Reasons For Treatment Discontinuation Research Articles

P464 Recurrence of ulcerative colitis during pregnancy in patients who became pregnant during remission

Background: Ulcerative Colitis (UC) has a marked influence on the lifestyle of patients, and its effects on pregnancy and childbirth can especially become a problem for women in their child-bearing years. Various studies have suggested that it is desirable for pregnant women with UC to give birth while remaining in a state of remission. The present study evaluated pregnant women with UC attending our hospital who became pregnant during remission, in order to examine the factors that contributed to recurrence of UC during pregnancy. Methods: We investigated 40 pregnant patients in remission (44 cases) attending our hospital between January 2008 and June 2016 who had remained in remission for one year prior to pregnancy. After becoming pregnant while in remission, patients who stayed remission until delivery were classified into the ongoing remission group (35 cases) and patients with recurrence during pregnancy were classified into the recurrence group (9 cases). Items examined: Clinical characteristics, the CAI and whether or not patients continued treatment during pregnancy were examined and compared between the two groups. The reasons for discontinuation of treatment were also investigated. Results: There were significant differences between the two groups with respect to the age of becoming pregnant, the CAI in the first, second, third trimester, and whether oral treatment was continued (continuation of treatment [yes:no] 30:5 in the ongoing remission group vs. 5:4 in the recurrence group). Regarding the discontinuation of oral treatment, two patients in the ongoing remission group and one patient in the recurrence group discontinued it on their own judgment, while two patients in the recurrence group discontinued it due to hyperemesis. Conclusions: The present study revealed that factors influencing the recurrence of UC during pregnancy were the age of becoming pregnant and the continuation of oral treatment. As expected, discontinuing oral treatment was a factor that contributed to recurrence. However, the reasons for discontinuing treatment during pregnancy differed from those for non-pregnant women. Some patients discontinued treatment on their own judgment because they were concerned about adverse effects on the fetus, while others had difficulty with continuing treatment due to hyperemesis. With regard to the effects of medications on the fetus, medical staff should provide an explanation about the safety of treatment and should be aware that patients may have various concerns about drug therapy. If patients have difficulty continuing oral treatment due to severe hyperemesis, administration of local therapy should be considered. During pregnancy, it is important to continue treatment for UC so that patients can give birth while remaining in remission.

Viral Suppression and Discontinuation Rates have Improved in HIV Patients with Modern Antiretroviral Therapies

Objective: Rates and determinants of first-line antiretroviral (ARV) discontinuation or change in prescribed regimen were assessed between old (pre-2006) and modern (post-2006) era stratified by dosing frequency [(once daily (QD) versus twice or more daily (BID+)]. Methods: A single-center retrospective cohort study was conducted. All adult HIV patients initiating ARVs from January 1995-November 2015 were included. Patients were stratified by old- or modern-era and by dosing frequency. The primary outcome was rate of ARV therapy discontinuation or change in initial regimen. The secondary outcome was reason for discontinuation. Results: 1,127 patients were included from the old (n=621) and modern era (n=506). Modern-era patients were more likely to receive QD regimens (p<0.001) and had increased viral suppression at the last recorded testing than oldera patients (70.9% vs. 43.2%, p<0.001). Modern-era and QD patients had better adherence and treatment duration. Patients on integrase inhibitor (INSTI)- and NNRTI-based therapy had longer treatment durations and better ARV adherence. Risk factors for treatment switch or discontinuation included old-era therapy, IDU and PI+NRTI treatment. Older ages and immigrants were less likely to discontinue therapy. Common reasons for treatment discontinuation included changing treatments to improve regimen profile, gastrointestinal side effects, and neuropsychological issues. Conclusion: In patients initiating first-line ARV, risk of discontinuation or regimen changes has diminished in the modern-era with QD, INSTI- or NNRTI-based regimens. More attention to high risk patients including IDU is advised in attempts to improve outcomes. These findings provide ‘real world’ support for current clinical practice guidelines.

Reasons for Discontinuation and Adverse Effects of TNFα Inhibitors in a Cohort of Patients With Rheumatoid Arthritis and Ankylosing Spondylitis.

The introduction of anti-tumor necrosis factor α (anti-TNFα) drugs has improved the clinical outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, these drugs may cause adverse effects that motivate a change in or discontinuation of the treatment. To evaluate the causes of discontinuation or changes in the dosage regimen in a cohort of patients with RA and AS treated with infliximab, adalimumab, etanercept, and golimumab under clinical practice conditions. This was a retrospective observational study that included patients with RA or AS treated with anti-TNFα drugs between 2008 and 2013. Changes in the dosage regimen, reasons for treatment discontinuation, and adverse effects were recorded and analyzed. Time to discontinuation was estimated using Kaplan-Meier survival analysis. A total of 123 patients with RA and 93 patients with AS were treated with anti-TNFα therapy. During the study, 55.3% of RA patients and 41.7% of AS patients had stopped the treatment. The most frequent changes were modifications in the dosing, and the most frequent adverse effects were reactions after the infusion or injection (53.8% and 66.7% in RA and AS, respectively). Drug survival of etanercept in RA (67.9%) is greater than for adalimumab and infliximab, whereas drug survival of infliximab in AS (70.0%) is greater than for etanercept and adalimumab at 5 years, although there were no significant differences ( P = 0.098 in RA and 0.194 in AS). The main cause of discontinuation of anti-TNFα is therapeutic failure in both diseases. Etanercept and infliximab have the best survival rates in RA and AS, respectively.

A Phase 1b Study of Vadastuximab Talirine As Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (AML)

A Phase 1b Study of Vadastuximab Talirine As Maintenance and in Combination with Standard Consolidation for Patients with Acute Myeloid Leukemia (AML)

Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial

Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial

Real-World Treatment Patterns in Relapsed or Refractory Multiple Myeloma: Evidence from a Cohort Review in the United Kingdom

INTRODUCTION: Despite advancements in induction and maintenance therapies leading to improved response rates and overall survival (OS), virtually all patients with multiple myeloma (MM) eventually relapse. Improvement in outcomes in relapsed and/or refractory multiple myeloma (RRMM) remains an area of unmet need, yet there is a shortage of data describing typical treatment patterns in these patients in real-world practice settings. Such data may help inform future health technology assessments and other regulatory evaluations of current and new therapies in RRMM. To help address this information gap, we analyzed retrospective data from a cohort of RRMM patients in the United Kingdom (UK).METHODS: A retrospective medical record review was conducted in a cohort (n = 216) of patients with RRMM in the UK. Patients were selected (based on randomly generated first letter of last name) from the caseloads of 41 hematology/oncology providers across the UK. Specific inclusion criteria were: ≥18 years of age at initial MM diagnosis; first determined to have RRMM between January 1, 2009 and December 31, 2011, where RRMM was defined by (1) receipt of a first-line (induction) treatment regimen of chemotherapy with or without stem cell transplant (SCT) and with or without post-induction/SCT maintenance therapy and (2) disease progression while on or at any time after completion of first-line therapy. Patients were retrospectively assessed on second- and third-line treatment regimens received, treatment duration, and reasons for treatment discontinuation from date of first relapse or progression (study index date). All analyses were descriptive and exploratory in nature.RESULTS: Demographic and clinical characteristics of the study sample are presented in Table 1. Mean (SD) age at study index (first relapse, or RRMM diagnosis) was 65.6 (8.7) years, with approximately half of patients (53%) having advanced age (≥65 years). The study sample was 62.5% male and more than two-thirds of patients (69%) were still alive at the time of the medical record review. Among the 216 patients studied, 208 (97%) received ≥1 additional line of systemic chemotherapy after first relapse (Table 2); 94 patients (43%) received ≥2 additional lines of therapy (i.e., at least second- and third-line therapy) during the observation period. The most common second-line regimen was bortezomib + dexamethasone with or without other agents (66% of second-line initiators), followed by lenalidomide + dexamethasone with or without other agents (20%). Median duration of second-line treatment was 6 cycles over a median of 5.4 months. Among the 98% of patients who discontinued second-line treatment, a majority (62%) stopped therapy due to reaching complete response with no additional benefit expected; 33 patients (16%) discontinued second-line treatment due to disease progression and 8% discontinued due to toxicities. Lenalidomide + dexamethasone with or without other agents was the predominant third-line regimen (67% of third-line initiators); bortezomib + dexamethasone with or without other agents was the next most common third-line regimen (14%). Among the 94 patients receiving third-line treatment, median duration was 6 cycles over a median of 5.7 months. The leading reason for third-line discontinuation was disease progression (48%); 30% of patients discontinued because they reached complete response with no anticipated additional benefit, and 20% discontinued because of loss or lack of response to therapy.CONCLUSIONS: In the RRMM cohort reviewed here, bortezomib-containing regimens were the predominant second-line therapy and lenalidomide + dexamethasone was the most common third-line regimen. The most common reasons for discontinuation of RRMM treatments were disease progression and physician-judged achievement of complete response with no additional benefit expected. While the most common reason for therapy discontinuation in second-line treatment was reaching complete response with no additional benefit expected, in third-line therapy it was disease progression. With growing evidence in the RRMM literature that treatment to progression may be superior to a fixed duration of therapy, as well as evidence of premature discontinuation being associated with inferior outcomes, the relatively short second-line duration reported here (<6 months) further highlights a potential unmet need in this disease area. [Display omitted] [Display omitted] DisclosuresLin:Takeda: Employment. Davis:Takeda: Research Funding. Kaye:Takeda: Research Funding. Luptakova:Takeda Oncology: Employment. Nagar:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

Phase 1/2 Study of NS-018, an Oral JAK2 Inhibitor, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF)

Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2).In the previously-reported Phase 1 portion, patients with myelofibrosis (MF) who received NS-018 achieved steady-state plasma levels above the IC50 for JAK2 at all doses (75mg QD - 400 mg BID). 300 mg QD was chosen as the recommended dose (RD) for Phase 2 portion of the study.OBJECTIVE: The purpose of this study was to determine the safety, tolerability and efficacy of orally-administered NS-018 in patients with PMF, post-PV MF, or post-ET MF.METHODS: This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, post-PV MF, or post-ET MF. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis was evaluated by biopsy, according to standard practice at the sites. Changes from baseline in grade of BM fibrosis were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study is complete. In the ongoing Phase 2 portion, spleen size is being assessed by palpation and by centrally-read MRI, and quality of life evaluated by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).RESULTS: 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID) in Phase 1. Patient characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF; median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor. The data cutoff for this analysis was June 30, 2016 (median follow-up time of 279.5 [range 5-1806] days from screening), at which time 10 patients remained on treatment. The median number of treatment cycles was 10 (1-65). Reasons for treatment discontinuation were disease progression (PD, n = 13), adverse events (AE, n = 8), physician consideration (n = 6), patient request (n = 4), and protocol non-compliance (n = 1).The 300 mg QD dose was selected as the phase 2 recommended dose (P2RD) in terms of tolerability and efficacy.For the 48 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including patients with priorJAK2 inhibitor treatment. Among 36 splenic-evaluable patients with baseline splenomegaly > 5 cm and treatment for > 1 cycle, 20 (56%) showed > 50% reduction in spleen size (confirmed for > 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement for > 8 weeks, 4 with hemoglobin CI, and 1 with platelet CI.Twenty-nine patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Patient characteristics: 13 PMF, 12 post-PV MF, 4 post-ET MF; median age (range) 67 yrs (48-86). The reason for discontinuation of prior JAK2 inhibitor treatment: AEs (62%) and PD (38%). To date, the median number of treatment cycles is 6 (1-20). The majority of grade 3/4 AEs were hematologic and the most common hematologic toxicities were anemia (21%) and thrombocytopenia (17%). Non-hematologic AEs were mostly grade 1/2, and the other AEs shown in > 10% of patients was nausea (14%). Updated Phase 2 efficacy and safety data will be presented at the meeting.CONCLUSIONS: The RP2D dose of NS-018 was 300 mg QD. This dose provided a durable dosing schedule, an acceptable safety profile, splenic size reductions and clinical symptom improvement. Phase 2 is ongoing and includes patients previously treated with a different JAK2 inhibitor. DisclosuresTalpaz:Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Ritchie:Pfizer: Honoraria; Arian: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Honoraria; Incyte: Speakers Bureau. Odenike:Suneisis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Geron: Research Funding; Spectrum: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Jamieson:GlaxoSmithKline: Research Funding; CTI Biopharma: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte: Membership on an entity’s Board of Directors or advisory committees. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy.

Ruxolitinib Remains Effective in Myelofibrosis after the Necessary Dose Reductions: Real-Life Data from a Multi-Center Observational Study

BACKGROUND - AIMRuxolitinib can be effectively used for the treatment of splenomegaly or constitutional symptoms in patients with myelofibrosis. Its main side effect is myelosuppression which leads to dose modifications. Real-life data from the use of ruxolitinib in every-day practice were analysed to assess efficacy, safety, dose modifications or reasons for treatment discontinuation.PATIENTS - METHODSA retrospective observational study was conducted in patients with primary or secondary myelofibrosis, treated in 13 sites. Statistical analysis was done with non-parametric tests using SPSSv17 software. A total of 116 patients, diagnosed between 1993 and 2016 were included in the analysis. The male:female ratio was 2:1, median age at diagnosis was 63 years (range 27 to 82) and median duration of ruxolitinib therapy was 15.3 months. The study expands over 664.2 patient-years of observation, including 176.7 patient-years while on ruxolitinib.RESULTSThe diagnosis, revisited according to the WHO 2008 criteria, was primary myelofibrosis in 56%, post-essential thrombocythemia myelofibrosis in 22% and post-polycythemia vera myelofibrosis in 22% of patients. At the beginning of ruxolitinib treatment, the international prognostic scoring system (IPSS) risk category was low (6.2%), intermediate-1 (26.5%), intermediate-2 (39.8%), high (23%). Constitutional symptoms were present in 48% of patients at diagnosis and in 73% of them at the onset of ruxolitinib therapy. Median spleen size was 5cm (centimeters) below costal margin at diagnosis and 12cm at onset of ruxolitinib.Ruxolitinib starting dose was 5mg (16%), 10mg (18%), 15mg (31%), 20mg (35%) twice daily (BID), while the final dose was <5mg (5%), 10mg (25%), 15mg (23%), 20mg (23%) and 25mg BID (2%). Starting dose was modified in 77% of patients; the median time to first modification was 3.7 months, while 90% of the modifications had occurred within 14.8 months from onset of therapy.Ruxolitinib was permanently discontinued in 29% of patients, due to progressive disease in 6.4%, transformation to acute leukemia in 2.7% and death in 8.2% of patients. Side effects (including anemia, thrombocytopenia, investigator decision, patient preference) was the reason for treatment discontinuation in 5.5% and lack of response in 2.7% of patients.Efficacy (reduction in constitutional symptoms and spleen size) and hematological toxicity (values of platelets, white blood cell counts, hemoglobin) of ruxolitinib was assessed after 1, 6 and 12 months of treatment (table 1). Thrombocytopenia (PLT<130 x 109/L) was present in 26% of patients at the beginning of treatment, in 46% at 6th month and in 42% at the 12th month, while grade III and IV thrombocytopenia (PLT<50 x 109/L) was present in 4%, 11% and 5% respectively.Constitutional symptoms after 1 month were significantly less frequent with increased doses of ruxolitinib, whereas there was no statistically significant difference among the various doses at 6 and 12 months of treatment. Platelet counts were significantly lower in patients taking 5mg BID at 6 months of treatment (p=0.02), and they also tended to be lower in 1 and 12 months (p=0.07, p=0.08 respectively). White blood cells and hemoglobin values did not differ significantly among the various doses of ruxolitinib in either time point.Table 1. Results at 1, 6, 12 months of treatment, according to different doses.CONCLUSIONSRuxolitinib can effectively improve splenomegaly and alleviate constitutional symptoms in patients with myelofibrosis. The symptoms are relieved slower with the low dosage, whereas the main side effect is thrombocytopenia. It can however be maintained within safety limits (grade < 3), with dose modifications without hampering efficacy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY.15

Background: The outcome of peripheral T-cell lymphomas (PTCLs) remains poor and improved therapies are needed. Retrospective data suggest that integration of anthracyclines in the primary therapy may not impact outcome, providing the rationale to explore alternative regimens. Histone deacetylase inhibitors appear to have a class effect in PTCLs andromidepsin monotherapy demonstrates activity in a proportion of patients with relapsed/refractory PTCLs and can induce durable remissions. Gemcitabine is reported to be a highly active agent in PTCL, and the GDP (gemcitabine, dexamethasone, cisplatin) regimen has become a standard chemotherapy backbone for relapsed aggressive lymphomas (Crump, JCO 2014). We investigated the feasibility, safety and efficacy of GDP combined with romidepsin in a phase I dose escalation trial. Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were also included.Methods: Patients with relapsed/refractory PTCL or DLBCL, PS 0-2, with measurable disease and who had received one or two prior lines of systemic therapy, were treated with standard doses of GDP (gemcitabine, 1000 mg/m2 d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 d1) every 21 days, plus escalating doses of romidepsin (6, 8, 10 and 12 mg/m2) on days 1 and 8 to a maximum of 6 cycles in a standard 3+3 design. After the first 4 patients were enrolled, based on the observed pattern of thrombocytopenia, the treatment schedule was modified so that gemcitabine and romidepsin were given on days 1 and 15 and cycles extended to every 28 days. Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles and defined as requiring platelet transfusion for bleeding, grade 3 hematological toxicity lasting >10 days, grade 4 hematological toxicity lasting >7 days, febrile neutropenia, or grade 3-4 non-hematological toxicity attributable to romidepsin. Responses were as per Cheson, JCO 2007 excluding PET scans.Results: 20 eligible patients (PTCL n=10; DLBCL n=10) were enrolled between 10/2013 and 01/2016 and treated with GDP plus romidepsin. The main PTCL subtype was PTCL, not otherwise specified (50%). Median age was 65 years (24-74); 9 were female; ECOG performance status was 0 (n=2), 1 (n=13), or 2 (n=5). Number of prior therapies was 1 (n=17) or 2 (n=3). 17 (85%) patients received >90% of the planned dose each cycle. The median number of cycles was 2 (range, 1-6); one patient is still on therapy. The reasons for treatment discontinuation were lymphoma progression (n=10), toxicity (n=2), proceeding to autologous stem cell transplant (ASCT, n=3), intercurrent illness (n=1), or completion of 6 cycles (n=3).On the 21-day schedule at 6 mg/m2 romidepsin, there were 3 DLTs among four patients (2 with grade 3-4 thrombocytopenia, 1 venous thromboembolic event). On the 28-day schedule, there were no DLTs observed in the three patients treated at each of the 6, 8 or 10 mg/m2 dose levels. At 12 mg/m2 there were 4 observed grade 3 DLTs among six evaluable patients (hypotension, acute kidney injury, anorexia, thrombocytopenia >10 days). Notable toxicities during any cycle were: febrile neutropenia (n=2); grade 3-4 thrombocytopenia (n=9); grade 3-4 neutropenia (n=4); and grade 3-4 anemia (n=4); grade 2 atrial fibrillation (n=2); grade 2 QTc prolongation (n=1); grade 1 sinus tachycardia (n=1); grade 2-3 infections (n=16); grade 1-3 cutaneous toxicity (n=9); grade 1-3 thromboembolic events (n=2); TIA (n=2) or stroke (n=1). One patient died after cycle 1 due to sepsis. 7 other patients have died of progressive lymphoma.The overall response rate was 9/20 (45%), all were partial remissions (PR), 3 had stable disease (SD), 4 had progressive disease (PD), and 4 were not objectively evaluable. Of the responders, 5 had PTCL and 4 had DLBCL. Four patients went on to ASCT. With a median follow-up of 5.8 months, the median duration of response was 2.8 months and median PFS is 2.2 months. For all patients, the 1 year PFS was 6% and 1 year OS was 43%Discussion: Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 given on a day 1, 15 every 28 days schedule. Thrombocytopenia prohibits this combination on a 21-day schedule. Toxicity is otherwise acceptable and as expected. Further study at the recommended dose and schedule would be required to properly define the activity of this regimen in PTCLs and DLBCL. DisclosuresReiman:Celgene: Honoraria, Research Funding. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

A systematic review of adverse event reporting in companion animal clinical trials evaluating cancer treatment.

OBJECTIVE To evaluate methods used to ascertain, define, and report adverse events (AEs) in companion animal clinical trials involving cancer treatment. DESIGN Systematic review. SAMPLE English-language articles describing prospective clinical trials involving dogs and cats with naturally occurring cancer published in peer-reviewed journals between 2008 and 2014. PROCEDURES Reports were identified via MEDLINE and CAB database searches combined with a hand-searching strategy. General article characteristics were abstracted and summarized. Data for AE reporting were collected with a 14-item checklist adapted from the 2004 CONSORT extension for reporting harms. Study characteristics associated with the AE reporting checklist score were identified by means of linear regression analysis. RESULTS 168 articles with data for 6,132 animals were included. Standardized terminology was significantly more likely to be used to describe AEs for trials that included chemotherapy (92/115 [80.0%]) than for trials that did not (16/53 [30.2%]). Median AE reporting checklist score was 5 out of 14 (range, 0 to 12). Poorly reported items included methods and time frame of AE ascertainment, AE data analysis, and reasons for treatment discontinuation and death. Trials with industry funding, a single-arm design, and treatment with chemotherapy were associated with a significantly higher quality of AE reporting. CONCLUSIONS AND CLINICAL RELEVANCE Reporting of adverse events in veterinary clinical trials evaluating cancer treatment was selective and heterogeneous. Harms associated with cancer treatments could be underestimated because of suboptimal collection and reporting of AE data. Findings supported the adoption of a higher standard for AE surveillance and reporting in veterinary patients.

Treatment Selection Choices Should Not Be Based on Benefits or Costs Alone: A Head-to-Head Randomized Controlled Trial of Antiviral Drugs for Hepatitis C.

BackgroundClinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options.MethodsWe randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved.ResultsHigher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs. $57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial.ConclusionTelaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631).

Clinical Impact of the Number of Treatment Cycles in First-Line Docetaxel for Patients With Metastatic Castration-Resistant Prostate Cancer

BackgroundWe investigated the impact of the number of docetaxel cycles administered in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line chemotherapy. Patients and MethodsCharts from 421 consecutive patients who initiated standard treatment with docetaxel-based chemotherapy (75 mg/m2 every 3 weeks) between 2007 and 2013 were reviewed. Patients who received < 6 cycles of docetaxel were excluded from the analysis. Remaining patients were divided into 2 groups on the basis of whether or not ≥ 9 cycles of docetaxel were administered (n = 108 and 184, respectively). Reasons for treatment discontinuation and postdocetaxel treatments were registered. Prostate-specific antigen (PSA) responses were defined as a confirmed ≥ 50% decrease in baseline PSA levels. Overall survival (OS) was calculated from start of therapy using the Kaplan–Meier method. Cox proportional hazards were calculated to estimate the effect of clinical variables on OS. ResultsOS was longer in patients treated with ≥ 9 cycles of docetaxel (21.9 months vs. 17.2 months; P < .0001, log rank). Survival also favored patients treated with ≥ 9 cycles of docetaxel when only patients ending docetaxel because of toxicity or treatment conclusion (22.3 vs. 19.4 months; P = .048, log rank) or patients who achieved a PSA response (22.3 vs. 18.7 months; P = .012, log rank) were evaluated. mCRPC-related prognostic factors and patients who received ≥ 1 subsequent line of therapy post-docetaxel were well balanced. ConclusionOn the basis of our retrospective findings, a superior OS was found in patients treated with ≥ 9 cycles of docetaxel when adjusting for known prognostic factors. Dose reductions might increase the number of docetaxel cycles administered.

Coronary angiography after cardiac arrest: Rationale and design of the COACT trial

Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography (CAG) and percutaneous coronary intervention (PCI) after restoration of spontaneous circulation following cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains debated. We hypothesize that immediate CAG and PCI, if indicated, will improve 90-day survival in post-cardiac arrest patients without signs of STEMI. In a prospective, multicenter, randomized controlled clinical trial, 552 post-cardiac arrest patients with restoration of spontaneous circulation and without signs of STEMI will be randomized in a 1:1 fashion to immediate CAG and PCI (within 2 hours) versus initial deferral with CAG and PCI after neurological recovery. The primary end point of the study is 90-day survival. The secondary end points will include 90-day survival with good cerebral performance or minor/moderate disability, myocardial injury, duration of inotropic support, occurrence of acute kidney injury, need for renal replacement therapy, time to targeted temperature control, neurological status at intensive care unit discharge, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, and reasons for discontinuation of treatment. The COACT trial is a multicenter, randomized, controlled clinical study that will evaluate the effect of an immediate invasive coronary strategy in post-cardiac arrest patients without STEMI on 90-day survival.

Observational cohort study focused on treatment continuity of patients administered XELOX plus bevacizumab for previously untreated metastatic colorectal cancer.

BackgroundThere has been remarkable progress in systemic chemotherapy for metastatic colorectal cancer due to the widespread use of irinotecan, oxaliplatin, anti-vascular endothelial growth factor antibody, and anti-epidermal growth factor receptor antibody. It is important to continue treatment with the optimal combination of these drugs and prolong progression-free survival (PFS) to improve overall survival (OS). We conducted a prospective observational cohort study of 40 patients treated with XELOX plus bevacizumab for previously untreated metastatic colorectal cancer to investigate treatment continuity.Patients and methodsEligibility criteria were as follows: 1) histologically confirmed metastatic colorectal cancer; 2) lesions evaluable by imaging; 3) previously untreated; 4) suitable condition to receive XELOX plus bevacizumab; and 5) written informed consent. Outcomes were treatment continuity, overall response rate, resection rate, liver resection rate, time to treatment failure, PFS, and OS. Forty patients were enrolled and followed up for 2 years.ResultsBetween July 2010 and June 2012, 40 patients were enrolled. The median number of treatment cycles was 7.5, and the reasons for discontinuation of treatment were as follows: complete response (five patients), resection (ten patients), progression (15 patients), adverse events (seven patients), and patient refusal (three patients). The overall response rate was 57.5%, resection rate was 25%, and liver resection rate was 15%. After a median follow-up of 31.4 months, the median time to treatment failure, PFS, and OS were 5.3, 13.3, and 38.9 months, respectively.ConclusionAlthough the median time to treatment failure was 5.3 months, the median PFS and OS were prolonged to 13.3 and 38.9 months, respectively. This may have resulted from the chemotherapy-free interval due to complete response in five patients and resection in ten patients.

Discontinuation of Dapoxetine Treatment in Patients with Premature Ejaculation: A 2-Year Prospective Observational Study

Objective: Although dapoxetine is the only oral agent approved for premature ejaculation (PE) and is very effective, its discontinuation rate is high compared to PDE5 inhibitors for ED treatment. We assessed discontinuation rate of dapoxetine in PE and the reasons for discontinuation. Design and Method: The study enrolled 182 patients (mean age 38.2). The PE type (life-long or acquired), self-estimated intravaginal ejaculation latency time (IELT), IIEF-EF questionnaire, and medical history were checked in all patients. The patients were evaluated 1, 3, 6, 12, and 24 months after initiating therapy regarding the treatment status and the reasons for treatment discontinuation. Results: Of the patients, 9.9% were still in treatment after 2 years. The discontinuation rates at 1, 3, 6, 12, and 24 months were 26.4, 35.2, 17.6, 8.2, and 2.7%, respectively. Cumulatively, 79.1% of the patients discontinued the treatment within 6 months. After 12 months, however, the discontinuation rate dropped sharply. The reasons for discontinuation were cost (29.9%), disappointment that PE is not a curable disease and dapoxetine was needed whenever he had sex (25%), side effects (11.6%), low efficacy (9.8%), to seek other treatment options (5.5%), and unknown (18.3%). Patients with acquired PE (vs. life-long), IELT &gt;2 min before treatment, older than 50 years, taking PDE-5 inhibitors, and IIEF-EF &lt;26 tended to discontinue early and had high drop-out rates. Conclusions: Only 9.9% patients continued treatment after 24 months, while 79.1% discontinued within 6 months. The main reasons for discontinuation were not related to its side effects or low efficacy.

EPS06.9 Real world introduction of Colobreathe™ in children and adults with cystic fibrosis

Objectives: To evaluate the introduction of ColobreatheTM (Colo) from June to November 2015 in French patients attending 2 paediatric and 2 adult CF centres. Methods: All patients were similarly educated on how to inhale Colo (explanations, video) and received a test dose at the CF centre. Telephone follow-up with a CF caregiver was set up at days 1, 3 and 14 in order to assess tolerance and advise patients. Reasons for treatment interruption during the first month were collected. Results: 123 patients (adults 71%, median age 24 years, mean FEV1 % pred. 64±25) received a test dose of Colo. 67% were previously treated by inhaled colistine and 20% had no inhaled antibiotics. Out of the 112 patients who completed the trial, 27.7% interrupted treatment within one month. The reasons were cough (n =22, 71%), bad taste (n = 3), technical problems (n =4), treatment burden (n =2), urticaria (n = 1), medical decision (n =1) or hemoptysis (n = 1). No difference could be seen between those who had and had not interrupted treatment at one month as to age or FEV1, but patients already treated by inhaled colistine were less likely to stop treatment. In the 81 patients who completed one month treatment, cough was also frequently reported but its incidence progressively decreased (50% at D1, 36% at D3, and 14% at D30). 13 out of 112 patients (12%) had technical problems, mainly blocking of the device or broken capsule. At one month, treatment burden was scored at 2 (on a 1–10 scale). Conclusion: Education at introduction of Colo resulted in continuation of treatment in 72% of the patients at one month, cough being the major reason for discontinuation of treatment. Long term assessment is needed. ePS06.10 Antibiotic desensitisation: a single centre review of 2015 M.K. Dooney, K.J. Cox, P.J. Barry, A.K. Webb, A.M. Jones, R.J. Bright-Thomas. Manchester Adult Cystic Fibrosis Centre, Manchester, United Kingdom

Reporting of Lost to Follow-Up and Treatment Discontinuation in Pharmacotherapy and Device Trials in Chronic Heart Failure

Background— Premature treatment discontinuation and loss to follow-up (LTFU) with unknown outcomes leave uncertainty about the true efficacy and safety of a treatment and a lack of confidence in the results of any trial. We reviewed the extent of (and trends over time in) reporting LTFU and treatment discontinuation in large studies in chronic heart failure published since 1990. Methods and Results— Online databases were systematically reviewed to identify randomized controlled clinical trials (RCTs) in chronic heart failure with &gt;400 participants and utilizing all-cause mortality as a component of the primary or secondary end point. Assessments were made of documentation of treatment discontinuation, LTFU, inclusion of and completeness of a Consolidated Standards Of Reporting Trials (CONSORT) diagram, and whether LTFU was differentiated from withdrawal of consent. Sixty-eight trials were identified, with &gt;154 000 participants. Reasons for treatment discontinuation in pharmacotherapy trials were infrequently reported (35%), particularly in a CONSORT diagram (20%). Eighty-three percent of trials reported LTFU, although only 34% of these differentiated LTFU for vital status from withdrawal of consent. Use of a CONSORT diagram increased over time, although reporting of LTFU in the CONSORT diagram remained low overall at 35%. Conclusions— Participant flow through RCTs in chronic heart failure has not been uniformly reported, and the use of a complete CONSORT diagram has been low, although it seems to be improving. All study participants should be accounted for within a CONSORT diagram in any RCT to enable the practicing cardiologist to interpret how the results should influence his/her clinical practice.

Anticholinergic use in children: Persistence and patterns of therapy.

Overactive bladder (OAB) symptoms are complex and generally require long-term therapy. Nevertheless, it has been demonstrated that persistence rates of antimuscarinic drug use are low in adults. Better understanding of the treatment patterns of children treated with antimuscarinics could help to improve drug management. Our objective was to evaluate persistence rates of patients under 20 years of age on antimuscarinic therapy over a four-year period. Patients having received a first-ever antimuscarinic drug prescription between April 2007 and March 2008 were identified using IMS Brogan's Public and Private Drug Plans database. Canadian drug claims data from Private Drug Plans, Régie de l'Assurance Maladie du Québec, and Ontario Public Drug Plans were analyzed retrospectively. Patients were followed for four years to assess the prescribed drugs, the lines of treatment, and the duration of each treatment. Data were available for 374 patients. The most prescribed drug as a first-line therapy was oxybutynin (87.2%), followed by tolterodine LA (5.9%). Patients refilled their index prescriptions for an average of 429 days. Solifenacin had the highest mean duration of index therapy (765 days). The median number of antimuscarinics prescribed was one. At the end of the followup, 44 patients were still on therapy. Reasons for discontinuation of treatment were not available. Overall discontinuation rate of antimuscarinic therapy in children is comparable to what has been reported in adult patients with OAB. However, children seem to persist on the medication for a longer duration before adherence rates start declining. The low rate of persistence highlights the need to identify the reasons for discontinuation of therapy in children in order to obtain better persistence rates.

Rehospitalization rate of first episode and chronic schizophrenia patients one year after discharge

IntroductionRelapse rate among patients with schizophrenia can determinate outcome of illness. Up to 40% of patients with first psychosis responds well to treatment. Despite this fact relapse rate is still high, in particular if treatment is discontinuated. Frequent use of first generation antipsychotics (FGA) in underdeveloped countries can be one of possible reasons for treatment discontinuation and consequent relapse.AimsTo analyse rehospitalisation rate in patients with first and multiple episodes of schizophrenia, and compare it with medication choice.MethodsRetrospective analysis of medical records of patients with schizophrenia hospitalised in Psychiatry Clinic of University Clinical Center Tuzla in period from year 2011 to 2013.ResultsDuring the two-year period, 37 patients with first episode of schizophrenia were hospitalised. Second generation antipsychotics (SGA) were used in 40.5%, and first generation in 13.5%, long acting injectibles - first generation (LAI) were used in 8.1%, and combination of FGA's and SGA's in 5.4% of cases. In the same period, 121 patients with multiple episodes of schizophrenia were hospitalised. SGA were used in 21.4%, FGA in 33%, LAI's in 47.1%, and combination FGA's and SGA's in 35.5% of cases. Relapse rate in the first year after discharge was 16.2% in group with first psychotic episode, and 33% in the group with multiple episodes of schizophrenia.ConclusionHigh relapse rate in group with multiple episodes can be explained with nonadherence regarding the side effects of too frequent use of FGA's.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Abstract P4-14-20: A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC)

Abstract Background: ONT 380 is a potent HER2 selective tyrosine kinase inhibitor with minimal EGFR-like side effects. Preclinical studies demonstrate synergism with trastuzumab (T) and chemotherapy, as well as activity in models of HER2+ CNS disease. Based on the potential for increased clinical activity of dual HER2 blockade in the context of a targeted cytotoxic agent, we evaluated the safety, tolerability, and anti-tumor activity of ONT-380 in combination with T-DM1 in patients (pts) with MBC with and without CNS metastases (mets). Methods: 3+3 dose escalation with MTD expansion cohorts in pts with/without CNS mets evaluating ONT-380 (300 or 350 mg PO BID) combined with T-DM1 3.6 mg/kg IV q 21 days. Prior treatment with T and taxane was required; prior lapatinib and asymptomatic brain mets (treated or untreated) were allowed. Assessments included safety, PK, and systemic (RECIST 1.1) and CNS (modified RECIST) tumor response, with brain MRI at baseline and q 6 wks in pts with CNS mets at baseline. DLT was defined as the occurrence of protocol-specified events during the 1st treatment cycle. Results: As of 01 June 2015, 51 pts have been enrolled and have received between 1 and 22 cycles, with safety data available for 43 pts (n=36 at 300 mg BID; n=7 at 350 mg BID). Pts had a median of 2 prior treatments for MBC, including T (n=43); pertuzumab (n=15) and lapatinib (n=7). The MTD for ONT-380 was 300 mg BID with 5/36 pts (14%) with DLT (Gr 3 AST/ALT [n=4]; Gr 2 vomiting/Gr1 diarrhea [n=1]) vs. 3/7 pts (43%) with DLT at 350 mg BID (Gr 3 vomiting [n=1]; Gr 3 hypersensitivity [n=1]; Gr 3 fatigue [n=1]). Overall, the majority of AEs have been Gr 1 or 2. The most common AEs, regardless of relationship, were nausea, fatigue, diarrhea, vomiting, thrombocytopenia, AST/ALT elevation, headache, decreased appetite, epistaxis, constipation, and hypokalemia. Gr 3 AST/ALT elevation has occurred in 7/43 pts (16%), with no events meeting Hy's law, and has been reversible with dose interruption and reduction except in 2 pts found to have progressive liver mets. No Gr 3 diarrhea has occurred at any dose. ONT-380 PK was dose proportional, and no drug-drug interaction was observed with T-DM1. In 33 of 43 pts with data available from at least one follow-up scan to evaluate response, best systemic response regardless of dose was 11 PR, 16 SD, and 6 PD, with clinical benefit rate (CBR= CR, PR, or SD &amp;gt;6 mos) of 19/33 (58%). The most common reason for treatment discontinuation was PD, with 3 pts coming off study for AEs (n=1 each of Gr 3 hypersensitivity, Gr 2 vomiting, Gr 3 AST/ALT). Eight pts to date have been evaluable for CNS response (untreated or progressive CNS mets with ≥1 follow-up MRI), with best CNS response of 1 CNS CR, 2 CNS PR, and 5 CNS SD, with a CNS CBR of 5/8 (63%). All pts with CNS response are still active. Conclusion: Treatment with ONT-380 300 mg BID and T-DM1 3.6 mg/kg has been tolerable. Early evidence of anti-tumor activity has been seen, including clinical benefit in patients with CNS mets. Updated results will be presented. Citation Format: Ferrario C, Hamilton E, Aucoin N, Falkson CI, Khan Q, Krop IE, Welch S, Bedard PL, Conlin A, Chaves J, Vo A, Walker L, Borges V. A phase 1b study of ONT 380, an oral HER2-specific inhibitor, combined with ado trastuzumab emtansine (T DM1), in HER2+ metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-20.