduced platelet production. Anagrelide also inhibits cyclic AMP phosphodiesterase III (PDE3), and common drug related adverse events (AEs; e.g., headache, palpitations, fluid retention, nausea and diarrhea) are believed to be due to this mechanism. Although initiating treatment at low doses and slowly increasing the dose to reach a target decreased platelet count may mitigate AEs, over 20% of patients still withdraw from treatment due to poor tolerability. As the currently marketed anagrelide product is an immediate release (IR) formulation with peak plasma concentrations (Cmax) that may exceed that needed for platelet reduction and cause unwanted PDE3 inhibition and AEs, an alternate formulation that modifies this pharmacokinetic (PK) profile may improve patient tolerability, adherence and treatment outcomes. This has led to the development and study of a controlled-release (CR) formulation of anagrelide (GALE-401).Methods: 98 healthy adult subjects were enrolled among 5 Phase 1 clinical trials of anagrelide CR, including 12 placebo-control subjects and 86 subjects who received single or multiple doses ranging from 0.2 to 0.6 mg twice daily (b.i.d.) for up to 41 days. The trials included an open-label, single dose developmental study; two placebo-controlled multiple dose ranging studies; a food effect study; and a comparative crossover PK study vs. IR reference product. Safety parameters included routine laboratory, ECG, and clinical evaluations. PK was assessed by measurements of plasma anagrelide and its active metabolite using a validated HPLC-MS/MS method. Pharmacodynamic activity was assessed by daily platelet count determinations in the multiple dosing studies.Results: Single doses of anagrelide CR were well tolerated, and the only drug-related AE reported in 2 or more subjects was headache. In the b.i.d. dose-ranging studies, the frequency and severity of AEs were similar between anagrelide CR and placebo groups, with the exception of decreased platelet counts in subjects receiving anagrelide CR. All AEs were transient, mild or moderate in severity, and no severe or serious AEs were reported.Anagrelide CR demonstrated dose proportional PK characteristics. Following a single 0.5 mg dose in the fasted state, the mean time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2) were 2.0±1.5 hrs and 10.4±9.3 hrs (mean ± SD), respectively; in contrast, Tmax and t1/2 following IR was 1.0±0.9 hrs and 1.4±0.2 hrs, respectively. Cmax and total plasma exposure (AUC0-inf) with anagrelide CR were reduced to 26% and 59% of IR, respectively. However, steady-state PK following 6 daily 0.5 mg b.i.d. doses of anagrelide CR or IR showed similar AUC0-inf values, while Cmax with anagrelide CR remained nearly unchanged (29%). Plasma exposure was higher when anagrelide CR was administered in the fed state, as demonstrated by the ratio of least-squares mean values for Cmax and AUC0-t, which were increased by 100% and 60%, respectively.The platelet lowering effect of anagrelide CR was evident in the 2 multiple dose ranging studies. In a placebo-controlled study of 0.2 to 0.6 mg b.i.d. dosing for up to 21 days, a dose-related decrease in platelet counts was observed, and the 0.6 mg cohort was halted early due to excessive platelet reductions. Anagrelide CR did not have a relevant impact on platelet function as assessed by template bleeding time. [Display omitted] Conclusion: Anagrelide CR is a promising, novel formulation of anagrelide that exhibited the desired PK profile of a significantly reduced Cmax, while maintaining plasma exposure to induce platelet count reductions. The product was well tolerated with an AE profile that was not distinguishable from placebo. These data support the importance of an ongoing Phase 2 study in patients with MPN-related thrombocytosis, including ET. DisclosuresLaliberte:Galena Biopharma, Inc.: Employment, Equity Ownership. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties. Hamilton:Galena Biopharma, Inc.: Employment, Equity Ownership.

How safe are our paediatric emergency departments? Protocol for a national prospective cohort study

IntroductionAdverse events (AEs), defined as unintended patient harm related to healthcare provided rather than an underlying medical condition, represent a significant threat to patient safety and public health. The emergency...

Safety of vaccines used for routine immunization of U.S. children: a systematic review.

Concerns about vaccine safety have led some parents to decline recommended vaccination of their children, leading to the resurgence of diseases. Reassurance of vaccine safety remains critical for population health. This study systematically reviewed the literature on the safety of routine vaccines recommended for children in the United States. Data sources included PubMed, Advisory Committee on Immunization Practices statements, package inserts, existing reviews, manufacturer information packets, and the 2011 Institute of Medicine consensus report on vaccine safety. We augmented the Institute of Medicine report with more recent studies and increased the scope to include more vaccines. Only studies that used active surveillance and had a control mechanism were included. Formulations not used in the United States were excluded. Adverse events and patient and vaccine characteristics were abstracted. Adverse event collection and reporting was evaluated by using the McHarm scale. We were unable to pool results. Strength of evidence was rated as high, moderate, low, or insufficient. Of 20 478 titles identified, 67 were included. Strength of evidence was high for measles/mumps/rubella (MMR) vaccine and febrile seizures; the varicella vaccine was associated with complications in immunodeficient individuals. There is strong evidence that MMR vaccine is not associated with autism. There is moderate evidence that rotavirus vaccines are associated with intussusception. Limitations of the study include that the majority of studies did not investigate or identify risk factors for AEs; and the severity of AEs was inconsistently reported. We found evidence that some vaccines are associated with serious AEs; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide.

SAT0377 Long-Term Safety and Tolerability of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: A Phase 3, Randomized, Controlled Trial

BackgroundApremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 4 compared the efficacy/safety of APR with placebo (PBO) in patients (pts) with active PsA who...

SAT0408 Long-Term Safety and Tolerability of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Pooled Safety Analysis of Three Phase 3, Randomized, Controlled Trials

BackgroundApremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 1, 2, and 3 compared the efficacy and safety of APR with placebo (PBO) in patients...

Characterization of immune-related adverse events (irAEs) in a phase 3 trial of ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel mCRPC.

52 Background: Ipi enhances antitumor immunity by blocking cytotoxic T-lymphocyte antigen-4. We recently reported the results of CA184-043, a phase 3 study of post-docetaxel mCRPC with Ipi vs Pbo, following single-dose radiotherapy (RT). While the study did not meet the primary endpoint of improving overall survival (HR=0.85, p=0.053), Ipi demonstrated antitumor activity in other efficacy endpoints, including progression-free survival. The present analyses further characterize the safety profile of Ipi in this study. Methods: Safety was evaluated for all treated patients (pts; N=393 for Ipi 10 mg/kg, N=396 for Pbo) starting from first study dose and ending 70 days after the last study dose, including maintenance dosing. Results: Any grade (Gr) irAEs occurred in 63.4% and 21.7% of pts in the Ipi and Pbo arms, respectively. Most common Gr 3/4 irAEs were gastrointestinal (GI) (18.1%; mostly diarrhea and colitis). Gr 3/4 liver irAEs (4.6%) were mostly elevations in AST or ALT. Other Gr 3/4 irAEs were uncommon: endocrine (2.0%), skin (1.0%), and neurological (0.3%). Among Ipi-treated pts, there were no meaningful differences in the frequency or severity of GI AEs between those who received baseline pelvic RT and those who did not (n=141 vs 252; any Gr 77.3% vs 69.8%; Gr 3/4 25.5% vs 21.8%, respectively). There were 5 GI perforations in the Ipi arm (3 within 70 days of last dose [2 related, 1 unrelated], 2 after 70 days of last dose, both related), and none in the Pbo arm. Deaths due to study drug toxicity, as per the investigators, occurred in 4 pts (4, Ipi and 0, Pbo). Conclusions: In this study of Ipi in mCRPC, the most frequent severe irAEs were diarrhea and colitis. Most irAEs were manageable using established treatment algorithms. Clinical trial information: NCT00861614. [Table: see text]

Abstract P4-12-16: Safety profile and costs of related adverse events of trastuzumab emtansine compared to other regimens in the Canadian health care system

Abstract Background Trastuzumab Emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprised of the microtubule inhibitory cytotoxic agent DM1 and trastuzumab which, in addition to its antitumor properties, targets T-DM1 to HER2–overexpressing cells. The phase III EMILIA study compared the safety and efficacy of T-DM1 (n = 496) versus capecitabine plus lapatinib (CAP+LAP, n = 495) in patients with HER2-positive locally advanced or MBC previously treated with trastuzumab and a taxane. The phase II TDM4450g study compared the safety and efficacy of T-DM1 (n = 67) versus trastuzumab plus docetaxel (TRAZ+DOCE, n = 70) in patients with previously untreated MBC. These trials demonstrated statistically and clinically meaningful differences between T-DM1 and its comparators. In the EMILIA trial, the proportion of patients who developed grade ≥3 treatment-related AEs that were deemed related to treatment by the investigators was lower in the T-DM1 arm (30.6%) compared to the CAP+LAP arm (48.8%) and 5.9% of patients on T-DM1 discontinued treatment due to an AE, compared with 10.7% of patients on CAP+LAP. In the TDM4450g study, the proportion of patients who developed grade ≥3 AEs that were deemed related to treatment by the investigators was lower in the T-DM1 arm (33.3%) versus the TRAZ+DOCE arm (81.82%) and 7.2% of patients on T-DM1 discontinued treatment due to an AE, compared with 34.8% of patients on TRAZ+DOCE. The objective of this analysis was to estimate and compare the Canadian costs of managing the treatment-related AEs of T-DM1 as reported in the EMILIA and TDM4450g trials, from the perspective of Canadian public payers. Methods An Excel based spreadsheet model was utilized to estimate the costs of managing the treatment-related AEs. Clinical data (number and severity of AEs) were obtained from the two trials. Resource utilization and costing information were obtained from the literature, clinical experts, and Canadian standard costing sources (minimum and maximum costs were used). Costs were reported as 2012 CAD. The AEs that were considered for costing in this analysis were all treatment-related grade ≥3 AEs as well as grade 2 AEs that occurred in ≥5% of patients in both arms of either study. Results The management of treatment-related AEs by using T-DM1 resulted in cost savings ranging from $1,684 - $8,036 versus CAP+LAP as reported in the EMILIA trial and from $4,326 - $25,402 versus TRAZ+DOCE as per the TDM4450g trial (see Table 1). Table 1: Range of Costs of Managing Treatment-Related AEs as Reported in the EMILIA and TDM4450g trials EMILIATDM4450g T-DM1CAP + LAPT-DM1TRAZ+DOCECost per patient$1,376 - $2,463$3,060 - $10,499$798 - $2,215$5,124 - $27,617Cost savings$1,684 - $8,036$4,326 - $25,402 Conclusions This analysis demonstrated that utilizing T-DM1 for the management of HER2-positive MBC results in significant cost savings of related AEs management due to the improved safety profile compared to CAP+LAP and TRAZ+DOCE. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-16.

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Introduction: In addition to traditional incident reporting, the MMC can augment the ability to surface AEs. Our objective is to determine the types, severity and preventability of AEs uncovered among patients discussed in a tertiary hospital PICU MMC over a specific time period and compare these with AEs reported for the same cohort through the hospital incident reporting system, the Patient Safety Network (PSN). Methods: Two independent reviewers conducted a systematic retrospective record review of patients discussed in the MMC over 8 months (Nov2011-June2012). AEs were identified and categorized as to type, severity and preventability. Discrepancies were resolved by 2nd-tier review with a PICU attending and nurse. Comparison with AEs reported via the PSN for the same cohort was performed. Descriptive statistical analysis was done, calculating proportions for categorical variables. Results: 48 cases were reviewed with 212 total AEs identified from either the MMC or PSN (4.4 AEs/patient, 29 AEs/100 patient-days). 169/212(79.7%) AEs were identified via the MMC, of which 85/169(40.1%) were specified in the MMC agenda, while 84/169(49.7%) were uncovered via chart review. 52/212(24.5%) AEs were identified via the PSN. Only 9/212(4.2%) AEs were identified through both the MMC and PSN. The most common types of AEs were similar for each group - medication errors (MMC 31.9%, PSN 51.9%), device-related events (MMC 16.0%, PSN 17.3%), and communication issues (MMC 14.2%, PSN 26.9%). MMC AEs were more severe with 60.6% requiring prolonged hospitalization/life-sustaining therapy or contributing to permanent harm/death. PSN AEs were less severe with 61.5% causing no harm and 28.9% causing only temporary harm. MMC AEs ranged in preventability, with 30% certainly preventable and 36.3% likely not preventable. PSN AEs were 98.1% preventable with no non-preventable cases reported. Conclusions: The PICU MMC with targeted chart review is a useful adjunct for AE surveillance in addition to traditional incident reporting. Overlap between the two is minimal, with the MMC providing data on unique, more severe, yet still preventable AEs. Combining data from the two systems results in more accurate AE surveillance.

Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease

SelG1 is a humanized anti-P-selectin monoclonal antibody being developed as a treatment for sickle cell disease (SCD). Extensive data have been published that suggest a pivotal role for P-selectin in the pathophysiology of SCD. Much of this work has been conducted in mice engineered to express human β hemoglobin S (sickle cell hemoglobin). These mice have a remarkably similar disease pathology to that observed in human SCD including vasoocclusion. Using these mice, investigators have demonstrated P-selectin interactions between the endothelium and sickled red blood cells, leukocytes and platelets. Additional studies have demonstrated direct P-selectin mediated binding of leukocytes with platelets. All of these cell-cell interactions have been implicated in SCD vasoocclusion. Further, blockade or genetic absence of P-selectin decreases or eliminates these cell-cell interactions and vasoocclusion.A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SelG1. This was a single-center, double-blind, placebo-controlled, first-in-human, ascending single dose and multiple dose study of intravenous (IV)-administered SelG1 in healthy adult male and female subjects.There were 5 dosing cohorts in the study (A through E):Ascending single dose cohorts:Cohort A:0.2 mg/kg IV dose of SelG1 (n=3) or placebo (n=1);Cohort B:0.5 mg/kg IV dose of SelG1 (n=3) or placebo (n=1);Cohort C:1.0 mg/kg IV dose of SelG1 (n=3) or placebo (n=1);Cohort D:5.0 mg/kg IV dose of SelG1 (n=6) or placebo (n=2).Multi-dose cohort:Cohort E:two 8.0 mg/kg IV doses of SelG1 (n=5) or placebo (n=2); the doses were given 2 weeks apart.In Cohorts A through D, SelG1 was slowly eliminated (mean t1/2 = 75.6 to 500 hours). Mean t1/2 values increased in a dose dependent manner. The exposure to SelG1 (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than proportional manner over the dose range. In Cohort E, SelG1 was slowly eliminated (mean t1/2 = 363 hours for the second infusion). The mean Cmax and AUC0-336values were 1.6- and 1.7-fold higher, respectively, after the second infusion relative to the first infusion. The PD data demonstrate that P-selectin function was completely blocked for a minimum of 28 days in Cohort D and at least 56 days in Cohort E.Twenty-six of the 27 subjects who received study drug completed the study, with 1 placebo subject in Cohort D withdrawing himself from the study due to the required travel commitment. There were no deaths, serious adverse events, or severe AEs reported in any subject. There were no increases in the number or severity of AEs with increasing dosages or with multi-dose administration. The percentage of subjects experiencing an AE was similar between the SelG1-treated subjects and the placebo-treated subjects; in Cohorts A-D, 66.7% of SelG1-treated subjects and 60.0% of placebo subjects reported at least 1 AE, while in Cohort E, 60.0% of SelG1-treated subjects and 50.0% of placebo-treated subjects reported at least 1 AE. Only 1 AE occurred in more than 1 subject; vessel puncture site hematoma occurred in 1 subject of Cohort A, 1 subject of Cohort C, and 2 subjects of Cohort E. All other AEs occurred in only 1 subject and were mild to moderate in severity. No AEs in any subject were deemed “related” to study drug.No clinically significant findings were noted from vital sign measurements, physical examinations, or 12-lead ECGs for this study. No biochemistry, hematology, or other laboratory data were reported as clinically significant or were reported as AEs; there were no trends that indicated increases or decreases in mean or median values over time, and there were no dose-dependent increases or decreases in mean or median values. There were no demonstrable changes in coagulation parameters or increased bleeding tendencies. No specific antibody response to SelG1 occurred in any of the subjects.In summary, the administration of SelG1 was well tolerated in this group of healthy male and female subjects. A Phase II clinical study to evaluate the clinical efficacy of SelG1 in SCD patients is currently underway. Disclosures:Stocker:Selexys Pharmaceuticals: Employment, Equity Ownership. Mandarino:Selexys Pharmaceuticals: CRO Other. Kawar:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Alvarez:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Falconer:Selexys Pharmaceuticals: Employment, Equity Ownership. Rollins:Selexys Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Rother:Selexys Pharmaceuticals: Employment, Equity Ownership.

Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia

Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of Phosphoinositide-3-Kinase-δ,γ, In Patients With Chronic Lymphocytic Leukemia

Exposure-Response Analysis For Pacritinib (SB1518), a Novel Oral JAK2/FLT3 Inhibitor, In Patients With Myelofibrosis

BackgroundPacritinib (SB1518) is a novel oral JAK2-FLT3 inhibitor. To date, once-daily (QD) dosing of pacritinib has been evaluated in two pharmacokinetic studies in healthy volunteers (n = 42) and in two phase 1/2 clinical trials in patients with advanced myeloid malignancies (n = 129). Due to less-than-proportional increase in systemic exposure with dose, administration of QD doses higher than 400 mg does not appreciably increase systemic exposure of pacritinib. Hence, the twice-daily (BID) regimen was conceived as an alternate dosing regimen to achieve higher systemic pacritinib exposure and potentially enhance clinical response of pacritinib. AimsCharacterize exposure-response relationship of pacritinib in early stage clinical development. MethodsTwo pharmacokinetic (PK) studies were conducted in healthy volunteers to assess the inter- and intra-individual PK variability and the effect of food on the PK of pacritinib. Two Phase 1/2 trials were also undertaken to characterize the population pharmacokinetics, safety, and efficacy of pacritinib in patients with advanced myeloid malignancies following oral administration of 100-600 mg QD. Safety (i.e., incidence and severity of key AEs including GI, thrombocytopenia and anemia) and efficacy (i.e., spleen size reduction) of pacritinib were assessed in patients. Based on the safety, tolerability and anti-tumor activity observed in the completed Phase 1/2 trials, the 400 mg QD regimen of pacritinib was selected for further clinical development in MF.A total of 65 patients received 400 mg QD regimen in Phase 2 trials for pacritinib. To construct the exposure-response relationship following QD dosing of pacritinib, patients with pharmacokinetic exposure data from completed Phase 1/2 trials (n = 129) were divided into quartiles [Q1-Q4] based on their model predicted area under the curve at steady-state (AUCss). For each exposure quartile, the mean reduction in spleen size was determined. In addition, exposure-response analysis on key safety parameters was similarly performed by comparing AE distributions across exposure quartiles. The key PK parameters were simulated for the 200 mg BID regimen and distribution of patients that fell into QD regimen-defined exposure quartiles was determined. ResultsPK simulation data indicated that administration of the 200 mg BID regimen is likely to result in a mean systemic exposure that is 41% higher relative to that of the 400 mg QD regimen. This is thought to be due to higher drug accumulation and reduced effect of saturable absorption processes on oral pacritinib bioavailability with the BID regimen. Evaluation of the efficacy time-course by exposure quartile revealed that patients in the highest quartile (Q4) exhibited the highest maximal response as well as the most durable clinical response over time relative to those that fell in the lower exposure quartiles (Figure 1). Whereas approximately 25% of patients from the completed Phase 1/2 trials fell in Q4 exposure zone with the 400 mg QD regimen, approximately 48% of patients on the 200 mg BID regimen are projected to fall in this exposure zone or higher. Moreover, assessment of key AEs including GI, anemia, and thrombocytopenia AEs by the exposure quartile, showed that these AEs were not worse with higher systemic exposure of pacritinib. [Display omitted] ConclusionsTogether, the exposure-safety and exposure-efficacy analyses support the potential utility of the 200 mg BID regimen of pacritinib in addition to the 400 mg QD regimen for the clinical development of pacritinib for myelofibrosis as well as other indications such as FLT3 mutated AML. The higher proportion of patients expected to achieve the Q4 exposure levels with the 200 mg BID regimen is predicted to correlate with higher splenic response rates relative to the 400 mg QD regimen. There was no significant exposure-response relationship on key AEs including GI, anemia and thrombocytopenia AEs. The lower local concentration of pacritinib in the GI tract with BID regimen may potentially decrease the incidence of GI adverse events such as diarrhea. Disclosures:Al-Fayoumi:Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc.: Employment. Li:Cell Therapeutics, Inc: Consultancy. Dean:Cell Therapeutics, Inc: Employment.

Abstract A120: A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors.

Abstract Background: CC-486, an oral formulation of 5-azacitidine, induces global genomic hypomethylation and clinical responses in MDS patients at doses of 200 mg and 300 mg/day for 14 or 21/28 days with acceptable safety. This non-randomized, multi-center Phase Ib study was designed to determine whether CC-486 can be delivered safely as priming for carboplatin or NAB-Paclitaxel (ABI-007) in patients with solid tumors. Methods: In Part 1 of this study, patients with refractory solid tumors were assigned to Arm A: CC-486 days 1 - 14 with carboplatin AUC 4 on day 8 of a 21 day cycle (n = 13) or Arm B: CC-486 days 1 - 14 with ABI-007 100 mg/m2 given weekly starting on Day 8 of Cycle 1 (n = 24). 200 mg and 300 mg dose levels (DLs) of CC-486 were evaluated in cohorts of 6 to identify a recommended Part 2 dose (RP2D). Results: On Arm A, 200 mg and 300 mg doses of CC-486 were tolerated. There was one DLT (Grade 3 pericardial effusion) at the 300 mg DL. Other related treatment-emergent adverse events (TEAEs) included anemia (53.8%) and neutropenia (46.3%). On Arm B, there were 2 DLTs of neutropenia at the 200 mg DL. The protocol was amended to give ABI-007 on days 8 and 15/21. No DLTs were encountered on 200 mg of CC-486 with intermittent ABI-007. At 300 mg, the MTD was exceeded with 2 DLTs of neutropenia (cholangiocarcinoma, pancreatic). Other common TEAEs in Arm B included nausea/vomiting (45.8%) and peripheral neuropathy (50%). Evidence of activity seen at both DLs included hypomethylation in PBMCs, 3 PRs in Arm B and 5 subjects with stable disease (&amp;gt; 4 mos) in Arm A. CC-486 plasma exposure showed high interpatient variability but was higher at 300 mg than 200 mg. Incidence and severity of AEs did not differ significantly between the 2 DLs. 300 mg was selected as the RP2D in combination with carboplatin and 200 mg in combination with ABI-007. Conclusion: CC-486 dosed 14/21 days is tolerated as a priming agent with carboplatin and ABI-007. Both combinations show evidence of clinical activity. Expansion cohorts at the RP2D of Arm A (relapsed/refractory bladder or ovarian carcinoma) and Arm B (relapsed/refractory NSCLC or pancreatic carcinoma) are enrolling to further characterize safety, PK/PD and anti-tumor activity. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A120. Citation Format: Patricia LoRusso, Drew Rasco, Johanna Bendell, Jasgit Sachdev, Ramesh Ramanathan, Glenn Weiss, Pamela Munster, William J. Edenfield, Kejian Liu, Anne Blackwood-Chirchir, Jorge DiMartino, Jorge DiMartino, Daniel D. Von Hoff. A Phase Ib study of CC-486 (Oral Azacitidine) as a priming agent for carboplatin or NAB-paclitaxel in subjects with relapsed and refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A120.